Leptin Deficiency Or Dysfunction

A number sign (#) is used with this entry because leptin deficiency or dysfunction (LEPD) is caused by homozygous mutation in the LEP gene (164160) on chromosome 7q32.

Description

Leptin deficiency is characterized by severe early-onset obesity, hyperphagia, hypogonadotropic hypogonadism, and neuroendocrine/metabolic dysfunction (Ozata et al., 1999).

Clinical Features

Montague et al. (1997) described 2 morbidly obese cousins, an 8-year-old girl and a 2-year-old boy, from an inbred Pakistani kindred. Although of normal weight at birth, both children suffered from severe, intractable obesity from an early age. The children had no additional clinical features to suggest that they might have a pleiotropic genetic syndrome associated with obesity. Montague et al. (1997) found that serum leptin levels in both patients were very low despite their markedly elevated fat mass. The female patient 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 6 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.

Farooqi et al. (1999) followed up on the older of the 2 cousins described by Montague et al. (1997), then 9 years of age. She had marked hyperphagia, was constantly hungry, demanded food continually, and was disruptive when denied food. As a result of her severe obesity, valgus deformities of the legs developed, for which she required bilateral proximal tibial osteotomies. When she was 6 years old, liposuction was performed to remove fat from her legs. Although there were no normative data for a child of this weight, there was no evidence of substantial impairment in her basal or total energy expenditure, and her body temperature was normal, which is not the case in ob/ob mice, whose oxygen consumption, energy expenditure, and body temperature are low (Trayhurn et al., 1977). Thus, leptin may be less central to the regulation of energy expenditure in humans than in mice. Another difference in all humans with either leptin or leptin receptor mutations is the consistently normal glucocorticoid concentrations, in contrast to the marked excess in ob/ob mice.

Farooqi et al. (2002) described a third child with leptin deficiency, from a consanguineous family of Pakistani origin living in the United Kingdom. Leptin deficiency was associated with reduced numbers of circulating CD4+ T cells and impaired T cell proliferation and cytokine release, all of which were reversed by recombinant human leptin administration.

Gibson et al. (2004) reported a child of consanguineous Pakistani parents in Canada who presented with severe hyperphagia and obesity. The family originated from the same area of Pakistan as the 2 United Kingdom families reported by Montague et al. (1997) and Farooqi et al. (2002), but was not known to be related over 4 generations. Four years of therapy with subcutaneous injections of recombinant leptin had dramatically beneficial effects on weight, appetite, metabolism, and neuroendocrine phenotypes and was associated with clinical improvement in asthma and recurrent infections. Biochemical hypothyroidism, which was persistent before treatment, was completely reversed by leptin therapy.

Infertility due to hypothalamic-pituitary hormone insufficiency is a feature of leptin-deficient ob/ob mice. Two of the homozygous individuals in the Turkish kindred of Strobel et al. (1998) were adults. One had primary amenorrhea; the male homozygote never entered puberty and had clinical features of hypogonadism: no beard, scanty pubic and axillary hair, bilateral gynecomastia, and small penis and testes. Testosterone rose after administration of human chorionic gonadotropin (see 118860) in the latter patient, and normal responses to gonadotropin-releasing hormone (152760) were also demonstrated. As in ob/ob mice, a sympathetic system dysfunction (low sympathetic tone) was observed in the propositus. The cold pressor test elicited an abnormally small response in systolic and diastolic blood pressures, and orthostatic hypotension was demonstrated. The phenotype of these adult patients suggested that leptin not only controls body mass but also is a necessary signal for the initiation of human puberty.

Ozata et al. (1999) analyzed endocrine, sympathetic, and immune function in 4 homozygous patients from the 5-generation consanguineous Turkish kindred with leptin deficiency, morbid obesity, and hypogonadism that was originally reported by Strobel et al. (1998). Heterozygous individuals in this family had normal weight. All 4 obese patients showed sympathetic system dysfunction, whereas heterozygous relatives did not. The patients also exhibited alterations in growth hormone (GH1; 139250), although their heights were not less than those of unaffected relatives. Parathyroid hormone (PTH; 168450)-calcium function was disturbed, with 1 patient (the only male) showing decreased bone mineral density. Despite their obesity, these patients did not exhibit risk factors for cardiovascular disease, such as hypertension, impaired lipid metabolism, or hyperglycemia. Ozata et al. (1999) noted that the 19 normal-weight individuals in this family were alive, whereas 7 of 11 obese individuals had died in childhood after infections, suggesting that the LEP mutation severely impairs key biologic functions during childhood with negative impact on survival. The oldest homozygous female patient started to menstruate at age 35 years, whereas the younger adult subjects were still hypogonadic. The authors concluded that humans who survive the negative effects of leptin deficiency during childhood can, in contrast to ob/ob mice, eventually compensate for some of the effects of leptin deficiency on immunity and endocrine function.

Wabitsch et al. (2015) studied a Turkish boy with early-onset extreme obesity who presented with a weight of 33.7 kg (BMI, 38.6) at 2.5 years of age. He was of normal weight at birth, but rapid weight gain started in the postnatal period. His parents reported food-seeking behavior, and he exhibited hyperphagia in an ad libitum test meal. He had a history of recurrent ear and pulmonary infections, requiring 2 intensive-care hospitalizations for severe pneumonia. Laboratory evaluation revealed an elevated serum leptin level but normal T-lymphocyte counts, subpopulation ratios, and function. The patient responded to the administration of exogenous metreleptin with a rapid change in eating behavior and a corresponding decrease in weight, from 43 to 35 kg, and in BMI, from 44 to 34.

