INTRODUCTION — Leptin is a product of the ob gene, which is expressed primarily in adipocytes. Leptin acts on leptin receptors (LEPRs), which are widely distributed and account for its pleiotropic effects on energy homeostasis and neuroendocrine, reproductive, and immune function [1]. Leptin is produced primarily in fat cells but also in other organs such as the placenta [2].
The physiology of leptin [3,4] and a review of disorders associated with leptin deficiency are reviewed here. The pathogenesis of obesity and lipodystrophy are reviewed separately. (See "Obesity: Genetic contribution and pathophysiology" and "Lipodystrophic syndromes".)
ACTION OF LEPTIN — In humans, the leptin gene is located on chromosome 7q32 and consists of three exons and two introns that span 20 kilobases (kb) of DNA. The mouse and human ob genes have 84 percent homology. The gene codes for a secreted protein of 167 amino acids. Leptin is a member of the cytokine family, and its receptor (LEPR) has similarities to the gp130 group of cytokine receptors.
There are at least six isoforms of LEPR (LEPR-a to -f) [5], and all the isoforms are encoded by the LEPR gene. The short isoform of the receptor, which is present in several tissues, serves to transport leptin into the brain. There is also a circulating form of the LEPR (LEPR-e) that binds leptin, functions as a leptin-binding protein, and may modulate its action [6].
The LEPR-b receptor is the "longest form," and in most of the cases, mutations in this isoform cause severe obesity. This form of the receptor is located in several organs but, most importantly, areas of the brain, including hypothalamic and other brainstem nuclei. A number of pathogenic mutations have been reported in both the LEP and LEPR [7], which can lead to obesity. LEPR-b is also expressed in cells of the immune system and regulates immune function, most importantly, Type 1/Type 2 T helper (Th1/Th2) cells balance. It is also expressed in the hypothalamic-pituitary-gonadal axis, where it contributes to the regulation of reproductive function.
BIOLOGY OF LEPTIN — Large fat cells produce more leptin than small ones, and serum leptin concentrations are highly correlated with overall body fat content in newborn infants, children, and adults [8].
Leptin mRNA and secretion by adipocytes declines rapidly during starvation, with circulating leptin levels falling to approximately 50 percent of baseline within a day and to approximately 20 percent of baseline within three days, before any substantial changes in body mass index (BMI) [9-11].
Regulation of food intake — Food intake is reduced by exogenous leptin administration at supraphysiologic doses to leptin-deficient or normal-leptin and normal-weight experimental animals, but the response decreases as the animals become obese, with obese animals developing tolerance to both supraphysiologic and pharmacologic doses of leptin. Similar observations have been made in normal-weight or lean human beings who have either normal or low leptin levels. These subjects retain their sensitivity to leptin [12-14] and lose weight (primarily fat) in response to supraphysiologic doses of leptin. Their weight returns to baseline when their leptin levels return to normal [15]. In contrast, obese humans, who are chronically exposed to higher leptin levels (proportional to their fat mass), are resistant or tolerant to exogenous leptin, even when administered in supraphysiologic doses [16,17]. However, when leptin is injected directly into the ventricular system of the brain of obese animals, they remain, to a certain extent, responsive [9].
Leptin decreases food intake in several ways. In the hypothalamus, it decreases expression of neuropeptide Y (NPY), one of the most potent stimulators of food intake [18]. In addition, the content of anorexigenic neuropeptides such as proopiomelanocortin (POMC) mRNA is increased [18,19]. Lastly, alpha-melanocyte-stimulating hormone (alpha-MSH), produced by post-translational cleavage of POMC, inhibits food intake [20].
Leptin production in humans — BMI and body fat are strongly correlated with both leptin production and circulating concentrations [6]. Under conditions of regular food intake, leptin concentrations communicate the proportion of adipose tissue and status of energy reserves to the brain (and other organs) [15]. Overeating increases serum leptin concentrations by nearly 40 percent within 12 hours, long before any changes in body fat stores. Conversely, in normal-weight and obese subjects, fasting reduces serum leptin concentrations by 60 to 70 percent in 48 hours and by approximately 80 percent within three days [21-24], indicating that leptin functions not only as an indicator of long-term energy stores but also as a marker of acute changes in energy intake.
