| LEPR |
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Entrez Gene: 3953
HUGO Accession: HGNC:6554
OMIM (Online Mendellian Inheritance in Man)
Leptin is a 16-kD protein that plays a critical role in the regulation of body weight by inhibiting food intake and stimulating energy expenditure. Defects in leptin production cause severe hereditary obesity in rodents and humans. In addition to its effects on body weight, leptin has a variety of other functions, including the regulation of hematopoiesis, angiogenesis, wound healing, and the immune and inflammatory response. Leptin acts through the leptin receptor (LEPR; 601007), a single-transmembrane-domain receptor of the cytokine receptor family, which is found in many tissues in several alternatively spliced forms. The LEP gene is the human homolog of the gene (ob) mutant in the mouse 'obese' phenotype.
Zhang et al. (1994) isolated the ob gene of the mouse by positional cloning. They likewise cloned and sequenced its human homolog. The gene encodes a 4.5-kb adipose tissue mRNA with a highly conserved 167-amino acid open reading frame. The predicted amino acid sequence is 84% identical between human and mouse and has features of a secreted protein.
Masuzaki et al. (1995) found that the nucleotide sequence of the human OB cDNA coding region is 83% identical to those of the mouse and rat ob cDNA coding regions. Analysis of the deduced amino acid sequences revealed that the human OB protein is a 166-amino acid polypeptide with a putative signal sequence and is 84% and 83% homologous to the mouse and rat ob proteins, respectively. Northern blot analysis using the cloned human OB cDNA fragment as a probe identified a single 4.5-kb mRNA species found in abundance in adipose tissues obtained from multiple sites.
Gong et al. (1996) cloned a 3-kb 5-prime flanking region of the OB gene; transient transfection assays with a luciferase reporter gene confirmed its promoter activity in differentiated adipocytes. They determined that the human OB gene encodes a 3.5-kb cDNA.
In the mouse, the Met oncogene (164860) is closely linked to the ob gene. The human MET gene is on chromosome 7. Friedman et al. (1991) found that the ob locus maps to chromosome 6 of the mouse in the following order: cen--Cola2--Met--ob--Cpa--Tcrb. Since the homologs of the markers that flank ob in the mouse map to human chromosome 7q, Friedman et al. (1991) suggested that the human ob homolog maps to 7q31. Their data suggested, furthermore, that the development of diabetes in the ob animal is a consequence of unlinked polygenes. They also had evidence that unlinked Mus spretus alleles can diminish the obesity of ob/ob mice.
Green et al. (1995) mapped the human OB gene on a YAC contig from 7q31.3 that contained sequence tagged sites corresponding to microsatellite-type genetic markers. Because of their close physical proximity to the human OB gene, these genetic markers represented valuable tools for analyzing families with evidence of hereditary obesity and for investigating the possible association between OB mutations and human obesity. Geffroy et al. (1995) mapped the human OB gene to 7q32 by fluorescence in situ hybridization. By fluorescence in situ hybridization, Isse et al. (1995) mapped the OB gene to 7q31.3.
Isse et al. (1995) found by Southern blot analysis a single copy of the OB gene in the human genome. The gene spans approximately 20 kb and contains 3 exons separated by 2 introns. The first intron, approximately 10.6 kb, is in the 5-prime untranslated region, 29 bp upstream of the ATG start codon. The second intron of 2.3 kb is located at glutamine +49. By rapid amplification of 5-prime cDNA ends (RACE), the transcription initiation sites were mapped 54 to 57 bp upstream of the ATG start codon.
He et al. (1995) determined the genomic organization of the 5-prime end of the mouse ob gene. The coding sequences are in exons 2 and 3. A single TATA-containing promoter was found upstream of exon 1. Transcription of the ob gene was detected only in adipose cells. The promoter contained consensus Sp1 (189906) and CCAAT/enhancer-binding protein (C/EBP; 116897) motifs.
Miller et al. (1996) described the structure of the human OB gene and an initial analysis of its promoter. The gene's 3 exons cover approximately 15 kb of genomic DNA. The entire coding region is contained in exons 2 and 3, which are separated by a 2-kb intron. The first small 30-bp untranslated exon is located more than 10.5 kb upstream of the initiator ATG codon.
Gong et al. (1996) demonstrated that the human OB gene consists of 3 exons and 2 introns and spans about 18 kb.
He et al. (1995) found that cotransfection of the mouse 'obese' gene promoter with C/EBP-alpha, a transcription factor important in adipose cell differentiation, caused 23-fold activation. He et al. (1995) suggested that the 'obese' promoter is a natural target of C/EBP-alpha.
Miller et al. (1996) determined that only 217 bp of 5-prime sequence are required for basal adipose tissue-specific expression of the human OB gene, as well as enhanced expression by C/EBP-alpha. Mutation of the single C/EBP-alpha site in this region abolished inducibility of the promoter by C/EBP-alpha in cotransfection assays. Miller et al. (1996) noted that knowledge of sequence elements and factors regulating OB gene expression should be of major importance in the prevention and treatment of obesity.
To investigate the effect of leptin on fetal growth, Matsuda et al. (1997) measured serum leptin concentrations in venous cord bloods of 82 newborns. Serum leptin concentrations in males were significantly lower than those in females and those in cord blood correlated positively with birth weight and body weight/body height. The serum concentrations of estradiol and testosterone did not differ between males and females and did not correlate with the leptin concentration. They concluded that gender differences in fetal leptin levels are not due either to body fat content or distribution or to reproductive hormone status, but rather to genetic differences between males and females. Harigaya et al. (1997) found that leptin levels in serum drawn from infants within 6 hours of birth correlated with birth weight (r = 0.59, P less than 0.01). After birth, the leptin levels of infants large for gestational age and for those of appropriate size for gestational age significantly decreased to levels found in infants small for gestational age within 48 hours of delivery (P less than 0.05). Beyond 48 hours after birth, no significant differences in leptin levels were observed among the 3 groups, and low levels continued to 7 days of age. Harigaya et al. (1997) concluded that leptin levels correlated with fetal weight gain. Koistinen et al. (1997) found that leptin levels correlated closely with both absolute and relative birth weights (r = 0.71; P less than 0.001 in both), cord blood insulin (176730) levels (r = 0.67; P less than 0.001), and with placental weight (r = 0.60; P less than 0.001). They concluded that leptin is synthesized in utero, and that the circulating leptin level relates to the intrauterine growth pattern.
Jaquet et al. (1998) investigated the ontogeny of serum leptin concentrations during the second half of gestation and at birth in small for gestational age and normal fetuses and newborns. Serum leptin concentrations were measured in arterial cord blood of 79 fetuses and 132 newborns, with or without intrauterine growth retardation, at 18 to 42 weeks' gestation. Serum leptin was detectable in fetal cord blood in all subjects as early as 18 weeks' gestation and increased dramatically after 34 weeks' gestation. In newborns, serum leptin concentrations were positively correlated with body weight (P less than 0.001) and body mass index (P less than 0.001). Newborns with intrauterine growth retardation had significantly lower serum leptin values (P less than 0.001) than those with normal growth, and leptin levels were only positively correlated with body mass index (P less than 0.001). The authors concluded that the development of adipose tissue and the accumulation of fat mass are the major determinants of fetal and neonatal serum leptin levels. A gender difference, with higher leptin concentrations in female fetuses, seen in the last weeks of gestation and confirmed at birth regardless of growth status, suggested that a sexual dimorphism exists in utero.
Chehab et al. (1996) demonstrated that administration of recombinant leptin to female ob/ob mice can correct their sterility, resulting in ovulation, pregnancy, and parturition. To investigate theories that the onset of puberty is triggered by the attainment of a critical amount and/or distribution of fat, Mantzoros et al. (1997) examined whether changes in circulating leptin levels could represent the hormonal signal responsible for triggering the onset of puberty in humans. Compared to baseline prepubertal levels (8 months before the onset of puberty, as defined by the initial rise in testosterone above the detection limit of the assay), leptin levels rose by approximately 50% just before the onset of puberty and decreased to approximately baseline values after the initiation of puberty (P less than 0.01), remaining stable for over 2 years. While these changes are consistent with the hypothesis that leptin is an important signal responsible for triggering the onset of puberty, the stimulus for a surge in leptin levels just before the onset of puberty is currently unknown.
Saad et al. (1997) studied plasma leptin levels in 267 subjects (106 with normal glucose tolerance, 102 with impaired glucose tolerance, and 59 with noninsulin-dependent diabetes). Fasting plasma leptin levels ranged from 1.8 to 79.6 ng/mL, were higher in the obese subjects, and were not related to glucose tolerance. Women had approximately 40% higher leptin levels than men at any level of adiposity. After controlling for body fat, postmenopausal women still had higher leptin levels than men of similar age; their levels were not different from those of younger women. Multiple regression analysis showed that adiposity, gender, and insulinemia were significant determinants of leptin concentration, explaining 42%, 28%, and 2% of its variance, respectively. Neither age nor the waist/hip ratio was significantly related to leptin concentration. Their data indicated that gender is a major determinant of the plasma leptin concentration. This sex difference is not apparently explained by sex hormones or body fat distribution. The sexual dimorphism of leptin suggests that women may be resistant to its putative lipostatic actions and that it may have a reproductive function. Matkovic et al. (1997) studied body composition, serum leptin levels, and the timing of menarche in 343 pubertal females over 4 years. Leptin was strongly associated with body fat (r = 0.81; P less than 0.0001) and change in body fat (r = 0.58; P less than 0.0001). The rise in serum leptin to the level of 12.2 ng/mL (95% CI, 7.2-16.7) was associated with the decline in age at menarche. An increase of 1 ng/mL in serum leptin lowered the age at menarche by 1 month. Matkovic et al. (1997) concluded that a critical blood leptin level is necessary to trigger reproductive ability in women, suggesting a threshold effect.