Clinical Management

Farooqi et al. (1999) described the results of a trial of recombinant human leptin in the older of the 2 cousins described by Montague et al. (1997). Treatment of this 9-year-old patient with recombinant leptin led to a sustained reduction in weight, predominantly as a result of a loss of fat. The weight loss during treatment indicated an average negative energy balance of approximately 400 kcal per day. The chief effect of leptin on energy balance was mediated by its suppressive effects on food intake. The patient's total energy expenditure was similar before and after 12 months of leptin therapy, with a reduction in her basal metabolic rate counterbalanced by an increase in her energy expenditure attributable to physical activity. All adults with congenital leptin or leptin receptor deficiency have had severe hypogonadotropic hypogonadism. After 12 months of leptin treatment, the nocturnal pattern of gonadotropin secretion was pulsatile, which is consistent with early puberty. Antibodies to leptin were detected in serum after 2 months of treatment, and they persisted thereafter. Although the antibodies interfered with measurements of serum leptin, they did not appear to interfere with the response to treatment or to be associated with any adverse effects; furthermore, they did not neutralize the action of leptin in a bioassay.

In 30 obese men, 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.

Licinio et al. (2004) reported the results of leptin replacement in 3 morbidly obese members of the Turkish kindred previously reported by Strobel et al. (1998). Patients were hypogonadal, and 1 of them also had type II diabetes (see 125853). After 18 months of treatment with doses of leptin chosen to achieve normal leptin concentrations, mean body mass index (BMI) dropped from 51.2 at baseline to 26.9, mainly because of loss of fat mass. Thus, Licinio et al. (2004) demonstrated that leptin replacement therapy in leptin-deficient adults resulted in profound weight loss, increased physical activity, changes in endocrine function and metabolism (including resolution of type II diabetes mellitus and hypogonadism), and beneficial effects on ingestive and noningestive behavior. The results highlighted the role of the leptin pathway in adults with key effects on the regulation of body weight, gonadal function, and behavior.

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 non-food 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.

Ebihara et al. (2007) treated 7 Japanese patients with generalized lipodystrophy, 2 acquired and 5 congenital type (see 608594), 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.

Baicy et al. (2007) paired functional MRI with presentation of food cues to the 3 adults from the Turkish family previously reported by Strobel et al. (1998) and found that leptin replacement reduced brain activation in regions linked to hunger (insula, parietal, and temporal cortex) while enhancing activation in regions linked to inhibition and satiety (prefrontal cortex). The authors suggested that leptin modulates feeding behavior through these circuits.

Biochemical Features

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. 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.

Molecular Genetics

In an inbred Pakistani kindred, Montague et al. (1997) found that 2 morbidly obese cousins, an 8-year-old girl and a 2-year-old boy, had a deletion of a guanine nucleotide in the leptin gene: there were 5 rather than the expected 6 guanine nucleotides present between nucleotides 393 and 398 (164160.0001). The mutation disrupted the reading frame of the leptin gene, leading to the introduction of 14 aberrant amino acids after gly132 in the leptin polypeptide, followed by a premature stop codon.

Farooqi et al. (2002) described a third child from a consanguineous family of Pakistani origin living in the United Kingdom homozygous for the guanine deletion in codon 133 of leptin (delta-G133). The family was not known to be related to the family identified by Montague et al. (1997) over at least 5 generations.

In a child of consanguineous Pakistani parents in Canada who presented with severe hyperphagia and obesity, Gibson et al. (2004) found homozygosity for the delta-133G mutation in leptin. The family originated from the same area of Pakistan as the 2 United Kingdom families reported by Montague et al. (1997) and Farooqi et al. (2002), but was not known to be related over 4 generations. Four years of therapy with subcutaneous injections of recombinant leptin had dramatically beneficial effects on weight, appetite, metabolism, and neuroendocrine phenotypes and was associated with clinical improvement in asthma and recurrent infections. Biochemical hypothyroidism, which was persistent before treatment, was completely reversed by leptin therapy.

In a Turkish patient with a body mass index of 55.8 kg/m(2), Strobel et al. (1998) found very low serum leptin concentrations and, in the LEP gene, a C-to-T transition in the leptin gene which resulted in an arg105-to-trp amino acid replacement in the mature protein (164160.0002). Two other markedly obese individuals with low levels of serum leptin were homozygous for the mutation. All 3 homozygotes were markedly hyperphagic. Plasma insulin concentrations were elevated, and 1 of the 3 was hyperglycemic. All other members of this highly consanguineous kindred were either heterozygous for the mutation or homozygous for the wildtype allele and had normal body weight, serum leptin levels, fasting blood glucose, and plasma insulin levels, indicating a recessive mutation responsible for monogenic obesity.

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.'

In a 2.5-year-old Turkish boy with early-onset extreme obesity and elevated circulating leptin levels, Wabitsch et al. (2015) sequenced the leptin receptor gene (LEPR; 601007) but found no mutations. Analysis of the leptin gene revealed homozygosity for a missense mutation (D100Y; 164160.0003) that was present in heterozygosity in the proband's unaffected, first-cousin parents and was not found in 720 pediatric controls, 146 of whom were of Turkish ancestry. Functional analysis demonstrated that the D100Y mutation does not interfere with expression or secretion of leptin, but that the mutant protein cannot bind to or activate the leptin receptor. Wabitsch et al. (2015) noted that this was the first reported case of leptin deficiency due to a biologically inactive leptin associated with high circulating hormone levels.

Animal Model

Zhang et al. (1994) identified a nonsense mutation in codon 105 of the ob gene in the original ob/ob mouse strain 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 with OB protein 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 (LEPR; 601007) 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.

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.

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 degrees 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.

Ducy et al. (2000) studied ob/ob and db/db mice, which 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.

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.

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.

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.