Leptin circulates in the blood stream as both free and bound forms. The binding protein is the extracellular cleaved product of the leptin receptor. Free leptin has unrestricted access to areas of the central nervous system (CNS) not protected by the blood brain barrier, whereas its access to other areas of the CNS depends on expression of the short form of the leptin receptor, which functions as leptin transporter into the CNS and is saturable at high circulating leptin levels.
In addition to the correlation with body fat content, other characteristics of leptin include:
●An increase in serum concentrations during childhood (highest in girls and children who gain the most weight). Higher serum leptin concentrations are associated with an earlier onset of puberty [25,26]. After puberty, levels start to decrease in response to rising testosterone in boys, but continue to rise in response to estrogens in females [27,28].
●Women have higher serum leptin concentrations than men, and pregnant women have higher concentrations than nonpregnant women [25]. Estrogens increase leptin levels, whereas androgens decrease leptin levels.
●The placenta and breast milk are sources of leptin [29].
●The concentrations are similar in normal subjects and patients with type 2 diabetes mellitus of the same weight, but hyperinsulinemia increases glucose utilization and leptin production in adipocytes [30].
●Ethnicity does not influence serum leptin concentrations [6].
●There is a diurnal rhythm of serum leptin concentrations, the values being 20 to 40 percent higher in the middle of the night as compared with daytime [31]. The peak shifts in parallel with shifts in the timing of meals.
Biological effects
Bone metabolism — Leptin's effects on energy balance occur primarily at the level of the CNS, although there are also effects in the periphery [32]. Leptin has direct effects on the bone, as well as an indirect effect (by increasing estrogen and insulin-like growth factor-1 [IGF-1] levels or decreasing circulating levels of cortisol [14]).
Metreleptin (ie, recombinant human leptin with one amino acid substitution, ie, methionine, to increase its stability) is currently the only commercially available leptin formulation. It is the preparation that has been used in trials for women with hypothalamic amenorrhea (who are leptin deficient); improvements in bone density were seen [12]. (See 'Hypothalamic amenorrhea' below.)
Metreleptin decreases intact parathyroid hormone (iPTH) and receptor activator of nuclear factor kappa B ligand (RANKL)-to-osteoprotegerin (OPG) ratio levels in hypoleptinemic women [33].
Studies in humans have reported both a positive [34-36] and negative [37-40] association between serum leptin concentrations and bone density. The positive associations have been seen in leptin-deficient (leptin-sensitive) patients. For example, in randomized, placebo-controlled studies of exogenous leptin administration in women with hypothalamic amenorrhea (who are leptin deficient), the negative/absent associations are in hyperleptinemic patients with apparent leptin tolerance or resistance [37-40]. (See 'Hypothalamic amenorrhea' below.)
Immune function — Leptin also links nutritional status with immune function. The decrease in leptin concentrations during prolonged negative energy balance or cachexia results in impaired immune function and, more specifically, a Type 1/Type 2 T helper (Th1/Th2) cells imbalance [1]. In addition, individuals with congenital leptin deficiency have a decrease in CD4 cells (cluster of differentiation 4, often called T-cells or T-helper cells) and reduced T-cell production [41] that is consistent with their higher rates of childhood infection [42]. Leptin replacement leads to a switch from secretion of predominantly Th2 cytokines to Th1 cytokines in both animals [43,44] and humans with congenital, complete [41] or acquired, partial leptin deficiency [13].
LEPTIN AND DISEASE
Chronic energy deficiency states — Circulating leptin levels are low not only in acute but also in chronic energy deficiency states. Clinical manifestations depend on whether adequate storage space in adipose tissue is available for fat, such as in subjects with anorexia nervosa or hypothalamic amenorrhea [45] (see 'Hypothalamic amenorrhea' below), or whether such storage space is not available, such as in subjects with congenital or acquired lipodystrophies [46]. (See 'Lipodystrophy' below.)
Individuals with anorexia nervosa or women with hypothalamic amenorrhea (due to weight loss, excessive exercise, or an eating disorder) have lower serum concentrations of leptin, a hormone deficiency that contributes to their dysregulated hypothalamic-pituitary-peripheral axes [11,15], including low gonadotropin secretion, as compared with similar-weight women with normal menstrual cycles [11,47] (see 'Hypothalamic amenorrhea' below). In addition, other endocrine axes are affected including the thyroid, insulin-like growth factor-1 (IGF-1), and hypothalamic-pituitary-adrenal axes. (See "Anorexia nervosa: Endocrine complications and their management", section on 'Hypothalamic-pituitary abnormalities'.)