Welt et al. (2004) administered recombinant leptin to 8 women with hypothalamic amenorrhea due to strenuous exercise or low weight. The treatment increased mean luteinizing hormone levels and luteinizing hormone pulse frequency after 2 weeks and increased maximal follicular diameter, the number of dominant follicles, ovarian volume, and estradiol levels over a period of 3 months. Three patients had an ovulatory menstrual cycle (p less than 0.05 compared to the expected rate of spontaneous ovulation of 10%); 2 others had preovulatory follicular development and withdrawal bleeding during treatment (p less than 0.05). Recombinant leptin significantly increased levels of free triiodothyronine, free thyroxine, insulin-like growth factor I (IGF1; 147440), insulin-like growth factor-binding protein-3 (IGFBP3; 146732), bone alkaline phosphatase, and osteocalcin (112260), but not cortisol, corticotropin, or urinary N-telopeptide. Welt et al. (2004) suggested that leptin is required for normal reproductive and neuroendocrine function.
Leptin may stimulate prostate growth and angiogenesis, and receptors for leptin are present in the prostate. To determine if leptin is associated with increased risk of prostate cancer, Stattin et al. (2001) identified 149 men with prostate cancer (together with 298 matched referents) who had participated in population-based health surveys in Northern Sweden before diagnosis. Leptin, insulin (176730), IGF1, IGFBP1 (146730), IGFBP2 (146731), IGFBP3, testosterone, and sex hormone-binding globulin (182205) were analyzed in stored samples. Relative risk estimates (95% confidence intervals) of prostate cancer over the quintiles of leptin were 1.0, 2.1 (1.1-4.1), 2.6 (1.4-4.8), 1.4 (0.7-2.7), and 1.6 (0.8-3.2). Adjustments for metabolic variables, testosterone, and IGF and its binding proteins did not attenuate this increased risk. The authors concluded that moderately elevated plasma leptin concentrations are associated with later development of prostate cancer. This may be due to direct effects of leptin on prostatic intraepithelial neoplasia lesions, or to indirect actions through other mechanisms.
Haffner et al. (1997) examined the relation of leptin levels to sex hormone-binding globulin, total and free testosterone, dehydroepiandrosterone sulfate, estradiol, and cortisol in 87 normoglycemic men. Leptin levels were significantly correlated with free testosterone, sex hormone-binding globulin, total testosterone and cortisol. However, after adjustment for body mass index (or, alternatively, waist or hip circumference), leptin concentrations were not found to be significantly related to sex hormones or cortisol. The authors concluded that sex hormones are not important independent modifiers of leptin concentrations in men.
Schubring et al. (1997) correlated the leptin concentrations in the mother and the newborn with birth weight, placental weight, and maternal weight at term. Placental weight correlated inversely with leptin levels in maternal serum at birth, and leptin levels in cord blood correlated positively with birth weight and placental weight. In contrast, there was no correlation between maternal serum leptin levels and birth weight. Thus, leptin levels are high in the fetus and in the mother at term. The authors hypothesized that high leptin levels represent an important feedback modulator of substrate supply and subsequently for adipose tissue status during late gestation.
Matkovic et al. (1997) studied the circadian rhythmicity of the serum leptin level in young females to determine if changes in body fat stores during growth affect nocturnal increases in serum leptin levels. Significant rises at midnight and 0400 hr suggested a diurnal variation in serum leptin concentrations. They also found an inverse correlation between relative total body fat and the average daytime serum leptin level. The authors concluded that if a nocturnal rise in serum leptin is absent over time, it may have implications for the development of obesity, presumably by inadequate suppression of nighttime appetite.
Lonnqvist et al. (1995) found overexpression of the human OB gene in subcutaneous and omental adipose tissue in massively obese persons. Hamilton et al. (1995) likewise reported that OB mRNA expression is elevated in ex vivo omental adipocytes isolated from massively obese humans despite the absence of an identifiable mutation in the OB gene. This led them to speculate that this increased expression results from an insensitivity to the putative regulatory function(s) of the OB gene product. Maffei et al. (1995) found that mice with lesions of the hypothalamus, as well as mice mutant at the db locus, expressed a 20-fold higher level of ob RNA in adipose tissue. These data suggested that both the db gene and the hypothalamus are downstream of the ob gene in the pathway that regulates adipose tissue mass and are consistent with previous experiments, suggesting that the db locus encodes the ob receptor.
Weigle et al. (1997) examined the correlation of plasma leptin and body mass index (BMI) in an ethnically mixed population, a group of subjects with the Prader-Willi syndrome (176270), and a group of Japanese-American subjects who underwent computerized tomographic measurement of adipose tissue cross-sectional areas. Highly significant and indistinguishable linear relationships between plasma leptin levels and BMI were found in all 3 study groups. The circulating leptin level reflects total adipose tissue mass rather than a combination of adipose tissue mass and distribution, and Prader-Willi syndrome does not alter the relationship between these 2 variables.
Chen et al. (1996) induced sustained hyperleptinemia for 28 days in normal Wistar rats by infusing a recombinant adenovirus containing the rat leptin cDNA. Hyperleptinemic rats exhibited a 30 to 50% reduction in food intake and gained only 22 g over the experimental period versus 115 to 132 g in control animals that received saline infusions or a recombinant virus containing the beta-galactosidase gene. Body fat was absent in hyperleptinemic rats, whereas control rats pair-fed to the hyperleptinemic rats retained approximately 50% body fat. Further, plasma triglycerides and insulin levels were significantly lower in hyperleptinemic versus pair-fed controls, while fatty acid and glucose levels were similar in the 2 groups, suggestive of enhanced insulin sensitivity in the hyperleptinemic animals. Thus, despite equivalent reduction in food intake and weight gain in hyperleptinemic and pair-fed animals, identifiable fat tissue was completely ablated only in the former group, raising a possibility of a specific lipoatrophic activity for leptin.
Kennedy et al. (1997) studied the relationship of leptin to metabolic abnormalities associated with obesity. To do this, 116 subjects (62 men and 54 women) with a wide range of body weight (BMI, 17 to 54 kg/m2), were characterized with regard to body composition, glucose intolerance, insulin sensitivity, energy expenditure, substrate utilization, and blood pressure. Their data indicated that there are important gender-based differences in the regulation and action of leptin in humans. Serum leptin levels increase with progressive obesity in both men and women. However, for any given measure of obesity, leptin levels are higher in women than in men, consistent with a state of relative leptin resistance. The authors concluded that these findings have implications regarding differences in body composition between men and women. Furthermore, their observation that serum leptin levels are not related to energy expenditure rates suggests that leptin regulates body fat predominantly by altering eating behavior rather than calorigenesis.
The circulating peptide leptin had been reported to be secreted by adipocytes and by placenta (Masuzaki et al., 1997). Bado et al. (1998) showed that leptin mRNA and leptin protein are present in rat gastric epithelium, and that cells in glands of the gastric fundic mucosa are immunoreactive for leptin. Both feeding and administration of CCK-8, the biologically active C-terminal end of cholecystokinin (CCK; 118440), resulted in a rapid and large decrease in both leptin cell immunoreactivity and the leptin content of the fundic epithelium, with a concomitant increase in the concentration of leptin in the plasma. These results indicated that gastric leptin may be involved in the early CCK-mediated effects activated by food intake, possibly including satiety.
Niswender et al. (2001) demonstrated that systemic administration of leptin in rat activates the enzyme phosphatidylinositol-3-hydroxykinase (see 171834) in the hypothalamus and that intracerebroventricular infusion of inhibitors of this enzyme prevents leptin-induced anorexia. They concluded that phosphatidylinositol-3-hydroxykinase is a crucial enzyme in the signal transduction pathway that links hypothalamic leptin to reduced food intake.
Nutritional deprivation suppresses immune function. Mice defective in leptin (ob/ob) or its receptor (db/db) have impaired T-cell immunity. Impaired cell-mediated immunity and reduced levels of leptin are both features of low body weight in humans. Indeed, malnutrition predisposes to death from infectious diseases. Lord et al. (1998) reported that leptin has a specific effect on T-lymphocyte responses, differentially regulating the proliferation of naive and memory T cells. Administration of leptin to mice reversed the immunosuppressive effects of acute starvation. Thus leptin has a role in linking nutritional status to cognate cellular immune function, and provides a molecular mechanism to account for the immune dysfunction observed in starvation.
Leptin, initially discovered as a regulator of food intake and energy expenditure, emerged subsequently as a pleiotropic molecule with a variety of physiologic and pathologic roles. Alterations in leptin levels and/or in the responsiveness to leptin were reported not only during starvation and obesity, but also in patients affected by diabetes, renal failure, hypothyroidism, and AIDS. T lymphocytes and cytokines are critical mediators of hepatic inflammation in patients affected by viral, allergic, autoimmune, and possibly alcoholic liver disease. Faggioni et al. (2000) demonstrated that leptin plays an important role in T cell-mediated liver toxicity in association with a regulatory effect on thymus and peripheral blood cellularity as well as on the production of 2 proinflammatory cytokines, TNF-alpha (191160) and IL18 (600953).
Sierra-Honigmann et al. (1998) demonstrated that the leptin receptor (601007), although expressed primarily in the hypothalamus, is also expressed in human vasculature and in primary cultures of human endothelial cells. In vitro and in vivo assays revealed that leptin has angiogenic activity. In vivo, leptin induced neovascularization in corneas from normal rats but not in corneas from fa/fa Zucker rats, which lack functional leptin receptors. These observations indicated that the vascular endothelium is a target for leptin and suggested a physiologic mechanism whereby leptin-induced angiogenesis may facilitate increased energy expenditure.
