The discovery of leptin and other genes responsible for obesity in rodents has had a considerable impact on our understanding of body weight regulation. Leptin (derived from Greek leptos, meaning thin) is a hormone that is produced by fat cells and circulates at levels proportional to body fat content. Leptin crosses the blood-brain barrier to bind to its receptor in the hypothalamus, thereby activating signals that inhibit food intake and increase energy expenditure. When leptin is given to leptin-deficient mice, obesity and metabolic abnormalities such as hyperglycemia, hyperinsulinemia, and hypercortisolemia are reversed. However, the initial hypothesis that human obesity results from a deficiency in leptin has not been upheld. In fact, most obese humans have high circulating concentrations of leptin, and only a few individuals with severe obesity have been identified either with congenital leptin deficiency or a mutation in the gene encoding the leptin receptor (Table 1). In early clinical trials, high doses of subcutaneously-administered leptin, resulting in greater than 20-fold increases in circulating leptin concentrations, were often associated with reactions at the injection site and had only a modest effect in reducing body weight.
Therefore, it has been suggested that obese persons are leptin resistant. If indeed a defect in the leptin pathway gives rise to human obesity, it may be due to a post-receptor defect in the transduction of leptin signaling through the janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway. Leptin is known to affect the gene expression and synthetic pathway of both anorectic (appetite-suppressing) and orexigenic (appetite-stimulating) substances (Figure 1). Neuropeptide Y (NPY) is a hypothalamic orexigenic peptide produced in the arcuate nucleus, which increases food intake and MedicGLP decreases energy expenditure. The expression of NPY mRNA is inhibited by leptin. In the lateral hypothalamus, melanin-concentrating hormone (MCH), an orexigenic peptide, is increased with fasting and leptin deficiency. Disruption of the MCH gene or administration of an MCH1 receptor antagonist results in hypophagia and leanness in rodents (3, 4). Glucagon-like peptide-1 (GLP-1) and neurotensin are peptides that inhibit the ability of MCH to induce eating.
Leptin also downregulates endocannabinoids that act as cannabinoid receptors in the hypothalamus and stimulate food intake (5). Conversely, leptin stimulates the expression of genes encoding anorexigenic peptides. Melanocyte-stimulating hormone (α-MSH), a peptide derived from proopiomelanocortin (POMC), and cocaine- and amphetamine-regulated transcript are hypothalamic peptides expressed in the same subset of neurons within the arcuate nucleus of the hypothalamus. These peptides are positively regulated by leptin and produce anorexia. Interaction of some hormonal and neural pathways that regulate food intake and body fat mass. A decrease in fat cell mass is sensed in the arcuate nucleus (ARC) of the hypothalamus by a decrease in leptin and insulin concentrations, causing suppression of anorexigenic signals, such as α-MSH, and stimulation of orexigenic signals such as AGRP and NPY. Neurons from the arcuate nucleus project to the paraventricular nucleus (PVN) and lateral hypothalamic area (LHA) to decrease TRH and increase MCH synthesis. The decrease in α-MSH also decreases TRH biosynthesis and release. The gastrointestinal hormone, ghrelin, modulates these pathways through activation of NPY/AGRP neurons.
The net balance of these signals results in an increase in food intake and a decrease in energy expenditure that ultimately aims to restore fat cell mass. The melanocortin system is under intensive investigation because of evidence in both rodents and humans of its control of energy homeostasis (6). There are five different receptors for α-MSH, two of which (MC3R and MC4R) are primarily expressed in the brain. The highest MC3R expression level is in the hypothalamus and limbic system, whereas MC4R mRNA is expressed in virtually all major brain regions. Some of the metabolic effects resulting from stimulation of MC4R are decreased food intake and an increase in energy expenditure through stimulation of thyrotropin-releasing hormone and activation of the sympathetic nervous system. Targeted deletion of the MC4R gene produces obesity, MedicGLP hyperphagia, hyperinsulinemia, and reduced energy expenditure. Targeted deletion of MC3R results in increased adiposity due to decreased energy expenditure.