They also have immune deficiencies due in part to low leptin levels [13]. In women with hypothalamic amenorrhea, physiologic doses of exogenous leptin improved the neuroendocrine and immune abnormalities, restored menstrual function in some women, and led to improvement of bone mineral density [11,12,14,47]. When leptin was administered in supraphysiologic doses that resulted in supraphysiologic circulating leptin levels, body weight (primarily fat) was decreased. When doses were adjusted to bring circulating leptin levels within the normal range, body weight returned to normal [14].
Complete congenital leptin deficiency — Complete congenital leptin deficiency with adequate adipose tissue storage capacity is due to a mutation in the leptin gene. This disorder produces massive obesity, similar to that seen in rodent models that lack leptin or leptin receptor (LEPR) [41,42,45]. Despite excess adipose tissue, adipocytes are not able to produce leptin due to specific mutations that lead to either absolutely no leptin production or production of an inactive, truncated leptin molecule.
Early-onset obesity and profound hyperphagia are characteristic of these individuals, as are hyperinsulinemia and advanced bone age [41]. Hypogonadotropic hypogonadism occurs in most patients [42]. Leptin deficiency also reduces thyroid-stimulating hormone (TSH) pulsatility [31] and leads to additional neuroendocrine and immune abnormalities. (See 'Immune function' above and 'Chronic energy deficiency states' above.)
Food intake decreases dramatically when treated with exogenous leptin, but energy expenditure does not change to a comparable degree [41,48]. In one study, exogenous leptin increased thyroid hormone levels and facilitated normal pubertal development [41]. Resolution of type 2 diabetes and hypogonadism have also been reported [48].
Several mechanisms appear to be involved in the reduction in food intake with leptin therapy, including enhanced perception of satiety after a meal and a diminished perception of food reward [49]. At the molecular level, leptin administration to hypoleptinemic subjects alters hypothalamic expression of orexigenic (neuropeptide Y [NPY], agouti-related peptide [AgRP]) and anorexigenic molecules (proopiomelanocortin [POMC], alpha-melanocyte-stimulating hormone [alpha-MSH], cocaine and amphetamine-regulated [CART] peptides), with a net result of anorexia and decreased food intake [50]. However, leptin does not influence levels of other molecules affecting appetite, such as peptide YY (PYY), pancreatic polypeptide (PP), or amylin [51,52].
Partial congenital leptin deficiency — Partial congenital leptin deficiency with adequate adipose tissue storage capacity has been described in heterozygous members of families with mutations in the leptin gene. Serum leptin levels were significantly lower than would be expected from their percent body fat [53]. However, these heterozygotes had normal thyroid function, secondary sexual characteristics, and reproductive function (including regular menstrual cycles), indicating that the relatively lower circulating leptin levels are adequate to normalize their immune and neuroendocrine function [24].
One would expect that these subjects would also be resistant to the weight-reducing effects of exogenous leptin, but data are currently unavailable.
Leptin receptor deficiency — Human obesity resulting from mutations in the LEPR has been described [54,55]. In one report, 8 of 300 subjects (3 percent) with severe early-onset obesity had nonsense or missense LEPR mutations (six probands were from consanguineous families) [55]. The study was performed at a highly specialized center, and one would therefore expect a much lower prevalence of such mutations in the general population (likely less than 1 percent). In addition to severe obesity and hyperphagia, other characteristics of affected patients included [55]:
●Alterations in immune function (decrease in the absolute CD4+ T-cell count with compensatory increase in the CD19+ B-cell count) [1].
●Normal linear growth but reduced adult height (due to lack of pubertal growth spurt).
●Delayed puberty due to hypogonadotropic hypogonadism.
●Increased serum leptin concentrations (consistent with their elevated fat mass, but not disproportionately increased, suggesting that serum leptin levels are not a useful marker for LEPR deficiency).
●Less severe clinical features when compared with patients with congenital leptin deficiency (less hyperphagia, lower body mass index [BMI], and lower percentage body fat).
●Genetic mutations have also been reported in molecules mediating leptin's effect downstream of the LEPR, the most frequent of which are melanocortin-4-receptor mutations [43]. (See "Obesity: Genetic contribution and pathophysiology", section on 'Common (multifactorial) obesity'.)
TREATMENT WITH LEPTIN — Leptin replacement therapy has been studied in a number of disorders [56], but it is currently only approved for the treatment of subjects with complete congenital lipodystrophy, metabolic abnormalities, and leptin deficiency [57]. (See 'Lipodystrophy' below and "Lipodystrophic syndromes", section on 'Persistent metabolic disturbances'.)