Friedman and Halaas (1998) provided a comprehensive review of the role of leptin in the regulation of body weight in mammals. Auwerx and Staels (1998) also provided an extensive review. Rosenbaum and Leibel (1999) reviewed the role of leptin in human physiology.
Wellhoener et al. (2000) tested the hypothesis that in humans leptin secretion is primarily regulated by glucose uptake and only secondarily by plasma insulin (176730) and glucose. In 30 lean and healthy men they induced 4 experimental conditions by using the blood glucose clamp technique. Multiple regression analysis revealed a significant effect of circulating insulin (low vs high insulin; P = 0.001) and blood glucose (hypoglycemia vs euglycemia; P = 0.001) on the rise of serum leptin. However, when the total amount of dextrose infused during the clamp (grams of dextrose per kg BW) was included into the regression model, this variable was significantly related to the changes in serum leptin (P = 0.001), whereas circulating insulin and glucose had no additional effect. The authors concluded that their findings in humans support previous in vitro data that leptin secretion is mainly related to glucose metabolism.
Both serum leptin and bone mineral density (BMD) are positively correlated with body fat, generating the hypothesis that leptin may be a systemic and/or local regulator of bone mass. To evaluate the relationship between serum leptin concentrations and bone mass in women, Pasco et al. (2001) measured bone mineral content, projected bone area, body fat mass, and fasting serum leptin in 214 healthy, nonobese Australian women aged 20 to 91 years. The authors demonstrated an association between serum leptin levels and bone mass consistent with the hypothesis that circulating leptin may play a role in regulating bone mass.
To assess whether leptin is an independent predictor of BMD in postmenopausal women, Blain et al. (2002) studied the relationships of BMD to serum leptin, 25(OH)D, 1,25(OH)2D, parathyroid hormone (PTH; 168450), estrogen (E2), dehydroepiandrosterone sulfate, growth hormone (GH; 139250), IGF1, creatinine clearance, calcium intake, fat mass, and lean mass in 107 women aged 50 to 90 years. They also related serum leptin to markers of bone formation (serum bone alkaline phosphatase and osteocalcin (112260)) and resorption (urine C-telopeptide of type I collagen). In stepwise multiple linear regression, lean mass explained 28.5%, age 10.3%, and leptin 7.2% of the whole body BMD variance. The authors concluded that these data demonstrate that leptin is an independent predictor of whole body and femoral neck BMD in postmenopausal women. They suggested that although the relationships between leptin and markers of bone formation appear complex, leptin may exert a protective effect on bone by limiting the excessive bone resorption coupled to bone formation associated with bone loss after menopause.
Takeda et al. (2002) showed in mice that hypothalamic leptin-dependent antiosteogenic and anorexigenic networks differ, and that the peripheral mediators of leptin antiosteogenic function appear to be neuronal. Neuropeptides mediating leptin anorexigenic function did not affect bone formation. Leptin deficiency resulted in low sympathetic tone, and genetic or pharmacologic ablation of adrenergic signaling led to a leptin-resistant high bone mass. Beta-adrenergic receptors on osteoblasts regulate their proliferation, and a beta-adrenergic agonist decreased bone mass in leptin-deficient and wildtype mice, while a beta-adrenergic antagonist increased bone mass in wildtype and ovariectomized mice. None of these manipulations affected body weight. This study demonstrated a leptin-dependent neuronal regulation of bone formation with potential therapeutic implications for osteoporosis.
Minokoshi et al. (2002) demonstrated that leptin selectively stimulates phosphorylation and activation of the alpha-2 catalytic subunit of AMPK (AMPK-alpha-2; 600497) in skeletal muscle, thus establishing an additional signaling pathway for leptin. Early activation of AMPK occurs by leptin acting directly on muscle, whereas later activation depends on leptin functioning through the hypothalamic-sympathetic nervous system axis. In parallel with its activation of AMPK, leptin suppresses the activity of ACC (200350, 601557), thereby stimulating the oxidation of fatty acids in muscle. Blocking AMPK activation inhibits the phosphorylation of ACC stimulated by leptin. Minokoshi et al. (2002) concluded that their data identify AMPK as a principal mediator of the effects of leptin on fatty acid metabolism in muscle.
Sooranna et al. (2001) determined the plasma leptin concentrations in twin pregnancies in relation to chorionicity and discordant fetal growth by studying 53 twin pregnancies of which 26 had growth discordance of at least 20% and 27 were concordant for growth, defined as discordance of 10% or less. Regardless of chorionicity, plasma leptin concentrations in the intrauterine growth-restricted twins were 2-fold lower than their cotwins with normal growth.
Shanley et al. (2002) demonstrated that leptin inhibits hippocampal neurons via phosphoinositide 3-kinase-driven activation of large-conductance, calcium-activated potassium channels (PK channels), but not KATP channels.
To examine the mechanism underlying leptin's metabolic actions, Cohen et al. (2002) used transcription profiling to identify leptin-regulated genes in ob/ob liver. Leptin was found to specifically repress RNA levels and enzymatic activity of hepatic stearoyl-CoA desaturase-1 (SCD; 604031), which catalyzes the biosynthesis of monounsaturated fatty acids. Mice lacking Scd1 were lean and hypermetabolic; ob/ob mice with mutations in Scd1 were significantly less obese than ob/ob controls and had markedly increased energy expenditure. Ob/ob mice with mutations in Scd1 had histologically normal livers with significantly reduced triglyceride storage and VLDL production. Cohen et al. (2002) concluded that downregulation of SCD1 is an important component of leptin's metabolic actions.
Using male Sprague-Dawley rats implanted with third intracerebroventricular cannulae, Zhao et al. (2002) found that cilostamide, a phosphodiesterase-3 (PDE3B; 602047) inhibitor, reversed the established effects of leptin on food intake and body weight; blocked, at the hypothalamic level, the leptin-induced tyrosine phosphorylation of signal transducer and activator of transcription-3 (STAT3; 102582); and blocked the DNA binding of STAT3 protein. In addition, Zhao et al. (2002) showed that intracerebroventricular administration of leptin increased hypothalamic phosphatidylinositol 3-kinase (PI3K; see 601232) and PDE3B activities and decreased cAMP concentration. Zhao et al. (2002) concluded that a PI3K-PDE3B-cAMP pathway interacting with the JAK2 (147796)-STAT3 pathway constitutes a critical component of leptin signaling in the hypothalamus.
Dumond et al. (2003) demonstrated leptin in synovial fluid obtained from osteoarthritis (165720)-affected joints, and showed that leptin concentrations correlated with a body mass index. Marked expression of the protein was observed in osteoarthritic cartilage and in osteophytes, while in normal cartilage few chondrocytes produced leptin. The pattern and level of leptin expression were related to the grade of cartilage destruction and paralleled those of growth factors IGF1 and TGFB1 (190180). Animal studies showed that leptin strongly stimulated anabolic functions of chondrocytes and induced the synthesis of IGF1 and TGFB1 in cartilage at both the mRNA and the protein levels. The findings were interpreted as suggesting a new peripheral function of leptin as a key regulator of chondrocyte metabolism, and indicated that leptin may play an important role in the pathophysiology of osteoarthritis.
Minokoshi et al. (2004) investigated the potential role of AMP-activated protein kinase (AMPK; see 602739) in the hypothalamus in the regulation of food intake. Minokoshi et al. (2004) reported that AMPK activity is inhibited in arcuate and paraventricular hypothalamus by the anorexigenic hormone leptin, and in multiple hypothalamic regions by insulin (176730), high glucose, and refeeding. A melanocortin receptor (see 155555) agonist, a potent anorexigen, decreased AMPK activity in paraventricular hypothalamus, whereas agouti-related protein (602311), an orexigen, increased AMPK activity. Melanocortin receptor signaling is required for leptin and refeeding effects of AMPK in the paraventricular hypothalamus. Dominant-negative AMPK expression in the hypothalamus was sufficient to reduce food intake and body weight, whereas constitutively active AMPK increased both. Alterations of hypothalamic AMPK activity augmented changes in arcuate neuropeptide expression induced by fasting and feeding. Furthermore, inhibition of hypothalamic AMPK is necessary for leptin's effects on food intake and body weight, as constitutively active AMPK blocks these effects. Thus, Minokoshi et al. (2004) concluded that hypothalamic AMPK plays a critical role in hormonal and nutrient-derived anorexigenic and orexigenic signals and in energy balance.
Leptin is a powerful inhibitor of bone formation in vivo. This antiosteogenic function involves leptin binding to its receptors on ventromedial hypothalamic neurons, the autonomous nervous system, and beta-adrenergic receptors on osteoblasts. To clarify the mechanism whereby leptin controls the function of ventromedial hypothalamic antiosteogenic neurons, Elefteriou et al. (2004) compared the ability of leptin to regulate body weight and bone mass and showed that leptin antiosteogenic and anorexigenic functions are affected by similar amounts of leptin. Elefteriou et al. (2004) generated mice with knockin of the LacZ gene in the leptin locus. They failed to detect any leptin synthesis in the central nervous system of the knockin mice. However, increasing serum leptin level, even dramatically, reduced bone mass. Conversely, reducing serum-free leptin level by overexpressing a soluble receptor for leptin increased bone mass. Congruent with these results, the high bone mass of lipodystrophic mice could be corrected by restoring serum leptin level, suggesting that leptin is an adipocyte product both necessary and sufficient to control bone mass. Consistent with the high bone mass phenotype of lipodystrophic mice, Elefteriou et al. (2004) observed an advanced bone age, an indirect reflection of premature bone formation, in lipodystrophic patients. Taken together, these results indicated that adipocyte-derived circulating leptin is a determinant of bone formation and suggested that leptin antiosteogenic function is conserved in vertebrates. Ethical considerations prevented the collection of bone biopsies from the prepubertal patients affected by congenital generalized lipodystrophy. Because of these limitations, Elefteriou et al. (2004) used the osseous age of the patients as an indirect but suggestive indicator of bone formation. All patients showed low to undetectable circulating levels of leptin and had, regardless of their sex, a marked advance in bone age. The same advance in bone age was also observed in a single leptin-deficient child.
By analyzing Adrb2 (109690)-deficient mice, Elefteriou et al. (2005) demonstrated that the sympathetic nervous system favors bone resorption by increasing expression in osteoblast progenitor cells of the osteoclast differentiation factor Rankl (602642). This sympathetic function requires phosphorylation by protein kinase A (PKA; see 176911) of ATF4 (604064), a cell-specific CREB (123810)-related transcription factor essential for osteoblast differentiation and function. That bone resorption cannot increase in gonadectomized Adrb2-deficient mice highlights the biologic importance of this regulation, but also contrasts sharply with the increase in bone resorption characterizing another hypogonadic mouse with low sympathetic tone, the ob/ob mouse. This discrepancy is explained, in part, by the fact that CART (602606), a neuropeptide whose expression is controlled by leptin and nearly abolished in ob/ob mice, inhibits bone resorption by modulating Rankl expression. Elefteriou et al. (2005) concluded that their study established that leptin-regulated neural pathways control both aspects of bone remodeling, and demonstrated that integrity of sympathetic signaling is necessary for the increase in bone resorption caused by gonadal failure.
Cohen (2006) reviewed the role of leptin in regulating appetite, neuroendocrine function, and bone remodeling, and discussed the downstream pathways, e.g., the melanocortin system and the sympathetic nervous system, that are involved in those effects.
Using leptin-affinity chromatography, mass spectrometry, and immunochemical analysis, Chen et al. (2006) found that C-reactive protein (CRP; 123260) is a major leptin-interacting protein. In vitro studies showed that human CRP directly inhibited the binding of leptin to its receptor and blocked cellular signaling. Infusion of human CRP into ob/ob mice blocked the effects of leptin on satiety and weight reduction, and the actions of human leptin were blunted in mice expressing human CRP. Further in vitro studies in human primary hepatocytes showed that physiologic levels of leptin stimulated expression of CRP. Chen et al. (2006) suggested that so-called 'leptin resistance,' which may play a role in obesity, may be mediated by circulating CRP that binds leptin and attenuates its physiologic functions. Farooqi and O'Rahilly (2007) found no significant differences in CRP levels between 4 congenitally leptin-deficient children and 20 age- and adiposity-matched obese children without leptin deficiency. Mean concentrations of CRP remained unchanged after 2 months and 6 months of daily subcutaneous injections of recombinant human leptin in the children with congenital leptin deficiency. Because leptin repletion in humans congenitally lacking leptin does not increase circulating CRP, Farooqi and O'Rahilly (2007) suggested that the leptin-stimulated increase in CRP mRNA and protein levels in primary human hepatocytes reported by Chen et al. (2006) is unlikely to be physiologically relevant.
Chan et al. (2006) assessed pituitary hormone pulsatility and hormone levels of several neuroendocrine axes and markers of immune function in 7 normal-weight women during a normoleptinemic-fed condition and 2 hypoleptinemic 72-hour fasting states. Administration of recombinant human leptin during fasting fully restored leptin to physiologic levels and reversed the fasting-associated decrease in overnight luteinizing hormone pulse frequency, but had no effect on fasting-induced changes in thyroid-stimulating hormone pulsatility, thyroid and IGF1 hormone levels, and hypothalamic-pituitary-adrenal and renin-aldosterone activity. FSH and sex steroid levels were not altered. Short-term reduction of leptin levels decreased the number of circulating cells of the adaptive immune response, but recombinant leptin did not have major effects on their number or in vitro function. Chan et al. (2006) concluded that changes in leptin levels within the physiologic range have no major physiologic effects in leptin-replete humans.
- Linkage to Obesity-Related Traits
See obesity (601665) for a discussion of linkage studies on obesity in various human populations.
Using sibship data obtained from 32 low-income Mexican American pedigrees ascertained on the basis of a type II (NIDDM) diabetic proband and applying a multipoint variance-components method, Duggirala et al. (1996) tested for linkage between various obesity-related traits plus associated metabolic traits in 15 markers on human chromosome 7. They found evidence for linkage between markers in the OB gene region and various traits: extremity skin folds (lod = 3.1), 32,33-split proinsulin level (lod = 4.2), and HCPA1 and proinsulin level (lod = 3.2). A putative susceptibility locus linked to the marker D7S514 explained 56% of the total phenotypic variation in extremity skin folds. Variation at the carboxypeptidase A1 locus (114850) explained 64% phenotypic variation in proinsulin level and approximately 73% of phenotypic variation in split proinsulin concentration. Weaker evidence for linkage to several other obesity-related traits (e.g., waist circumference, body-mass index, fat mass by bioimpedance, etc.) was observed for a genetic location approximately 15 cM telomeric to OB.
The human homolog of the murine ob locus is on chromosome 7q31.3. Clement et al. (1996) used 8 microsatellite markers spanning this region to genotype 101 obese French families. Affected-sib-pair analyses for extreme obesity, defined by BMI greater than 35 kg per sq m, suggested evidence for linkage to 3 markers located within 2 cM of the human OB gene. Similarly, Reed et al. (1996) genotyped sibs from 78 families using markers flanking the OB gene. Fifty-nine pairs of sibs with extreme obesity (BMI 40 or greater) shared haplotypes identical by descent for the region containing the OB gene at greater than chance levels (corrected p = 0.04). Furthermore, 1 haplotype containing the OB gene was transmitted by heterozygous parents to extremely obese offspring more frequently than expected by chance, indicating significant allelic disequilibrium (corrected p = 0.027). One explanation for these linkage findings is that some individuals with extreme obesity have an allelic variant of the OB gene.
See Comuzzie et al. (1997) for data regarding a major quantitative trait locus (QTL) on 2p21 affecting leptin serum levels (601694).
Buettner et al. (2008) infused leptin into the mediobasal hypothalamus (MBH) of rats and observed STAT3-independent inhibition of white adipose tissue (WAT) lipogenesis; correspondingly, mice with a mutant Y1138 leptin receptor (601007) that fails to activate Stat3 (s/s mice) had reduced adipose mass compared to db/db mice. Hypothalamic leptin suppression of WAT lipogenesis in rats was lost when PIK3 (see 171833) signaling was prevented and after sympathetic denervation of adipose tissue. MBH leptin suppressed the endocannabinoid anandamide in WAT, and when this suppression of endocannabinoid tone was prevented by systemic Cnr1 (114610) activation, MBH leptin failed to suppress WAT lipogenesis. The authors suggested that the increased endocannabinoid tone observed in obesity is linked to a failure of central leptin signaling to restrain peripheral endocannabinoids.
- Gene-Environment Interaction
Prenatal famine in humans has been associated with various consequences in later life, depending on the gestational timing of the insult and the sex of the exposed individual. Epigenetic mechanisms have been proposed to underlie these associations. Tobi et al. (2009) investigated the methylation of 15 loci implicated in growth and metabolic disease in individuals who were prenatally exposed to war-time famine in the Netherlands from 1944 to 1945. Methylation of INSIGF (see INS, 176730), which is an alternately spliced read-through transcript of INS and IGF2 (147470), was lower among 60 individuals who were periconceptionally exposed to the famine compared to 60 of their unexposed same-sex sibs, whereas methylation of IL10 (124092), LEP, ABCA1 (600046), GNASAS (610540) and MEG3 (605636) was higher than control. A significant interaction with sex was observed for INSIGF, LEP, and GNASAS. When methylation of 8 representative loci was compared between 62 individuals exposed late in gestation and 62 of their unexposed sibs, methylation was different for GNASAS in both men and women, and LEP methylation was different in men only. Tobi et al. (2009) concluded that persistent changes in DNA methylation may be a common consequence of prenatal famine exposure, and that these changes may depend on the sex of the exposed individual and the gestational timing of the exposure.
To understand the evolutionary history of the gene region containing the leptin gene, Moffett et al. (2002) genotyped 1,957 individuals from 12 world populations for a highly variable tetranucleotide repeat polymorphism located 476 bp 3-prime of exon 3 of the leptin gene. The data revealed a common set of alleles shared among world populations, presumed to have arisen from a great ape ancestral allele before divergence of the major geographic subdivisions of the human population, a subset of alleles specific to populations of African ancestry, and a second set of alleles that arose by tandem duplication of the core repeat unit following the separation of African and non-African populations. These findings emphasized the complex evolutionary history of this locus and raised cautions about the pooling of alleles at this locus in association studies.
Considine et al. (1995) studied OB gene expression in abdominal subcutaneous adipocytes from lean and obese humans. The full coding region of the OB gene was isolated from a human adipocyte cDNA library. They detected no difference in the sequence of an RT-PCR product of the coding region from 5 lean and 5 obese subjects. The nonsense mutation in the ob mouse that results in the conversion of arginine-105 to a stop codon was not present in human obesity. In all 10 human cDNAs, arginine-105 was encoded by CGG; consequently, 2 nucleotide substitutions would be required to result in a stop codon. Whereas the mutations in the ob mouse cause absence of the signaling protein and result in overeating, OB gene expression in humans was, in fact, 72% greater in 8 obese subjects than in 8 lean controls.