It is anticipated that, like in any other hormone deficiency syndrome, leptin administration will be most useful in cases of complete or severe leptin deficiency, whereas its effect will be less pronounced in cases of relative leptin deficiency.
Lipodystrophy — Leptin replacement therapy is effective in patients with either congenital (partial or complete) or acquired lipodystrophy [58] and associated leptin deficiency [57]. The most common cause is human immunodeficiency virus (HIV)-associated lipodystrophy and metabolic syndrome [59-61]. Leptin is, however, only approved by the US Food and Drug Administration (FDA) for the treatment of subjects with complete congenital lipodystrophy, metabolic abnormalities, and leptin deficiency. Clinical trials are now evaluating the efficacy and safety of leptin in patients with partial lipodystrophy and relative leptin deficiency. (See "Lipodystrophic syndromes", section on 'Persistent metabolic disturbances'.)
Obesity — Leptin replacement therapy is effective in patients with leptin gene mutations that result in extremely low leptin levels and obesity [31,62,63]. The vast majority of obese people are not leptin deficient. Their serum leptin concentrations are elevated and directly related to their amount of body fat. In several surveys of obese subjects, no mutations in the leptin (LEP) or the leptin receptor (LEPR) gene were detected [9]. Given the high leptin levels, resistance to exogenous leptin would be expected [9]. In one trial, leptin administration did not result in weight loss [64], while in another dose-escalation trial, leptin helped with weight loss in some obese individuals, but the effect was modest [65].
In overweight or obese women on a hypocaloric diet (who are generally resistant to leptin), the addition of metreleptin results in an increase in free serum leptin levels but no additional weight loss and no change in neuroendocrine function (hormones of the thyroid and insulin-like growth factor [IGF] axes) [16].
In one report, leptin administration prevented the decline in metabolic rate and circulating concentrations of thyroid hormone in patients who had lost weight [66]. Changes in circulating leptin with weight loss are not predictive of weight regain [67] or changes in intracellular signaling pathways that would be indicative of increased leptin sensitivity or efficacy [68]. Leptin sensitizers or enhancers of leptin action are unavailable, and it is not known if they would be effective.
Hypothalamic amenorrhea — Women with secondary hypothalamic amenorrhea (due to weight loss, excessive exercise, or an eating disorder) have lower serum concentrations of leptin [11,69]. Leptin administration in physiologic replacement doses corrects the relative leptin deficiency and improves function of the immune system, the reproductive axis (increased serum luteinizing hormone [LH] concentrations and pulsatility), and the thyroid and growth hormone axes. In addition, improvements of bone density are observed (without any changes of fat mass or body weight) to the extent circulating leptin levels remain within the normal range [13,14,28]. (See "Epidemiology and causes of secondary amenorrhea", section on 'Role of leptin deficiency' and "Evaluation and management of secondary amenorrhea".)
SUMMARY
●Leptin, the prototype adipokine, is a hormone primarily secreted by adipocytes. Its primary role is to convey information on adequacy of energy reserves to the brain and other peripheral organs. In states of food deprivation, leptin is involved in linking nutritional status with neuroendocrine and immune modulation, the regulation of food intake, and energy homeostasis. (See 'Biology of leptin' above.)
●Serum leptin concentrations increase during childhood, with the highest concentrations in children who gain the most weight and in girls. Higher serum leptin concentrations are associated with an earlier onset of puberty, and leptin levels start decreasing in response to rising testosterone in males postpubertally, whereas they continue to rise in response to estrogens in females. (See 'Leptin production in humans' above.)
●In women with hypothalamic amenorrhea (a state of relative leptin deficiency), administration of leptin improves the related immune and neuroendocrine abnormalities, results in resumption of menses in some women, and, over time, leads to improved bone density. Their body weight remains unchanged to the extent that circulating leptin levels are kept within the normal range. (See 'Hypothalamic amenorrhea' above.)
●Leptin administration in patients with congenital or acquired leptin deficiency (eg, patients with lipodystrophy or hypothalamic amenorrhea) is effective in reversing the neuroendocrine, immune, energy homeostasis, or metabolic abnormalities associated with the deficiency, whereas leptin is ineffective in obese patients with leptin excess (leptin tolerance or resistance). (See 'Treatment with leptin' above.)