Hager et al. (1997) screened patients with morbid obesity for mutations in the leptin gene and for association with a polymorphism in the 5-prime untranslated region of the gene. The patients studied had low leptin levels and the same group had shown evidence for linkage of the LEP gene with morbid obesity. Although no polymorphisms were detected in the coding region of the gene, a single A-to-G transition was found in nucleotide 26 of the untranslated first exon. This base exchange created a new restriction site which was used in the study of 199 morbidly obese individuals and in 153 lean controls. Under a codominant or recessive model, the variant was positively associated with morbid obesity (p = 0.01 and p = 0.0027, respectively). In metabolic studies, they showed that patients homozygous for the G allele of the exon 1 variant had significantly lower fasting leptin levels compared to subjects being either heterozygous (AG) or homozygous for the A allele despite a similar BMI (p = 0.01).
Karvonen et al. (1998) investigated the LEP gene for variants by screening both its putative promoter and its coding region in 200 obese Finnish subjects (BMI greater than 27 kg/m2). PCR-amplified DNA samples were subjected to single-strand conformation analysis. A 144G-A transition in codon 48 and a 328G-A transition in codon 110 were identified in 2 obese subjects, both of whom had very low serum leptin levels. A rare silent polymorphism (538C-T) was detected 33 basepairs downstream of the translation stop codon (TGA), and a common polymorphism (19A-G) was identified in the untranslated exon 1. This polymorphism was not associated with obesity and the allele frequencies were similar between 64 normal-weight and 141 obese Finns. The authors concluded that there is no common LEP gene variation associated with obesity.
On the basis of studies of adipose tissue obtained from 94 adult obese subjects and from 6 children who had developed obesity after surgery in the hypothalamic region, Carlsson et al. (1997) reported studies of total mRNA for the OB gene as examined by RT-PCR. Sequencing of the coding region of the gene detected no mutations and gene expression was detectable in all subjects. None of the subjects had an extreme overexpression. There was no systematic increase in overt expression in obese children with hypothalamic disease compared to their healthy brothers and sisters. Carlsson et al. (1997) concluded that OB gene defects are rare in human obesity.
In studies of 2 severely obese children who were members of a highly consanguineous Pakistani pedigree (164160.0001), Montague et al. (1997) found that their serum leptin levels were very low despite their markedly elevated fat mass and, in both, a homozygous frameshift mutation involving deletion of a single guanine nucleotide in codon 133 of the leptin gene was found. One of the affected children, a female, weighed 86 kg at the age of 8 years, with 57% body fat and height of 137 cm. Her birth weight had been normal, but she gained weight rapidly in the early postnatal period and was clearly outside the normal range by 4 months of age. As the result of her obesity she developed abnormalities of growth in the long bones of the legs, resulting in the need for corrective orthopedic surgery. She underwent liposuction of lower limb fat at the age of 5 years in an attempt to improve her mobility. Her affected cousin, a male aged 2 years, had a weight of 29 kg, with 54% body fat. He had difficulty in walking because of extreme obesity. He likewise was of normal weight at birth but rapidly became obese, deviating far above the normal range by 3 months of age. Both children had a clear history of marked hyperphagia, being noted from early infancy to be constantly hungry, demanding food continuously, and eating considerably more than their sibs. Thus, in both mice and humans, congenital leptin deficiency is associated with normal birth weight followed by rapid development of severe obesity associated with hyperphagia and impaired satiety. Detailed assessment of energy expenditure in these children had not been performed, although their mean body temperatures were within the normal range. Since they were prepubertal, it was impossible to determine whether they would show hypogonadotropic hypogonadism with sterility, which is found in ob/ob mice; serum concentrations of luteinizing hormone, follicle-stimulating hormone, estradiol, and testosterone were at prepubertal levels. In contrast to ob/ob mice, which are markedly hypercortisolemic, plasma cortisol levels in both children were within the reference range. Fasting plasma glucose was normal in both children, but fasting insulin levels were elevated in the older child, consistent with the hyperinsulinemia and insulin resistance seen in ob/ob mice. None of the 4 heterozygous parents, nor the one heterozygous sib, was morbidly obese, a finding consistent with the absence of severe obesity in the murine heterozygotes.
Verploegen et al. (1997) used site-directed mutagenesis to construct a series of point mutations in human leptin involving single amino acid residues that are critical for receptor binding and biologic activity. An arg128-to-gln (R128Q) substitution does not affect receptor binding but knocks out biologic activity. Repeated injection of leptin R128Q in normal C57BL/6J mice resulted in progressive increase in body weight, demonstrating that R128Q is able to interfere with the negative feedback control of endogenous leptin.
Lucantoni et al. (2000) screened 205 obese patients for presence of the A19G polymorphism; 61 normal-weight controls were also screened to compare polymorphism frequency. No significant differences in genotype distribution between control and obese subjects were found. No significant correlations were found between this polymorphism and serum leptin levels and the other parameters considered.
Mammes et al. (1998) identified 8 genetic variants in the 5-prime region of the LEP gene. One of the mutations, 2548G-A (wrongly designated 2549C-A at that time), was associated with a difference in BMI reduction following a low calorie diet in overweight women. Li et al. (1999) found the same polymorphism associated with extreme obesity in women. Mammes et al. (2000) genotyped a new sample from the general population including 314 normal weight and 109 overweight subjects. The genotype and allele frequencies were significantly different between groups, with the G allele being more frequent in the overweight subjects (p less than 0.01). In men, carriers of this allele had lower leptin concentrations adjusted for fat mass. The results indicated that variations at the leptin locus are associated with common obesity phenotypes, and not only with extreme obesity or the rare mendelian obesity syndromes.
Farooqi et al. (2001) examined 13 subjects who were heterozygous for the frameshift mutation delta-G133 (164160.0001). Serum leptin levels and anthropometric measurements in these subjects were compared with those in 96 ethnically matched controls with a similar sex distribution and age. Serum leptin concentrations in heterozygotes for the mutation were markedly lower than in controls. These were positively correlated with BMI in control subjects and in wildtype relatives of the heterozygotes. In contrast there was no significant correlation between BMI and serum leptin in the delta-G133 heterozygotes. Lower leptin levels in the delta-G133 heterozygotes were accompanied by an increased prevalence of obesity, with 76% of heterozygotes having a BMI greater than 30 compared with 26% of controls. Dual energy x-ray absorptiometry in 12 of the heterozygotes and in 6 Pakistani subjects who were wildtype at the leptin locus indicated that the mean measured percentage of body fat was similar to the predicted value in wildtype subjects; however, in the heterozygotes it significantly exceeded the predicted proportion of body fat, with all 12 heterozygous individuals showing a deviation in the same direction. Farooqi et al. (2001) concluded that a relatively small drop in leptin production may be sensed by the homeostatic feedback system that controls energy balance, with fat mass being increased in an attempt to restore leptin levels to some 'set point.'
Shintani et al. (2002) examined the genetic association of the leptin gene polymorphism with obesity, insulin resistance, and hypertension. A highly polymorphic tetranucleotide repeat polymorphism in the 3-prime-flanking region of the leptin gene was examined. The alleles of the polymorphism consisted of 2 groups with different size distributions: a shorter one (class I) and a longer one (class II). The frequency of class I/class I genotype was much higher in hypertensive subjects than in control subjects (13.5% vs 3.4%; P = 0.0027). No significant difference in BMI was observed with different genotypes in either patients with hypertension or control subjects. The authors concluded that the leptin gene polymorphism was associated with hypertension independent of obesity.
In a search for QTLs for BMI, Feitosa et al. (2002) reported a combined multipoint lod score of 4.9 for 2 markers on chromosome 7q32.3 (see 606641) in families participating in the National Heart, Lung, and Blood Institute Family Heart Study. The LEP gene is positioned near the linkage peak. Jiang et al. (2004) employed family-based tests of association with both a quantitative measure of BMI adjusted for age and sex and a dichotomously defined obesity trait. A number of SNPs spanning 240 kb around the LEP gene showed association in men, but not in women, for both the quantitative and qualitative trait definitions. A 5-marker haplotype located 2 kb 5-prime of the previously reported LEP promoter region and spanning approximately 1.2 kb had a frequency of 49% in this sample, and was overtransmitted to obese offspring (p = 0.00005). All 5 of the SNPs were predicted to modify transcription factor binding sites. Jiang et al. (2004) concluded that their results suggested that there are functional variants in an extended promoter region of LEP.
Gaukrodger et al. (2005) examined the impact of both common and rare polymorphisms of the LEP gene on blood pressure, subclinical atherosclerosis as measured by carotid intima-medial thickness, and BMI in a large family study. They found that the rare T allele at the 538C/T polymorphism substantially influenced pulse pressure and carotid intima-medial thickness, but did not appear to exert this effect through actions on plasma leptin level or BMI. This suggested that an autocrine or paracrine effect in vascular tissue may be an important physiologic function of leptin.
Fairfax et al. (2010) employed a combined approach of mapping protein and expression quantitative trait loci in peripheral blood mononuclear cells (PBMCs) using high-density SNP typing for about 2,000 loci implicated in cardiovascular, metabolic and inflammatory syndromes. Common SNP markers and haplotypes of the LEP gene associated with a 1.7- to 2-fold higher level of lipopolysaccharide (LPS)-induced IL6 (147620) expression. Basal leptin expression significantly correlated with LPS-induced IL6 expression, and the same LEP variants that associated with IL6 expression were also major determinants of LEP expression in PBMCs.
Farooqi et al. (1999) demonstrated success in the treatment of congenital leptin deficiency with recombinant leptin; see 164160.0001.
Hukshorn et al. (2000) found that weekly injection of pegylated recombinant native human leptin (PEG-OB) led to sustained serum concentration of PEG-OB and leptin throughout a 12-week treatment period and was generally well tolerated. No significant differences in the delta or percent weight loss, percent body fat, sleeping metabolic rate, or respiratory quotient were observed between the PEG-OB and placebo groups. Percent change in serum triglycerides from baseline was significantly correlated with body weight loss in the PEG-OB group, but not in the placebo group. The trends observed in serum triglycerides suggested that a weekly 20-mg subcutaneous treatment with PEG-OB may have biologic effects in obese men.
Ebihara et al. (2007) treated 7 Japanese patients with generalized lipodystrophy, 2 acquired and 5 congenital type, with the physiologic replacement dose of recombinant leptin during an initial 4-month hospitalization followed by outpatient follow-up for up to 36 months. The leptin replacement therapy with the twice daily injections dramatically improved fasting glucose (mean +/- SE, 172 +/- 20 to 120 +/- 12 mg/dl, P less than 0.05) and triglyceride levels (mean +/- SE, 700 +/- 272 to 260 +/- 98 mg/dl, P less than 0.05) within 1 week. They concluded that their study demonstrates the efficacy and safety of the long-term leptin-replacement therapy and possible mechanisms of leptin actions in patients with generalized lipodystrophy.
Farooqi et al. (2007) studied a 14-year-old boy and a 19-year-old girl with congenital leptin deficiency before and after 7 days of treatment with recombinant human leptin. Although no changes in body weight were seen over this time, leptin treatment had a major effect on food intake. Ad libitum energy intake at a test meal was reduced from 152 to 64 kJ/kg of lean mass and from 169 to 98 kJ/kg of lean mass in subjects 1 and 2, respectively. Normal was 54 +/- 12 kJ/kg of lean mass in age-related controls. Farooqi et al. (2007) used functional magnetic resonance imaging (MRI) to measure differential brain activation by visual images of food compared with images of nonfood in the leptin-deficient and leptin-treated states. After leptin treatment, hunger ratings in the fasted state decreased, and satiety following a meal increased. Whereas visual images of food elicited no differential activation of mesolimbic areas in the leptin-related state, the leptin-deficient state was associated with marked activation in the anteromedial ventral striatum and posterolateral ventral striatum. Farooqi et al. (2007) concluded that the data supported the notion that leptin acts on neural circuits governing food intake to diminish perception of food reward while enhancing the response to satiety signals generated during food consumption.
Zhang et al. (1994) identified a nonsense mutation in codon 105 of the original mouse strain which was described by Ingalls et al. (1950). The original mutation resulted in a change of arginine-105 to a stop codon. This mutation was associated with a 20-fold increase in the expression of ob mRNA. A second ob mutant did not synthesize ob RNA. The mutation was thought to be a structural alteration or sequence variation in the promoter. Taken as a whole, the data suggested that the ob gene product may function as part of a signaling pathway from adipose tissue to a satiety center in the central nervous system that acts to regulate the size of the body fat depot. Of the brain regions implicated in the regulation of feeding behavior, the ventromedial nucleus of the hypothalamus is considered to be the most important satiety center. It remained to be determined whether the active form of the ob protein circulates in the blood; such was subsequently shown to be the case. Mice heterozygous for the ob mutation have an enhanced ability to survive a prolonged fast (Coleman, 1979). Heterozygous mutations at OB might provide a selective advantage in human populations subjected to caloric deprivation and in that way represent a 'thrifty gene' (Neel, 1962). Rink (1994) concluded that 'it will not have escaped the notice of the authors or readers that cloning the ob gene may provide new and rational approaches to the therapy of obesity.'
The OB gene product is present as a 16-kD protein in mouse and human plasma but is undetectable in plasma from C57BL/6J ob/ob mice. Pelleymounter et al. (1995) found that daily intraperitoneal injection of these mice lowered their body weight, percent body fat, food intake, and serum concentrations of glucose and insulin. In addition, metabolic rate, body temperature, and activity levels were increased by this treatment. None of these parameters was altered beyond the level observed in lean controls, suggesting that the OB protein normalized the metabolic status of the ob/ob mice. Lean animals injected with OB protein maintained a smaller weight loss throughout the 28-day study and showed no change in any of the metabolic parameters. These data suggested that the OB protein regulates body weight and fat deposition through effects on metabolism and appetite.
Halaas et al. (1995) stated that plasma levels of the OB protein are increased in db/db mice, a mutant that appears to be resistant to the effects of the ob protein. The authors found that daily intraperitoneal injections of either mouse or human recombinant OB protein reduced the body weight of ob/ob mice by 30% after 2 weeks of treatment with no apparent toxicity; the treatment had no effect, however, on db/db mice. The ob protein injections reduced food intake and increased energy expenditure in ob/ob mice. Surprisingly, injections of wildtype mice twice daily with the mouse ob protein resulted in a sustained 12% weight loss, decreased food intake, and a reduction of body fat from 12.2 to 0.7%. These data suggested that the OB protein serves an endocrine function to regulate body fat stores.
Campfield et al. (1995) found that peripheral and central administration of microgram doses of OB recombinant protein reduced food intake and body weight of ob/ob and diet-induced obese mice but not in db/db obese mice. The behavioral effects after brain administration suggested that OB protein can act directly on neuronal networks that control feeding and energy balance. See Gloaguen et al. (1997) for discussion of the effects of ciliary neurotropic factor (CNTF; 118945) administration on both ob/ob and db/db mice.
Ogawa et al. (1995) isolated rat ob cDNA and examined the tissue distribution of ob gene expression in rats. It showed the rat ob gene product, a 167-amino acid protein with a putative signal sequence, was 96% and 83% homologous to the mouse and human ob proteins, respectively. Northern blot analysis using the rat ob cDNA probe identified a single mRNA species of 4.5 kb in adipose tissue, while no significant amount of ob RNA was present in other tissues in rats. The ob gene was expressed in adipose tissue with regional specificities and in mature adipocytes rather than in stromal-vascular cells isolated from rat adipose tissue. Expression of the ob gene was markedly augmented in all adipose tissue examined in Zucker 'fatty' (fa/fa) rats at this stage of established obesity.
Frederich et al. (1995) confirmed that the adipocyte is the source of ob mRNA in rats and mice and that the predicted 16-kD ob protein is present in rodent serum as detected by Western blot. Both ob protein and ob mRNA expression was markedly increased in obesity. The levels of ob protein were elevated in serum of db/db mice, in mice with hypothalamic lesions caused by neonatal administration of monosodium glutamate, and in mice with brown fat ablation by means of a toxigene. (The UCP-DTA model (see UCP1; 113730) of murine obesity was produced by transgenically expressing the A chain of diphtheria toxin under the UCP1 promoter. No serum ob protein could be detected in the ob/ob mice. By contrast to obesity, starvation of normal rats and mice markedly suppressed ob mRNA abundance, and this was reversed by refeeding.) Iida et al. (1996) demonstrated that a gln269-to-pro mutation in the leptin receptor gene is responsible for the obese phenotype in the Zucker fa/fa rat.
Neuropeptide Y (NPY; 162640) is a neuromodulator implicated in the control of energy balance and is overproduced in the hypothalamus of ob/ob mice. To determine the role of NPY in the response to leptin deficiency, Erickson et al. (1996) generated ob/ob mice deficient in NPY. In the absence of NPY, ob/ob mice were less obese because of reduced food intake and increased energy expenditure, and were less severely affected by diabetes, sterility, and somatotropic defects. These results were interpreted as indicating that NPY is a central effector of leptin deficiency.
Muzzin et al. (1996) demonstrated that the obesity and diabetes in the ob/ob mouse is corrected by treatment with a recombinant adenovirus expressing the mouse leptin cDNA. Treatment resulted in dramatic reductions in both food intake and body weight, as well as the normalization of serum insulin levels and glucose tolerance. Subsequent diminution in serum leptin levels resulted in the rapid resumption of food intake and a gradual gain of body weight, which correlated with the gradual return of hyperinsulinemia and insulin resistance. Muzzin et al. (1996) concluded that the obese and diabetic phenotypes in the adult ob/ob mice are corrected by leptin gene treatment and provided confirming evidence that body weight control may be critical in the long-term management of noninsulin-dependent diabetes mellitus (NIDDM; 125853) in obese patients.
Yamauchi et al. (2003) crossed leptin-deficient ob/ob mice with mice carrying a transgene for the globular domain of adiponectin (605441). The ob/ob mice carrying the transgene showed reduced insulin resistance, beta-cell degranulation, and diabetes. Amelioration of diabetes and insulin resistance was associated with increased expression of molecules involved in fatty acid oxidation, such as acyl-CoA oxidase (609751), and molecules involved in energy dissipation, such as uncoupling protein-2 (601693) and -3 (602044).
In a subset of obese humans, a relatively low plasma level of leptin is found. This finding suggested that in some cases abnormal regulation of the leptin gene in adipose tissue causes the obese state. Ioffe et al. (1998) tested the possibility that a relative decrease in leptin production can lead to obesity by mating animals carrying a weakly expressed adipocyte-specific human leptin transgene to ob/ob mice, which do not express leptin. The transgene did not contain the regulatory elements of the leptin gene and was analogous to a circumstance in which the cis element and/or trans factors regulating leptin RNA production are abnormal. The ob/ob mice carrying the transgene had a plasma leptin approximately one-half that found in normal, nontransgenic mice. These animals were markedly obese, though not as obese as ob/ob mice without the transgene; furthermore, the infertility and several of the endocrine abnormalities evident in ob/ob mice were normalized in the transgenic mice. The transgenic mice had an abnormal response when placed at an ambient temperature of 4 degree centigrade, suggesting that different thresholds exist for the different biologic effects of leptin. Leptin treatment of the transgenic mice resulted in marked weight loss with efficacy similar to that seen after treatment of wildtype mice. In aggregate, these data suggested that dysregulation of the leptin gene can result in obesity with relatively normal levels of leptin and that this form of obesity is responsive to leptin treatment.
In a mouse model of congenital generalized lipodystrophy (269700), Shimomura et al. (1999) demonstrated that insulin resistance could be overcome by continuous systemic infusion of low doses of recombinant leptin, an effect that was not mimicked by chronic food restriction. Shimomura et al. (1999) concluded that their results supported the idea that leptin modulates insulin sensitivity and glucose disposal independently of its effect on food intake, and that leptin deficiency accounts for the insulin resistance found in congenital generalized lipodystrophy.
Ducy et al. (2000) studied ob/ob and db/db mice that were obese and hypogonadic. Both mutant mice had increased bone formation, leading to high bone mass despite hypogonadism and hypercortisolism. This phenotype was dominant, independent of the presence of fat, and specific for the absence of leptin signaling. There was no leptin signaling in osteoblasts, but intracerebroventricular infusion of leptin caused bone loss in leptin-deficient and wildtype mice. This study identified leptin as a potent inhibitor of bone formation acting through the central nervous system.
Szczypka et al. (2000) generated mice lacking both dopamine and leptin to determine if leptin deficiency overcomes the aphagia of dopamine-deficient mice. Double-mutant mice became obese when treated daily with L-DOPA, but when L-DOPA treatment was terminated the double mutants were capable of movement but did not feed, suggesting that dopamine is required for feeding in leptin-null mice.
Leptin acts as a potent inhibitory factor against obesity by regulating energy expenditure, food intake, and adiposity. The obese diabetic db/db mouse, which has defects in leptin receptor, displays enhanced neural responses and elevated behavioral preference to sweet stimuli. Kawai et al. (2000) showed the effects of leptin on the peripheral taste system. The administration of leptin into lean mice suppressed responses of peripheral taste nerves to sweet substances without affecting responses to sour, salty, and bitter substances. Whole-cell patch-clamp recordings of activities of taste receptor cells isolated from circumvallate papillae (innervated by the glossopharyngeal nerve) demonstrated that leptin activated outward K+ currents, which resulted in hyperpolarization of taste cells. The db/db mouse with impaired leptin receptors showed no such leptin suppression. Kawai et al. (2000) concluded that the taste organ is a peripheral target for leptin, and that leptin may be a sweet-sensing modulator (suppressor) that may take part in regulation of food intake.
By studying lipodystrophic (see SREBP1; 184756) and ob/ob mice, Shimomura et al. (2000) showed that chronic hyperinsulinemia downregulates the mRNA for IRS2 (600797), an essential component of the insulin-signaling pathway in liver, thereby producing insulin resistance. Despite IRS2 deficiency, insulin continues to stimulate production of SREBP1c, a transcription factor that activates fatty acid synthesis. The combination of insulin resistance (inappropriate gluconeogenesis) and insulin sensitivity (elevated lipogenesis) establishes a vicious cycle that aggravates hyperinsulinemia and insulin resistance in lipodystrophic and ob/ob mice.
Leptin deficiency results in a complex obesity phenotype comprising both hyperphagia and lowered metabolism. The hyperphagia results, at least in part, from the absence of induction by leptin of melanocyte-stimulating hormone (MSH) secretion in the hypothalamus; the MSH normally then binds to melanocortin-4 receptor-expressing neurons and inhibits food intake. Forbes et al. (2001) showed that leptin administered to leptin-deficient (ob/ob) mice results in a large increase in peripheral MSH levels; further, peripheral administration of an MSH analog results in a reversal of their abnormally low metabolic rate, in an acceleration of weight loss during a fast, in partial restoration of thermoregulation in a cold challenge, and in inducing serum free fatty acid levels. These results supported an important peripheral role for MSH in the integration of metabolism with appetite in response to perceived fat stores indicated by leptin levels.
Most endocrine hormones are produced in tissue and organs with permeable microvessels that provide an excess of hormones to be transported by the blood circulation to the distal target organ. Cao et al. (2001) investigated whether leptin induces the formation of vascular fenestrations and permeability, and characterized its angiogenic property in the presence of other angiogenic factors. From studies in mice, they provided evidence that leptin-induced new blood vessels are fenestrated. Under physiologic conditions, capillary fenestrations were found in the leptin-producing adipose tissue in lean mice. In contrast, no vascular fenestrations were detected in the adipose tissue of leptin-deficient ob/ob mice. Thus, leptin plays a critical role in the maintenance and regulation of vascular fenestrations in the adipose tissue. Leptin induces a rapid vascular permeability response when administered intradermally. Further, leptin synergistically stimulated angiogenesis with fibroblast growth factor-2 (FGF2; 134920) and vascular endothelial growth factor (VEGF; 192240), the 2 most potent and commonly expressed angiogenic factors. The findings demonstrated another function of leptin: to increase vascular permeability.
Yuan et al. (2001) demonstrated that high doses of salicylates reverse hyperglycemia, hyperinsulinemia, and dyslipidemia in obese rodents by sensitizing insulin signaling. Activation or overexpression of IKBKB (603258) attenuated insulin signaling in cultured cells, whereas IKKB inhibition reversed insulin resistance. Thus, Yuan et al. (2001) concluded that IKKB, rather than the cyclooxygenases (see 600262), appears to be the relevant molecular target. Heterozygous deletion (IKKB +/-) protected against the development of insulin resistance during high-fat feeding and in obese Lep (ob/ob) mice. Yuan et al. (2001) concluded that their findings implicate an inflammatory process in the pathogenesis of insulin resistance in obesity and type II diabetes mellitus (125853) and identified the IKKB pathway as a target for insulin sensitization.
Hasty et al. (2001) generated mice deficient in both the low density lipoprotein receptor (LDLR; 606945) and leptin (ob/ob). These doubly mutant mice exhibited striking elevations in both total plasma cholesterol and triglyceride levels and had extensive atherosclerotic lesions throughout the aorta by 6 months of age. Although fasting, diet restriction, and low-level leptin treatment significantly lowered total plasma triglyceride levels, they caused only slight changes in total plasma cholesterol levels. Hepatic cholesterol and triglyceride contents as well as mRNA levels of cholesterologenic and lipogenic enzymes suggested that leptin deficiency increased production of hepatic triglycerides, but not cholesterol, in the ob/ob mice regardless of their Ldlr genotype. These data provided evidence that the hypertriglyceridemia and hypercholesterolemia in the doubly mutant mice were caused by distinct mechanisms, suggesting that leptin might have some impact on plasma cholesterol metabolism, possibly through an LDLR-independent pathway.
Mancuso et al. (2002) showed that Lep-deficient mice had increased susceptibility to intratracheal infection with Klebsiella pneumoniae associated with reduced bacterial clearance and alveolar macrophage phagocytosis in vitro. Wildtype mice, on the other hand, responded with increased leptin levels in serum, bronchoalveolar lavage fluid, and whole lung homogenates. Both mutant and normal mice synthesized TNF, IL12 (see 161561), and MIP2 (GRO2; 139110), but the Lep-deficient mice had reduced leukotriene (see LTB4R; 601531) synthesis. Exogenous addition of leptin reversed both the alveolar macrophage and leukotriene synthesis defects in vitro. Mancuso et al. (2002) noted that humans who are most susceptible to bacterial pneumonia exhibit altered leptin secretion or responsiveness as well as reduced leukotriene synthesis.
Xia et al. (2002) developed C3 (120700) and leptin double knockout mice. Several metabolic measures were improved in comparison to ob/ob mice although they were not returned to normal.
Sanna et al. (2003) found that the expression of serum leptin increased before the clinical onset of experimental autoimmune encephalomyelitis (EAE) in disease susceptible C57BL/6J (H-2b) and SJL/J (H-2s) mice. The increase in serum leptin correlated with disease susceptibility, reduction in food intake, and decrease in body weight. Acute starvation, which prevented the increase in serum leptin, delayed disease onset and attenuated clinical symptoms by inducing a Th2 cytokine switch. In situ production of leptin in inflammatory infiltrates and in neurons occurred only during the acute/active phase of chronic-progressive and relapsing-remitting EAE. The secretion of leptin by activated T cells was maintained by an autocrine loop as demonstrated by the in vitro inhibition of the proliferative response of autoreactive T cells by antileptin receptor antibodies.
To investigate the direct contribution of leptin deficiency to cardiac hypertrophy in obesity and separate it from that caused by the mechanical effects of obesity, Barouch et al. (2003) induced weight loss in ob/ob mice by either leptin infusion or caloric restriction. Mice in both groups lost similar weight compared with placebo-treated controls. Leptin infusion completely reversed the increase in left ventricular wall thickness with partial resolution of myocyte hypertrophy, whereas calorie-restricted mice had no decrease in wall thickness and a lesser change in myocyte size. Barouch et al. (2003) concluded that the effect of leptin on left ventricular remodeling is not attributable to weight loss alone and that leptin has antihypertrophic effects on the heart, either directly or through a leptin-regulated neurohormonal pathway.
Using in situ peroxidase and immunofluorescence staining in mouse hearts, Raju et al. (2006) localized Cntf receptors (CNTFR; 118946) to the sarcolemma and confirmed the localization by immunoblot on isolated myocytes. Subcutaneous administration of recombinant CNTF (118945) in ob/ob and db/db mice resulted in significant reductions in cardiac hypertrophy. Western blotting showed that both leptin and CNTF activated STAT3 and ERK1 (MAPK3; 601795)/ERK2 (MAPK1; 176948) pathways in cultured adult mouse cardiomyocytes and cardiac tissue from ob/ob and db/db mice. Raju et al. (2006) concluded that CNTF plays a role in a cardiac signal transduction pathway that regulates obesity-related left ventricular hypertrophy.
Using a SREBP1 (184756)-deficient mouse model of lipodystrophy, Asilmaz et al. (2004) found that low-dose central intracerebroventricular administration of leptin corrected hepatic steatosis by repressing liver Scd1. Central leptin also corrected insulin resistance by improving insulin signal transduction in the liver, a response that was Scd1-independent. Although subcutaneous leptin administration also improved hyperglycemia and insulin resistance, it did not improve hepatic steatosis.
Balthasar et al. (2004) generated mice with conditional deletion of leptin receptors on proopiomelanocortin (POMC; 176830) neurons and observed mild obesity, hyperleptinemia, and altered expression of hypothalamic neuropeptides. Because the body weight increase was only 18% of that seen in mice with complete deficiency of leptin receptors, the authors concluded that leptin receptors on POMC neurons are required but not solely responsible for leptin's regulation of body weight homeostasis.
Gao et al. (2007) administered estradiol (E2) to wildtype mice and rats and observed a robust increase in the number of excitatory inputs to POMC neurons in the arcuate nucleus. The rearrangement of synapses was leptin independent, as it was also observed in leptin-deficient (ob/ob) and leptin receptor-deficient (db/db) mice, and was paralleled by decreased food intake and body weight gain, as well as increased energy expenditure. Chronic E2 administration in a brain-specific Stat3 (102582)-knockout mouse model, a phenotype that closely resembles that of ob/ob and db/db mice, had no effect on body weight, demonstrating that the estrogen-induced decrease in body weight was dependent on Stat3 activation in the brain. Gao et al. (2007) concluded that synaptic plasticity of arcuate nucleus feeding circuits is an inherent element in body weight regulation.
In Koletsky fa(k)/fa(k) (LEPR-null) rats, Morton et al. (2005) observed markedly increased meal size and reduced satiety in response to cholecystokinin (CCK; 118440), suggesting a role for leptin signaling in the response to endogenous signals that promote meal termination. Restoration of LEPR in the area of the hypothalamic arcuate nucleus of fa(k)/fa(k) rats by adenoviral gene therapy normalized the effect of CCK on the activation of neurons in key hindbrain areas for processing satiety signals and also reduced meal size and enhanced CCK-induced satiety. Morton et al. (2005) concluded that forebrain signaling by leptin limits food intake on a meal-to-meal basis by regulating the hindbrain response to short-acting satiety signals.
Montez et al. (2005) treated wildtype mice with high-dose leptin until fat mass was depleted, thus reducing endogenous leptin production; then exogenous leptin was abruptly withdrawn, thereby inducing a state of leptin deficiency in otherwise normal mice. The biologic response to leptin deficiency so induced included altered neuropeptide levels, decreased energy expenditure, and impaired reproductive and immune function. Replacement of leptin at physiologic concentrations after withdrawal of high-dose leptin blunted, but did not completely block, the hyperphagia and weight regain caused by acute leptin deficiency, nor did it correct the resulting reproductive and immune dysfunction. Montez et al. (2005) suggested that high-dose leptin treatment induces a state of partial leptin resistance, and concluded that these studies established the role of acute hypoleptinemia in regulating energy balance, the immune system, and reproductive function.
In rats exposed to chronic stress, Lu et al. (2006) detected low levels of plasma leptin; systemic leptin treatment reversed the depression-like phenotype and was accompanied by increased activity in the hippocampus. Intrahippocampal administration of leptin produced an antidepressant effect similar to that of systemic delivery, whereas infusion into the hypothalamus decreased body weight but had no effect on the depression-like phenotype. Lu et al. (2006) suggested that impaired leptin production and secretion may contribute to chronic stress-induced depression-like phenotypes, and that the hippocampus is a brain site mediating leptin's antidepressant-like activity.
In studies in rodents, Kitamura et al. (2006) demonstrated that Foxo1a (136533) and Stat3 exerted opposing actions on the expression of Agrp (602311) and Pomc through transcriptional interference, with Foxo1a promoting activation of Agrp and inhibition of Pomc. Kitamura et al. (2006) concluded that Foxo1a mediates the Agrp-dependent effects of leptin on food intake.
In studies in rats, Gao et al. (2007) observed that intracerebroventricular (ICV) injection of leptin inhibited AMPK while concomitently activating acetyl-CoA carboxylase (ACC; see ACACA, 200350) in the arcuate and paraventricular nuclei of the hypothalamus. In the arcuate nucleus, overexpression of constitutively active AMPK prevented arcuate ACC activation in response to ICV leptin, and inhibiting hypothalamic ACC with 5-tetradecyloxy-2-furoic acid (TOFA) blocked leptin-mediated decreases in food intake, body weight, and mRNA level of the orexigenic neuropeptide NPY (162640), demonstrating that hypothalamic ACC makes an important contribution to leptin's anorectic effects. ICV leptin also upregulated arcuate nucleus levels of malonyl-CoA and periventricular nucleus levels of palmitoyl-CoA; the increase in both was blocked by TOFA, which also blocked leptin-mediated hypophagia. Gao et al. (2007) suggested that while malonyl-CoA is a downstream mediator of ACC in the leptin signaling pathway in the arcuate nucleus, palmitoyl-CoA might be an effector in relaying ACC signaling in the periventricular nucleus, thus highlighting site-specific impacts of hypothalamic ACC activation in the leptin anorectic signaling cascade.
Ren et al. (2007) generated Sh2b1 (608937)-knockout mice that developed hyperlipidemia, leptin resistance, hyperphagia, obesity, hyperglycemia, insulin resistance, and glucose intolerance. Neuron-specific restoration of Sh2b1 corrected the metabolic disorders in the knockout mice and improved leptin signaling and leptin regulation of orexigenic neuropeptide expression in the hypothalamus. Neuron-specific overexpression of Sh2b1 dose-dependently protected against high fat diet-induced leptin resistance and obesity. Ren et al. (2007) suggested that neuronal SH2B1 regulates energy balance, body weight, peripheral insulin sensitivity, and glucose homeostasis at least in part by enhancing hypothalamic leptin sensitivity.
Rahmouni et al. (2008) studied Bbs2 (606151) -/-, Bbs4 (600374) -/-, and Bbs6 (604896) -/- mice and found that obesity was associated with hyperleptinemia and resistance to the anorectic and weight-reducing effects of leptin. Although all 3 of the BBS mouse models were similarly resistant to the metabolic actions of leptin, only Bbs4 -/- and Bbs6 -/- mice remained responsive to the effects of leptin on renal sympathetic nerve activity and arterial pressure and developed hypertension. The authors also found that BBS mice had decreased hypothalamic expression of proopiomelanocortin and suggested that BBS genes play an important role in maintaining leptin sensitivity in POMC neurons.
Lim et al. (2009) found that leptin contributed to pain behaviors in a rat model of neuropathic pain induced by chronic constriction sciatic nerve injury. Spinal administration of a leptin antagonist prevented and reversed neuropathic pain behaviors. Further examination revealed that levels of both leptin and the long form of the leptin receptor were substantially increased within the ipsilateral spinal cord dorsal horn after peripheral nerve injury. Mechanistic studies showed that leptin upregulated the expression of both the spinal NMDA receptor (GRIN1; 138249) and IL1-beta (147720) through the JAK/STAT pathway. Furthermore, these pain-induced behavioral and cellular responses were diminished in leptin-deficient mice and mimicked by spinal administration of exogenous leptin in naive rats. The findings revealed a critical role for spinal leptin in the pathogenesis of neuropathic pain.
Sennello et al. (2008) found that dosing of IL12 (161560) and IL18 (600953) induced severe acute pancreatitis in obese (ob/ob) mice, but not in nonobese leptin-deficient mice or wildtype mice. Mutant ob/ob mice showed disruption of pancreatic exocrine tissue and acinar cell death and increased serum amylase and lipase, characteristic of necrotizing acute pancreatitis. They also showed adipose tissue necrosis and saponification, severe hypocalcemia, and an elevated acute-phase response. Wildtype mice treated with IL12 and IL18 developed nonlethal edematous acute pancreatitis without the other abnormalities. Short-term leptin reconstitution in the absence of major weight loss did not protect ob/ob mice from cytokine-induced pancreatitis, but leptin deficiency in the absence of obesity resulted in a significant reduction in the severity of the pancreatitis. Sennello et al. (2008) concluded that this model of acute pancreatitis indicated that obesity itself, not leptin deficiency, is associated with increased severity of acute pancreatitis.
Claycombe et al. (2008) compared hematopoietic processes in ob/ob mice and C57BL/6 lean wildtype controls and found that despite their large size and consumption of substantial amounts of nutrients, ob/ob mice had only 60% as many nucleated cells in their marrow as controls. The B cell compartment was the most affected, with 70% fewer cells, reducing the absolute number of pre-B and immature B cells to 21% and 12% of normal, respectively. While the proportion of myeloid cells remained nearly normal in the obese mice, there was a reduction of 40% and 25%, respectively, in absolute numbers of granulocytes and monocytes. Seven days of provision of recombinant leptin promoted substantial lymphopoiesis, increasing the number of B cells in the marrow of the obese mice 2-fold, while doubling pre-B and tripling immature B cells; at 12 days of supplementation, these subpopulations were at near-normal levels. Leptin treatment also facilitated myelopoiesis such that the marrow of the obese mice contained normal numbers of monocytes and granulocytes after 7 days. Claycombe et al. (2008) suggested that leptin plays an essential role in sustaining lymphopoiesis and myelopoiesis in the marrow.
Leptin (from the Greek for 'thin') was the name proposed by Halaas et al. (1995) for the fat-regulating hormone. LEP is the preferred gene symbol.
HPRD (Human Protein Reference Database)
Proteins Linked to LEPR: 13