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6.18.8.1 Leptin

The discovery of the peptide hormone leptin was a major advance in obesity research.17 Leptin is a 148-amino-acid protein that is primarily secreted from adipose tissue in proportion to fat mass. Structurally, it belongs to the type 1 cytokine superfamily and is characterized by a long-chain four-helical bundle structure similar to growth hormone (GH), prolactin, and interleukin-3. The leptin receptor (Ob-R) was originally cloned from mouse choroid plexus and is alternatively spliced, giving rise to six different forms of the receptor, known as Ob-Ra, Ob-Rb, Ob-Rc, Ob-Rd, Ob-Re, and Ob-Rf. Ob-R is a member of the class 1 cytokine receptor superfamily. Ob-Rb is expressed at high levels in the hypothalamus and is believed to mediate the central effects of peripherally secreted leptin. Natural mutation of the leptin gene is found in genetically obese (ob/ob) mice, while the gene for the receptor is mutated in fatty (fa/fa) rats and in diabetic (db/db) mice. Chronic administration of leptin to rodents produced impressive reductions in food consumption, body weight, and adiposity. Given these data, the obesity research community had high expectations for leptin as a therapeutic agent for obesity.

In clinical studies, it was found that obese patients had raised plasma levels of leptin when compared to normal-weight controls. Furthermore, increased plasma levels of leptin were associated with increases in adiposity. In phase II clinical studies, administration of leptin or leptin analogs did not reduce food consumption or body weight in a broad segment of the population.18 However, in select individuals with mutations in the leptin sequence, leptin did reduce food consumption and body weight. While Amgen has discontinued the commercial development of leptin, this is still a very active area of research and a number of alternative approaches are being attempted to understand regulation of body weight by the leptin pathway.

6.18.8.2 Cannabinoid Receptor Antagonists

The ability of marijuana to stimulate appetite in humans has been well known for centuries.19 Administration of cannabinoids, the active ingredients in marijuana, has been established to stimulate food intake in animal models of feeding. Central and peripheral administration of anandamide (Figure 9), one of the major endocannabinoids, also increases food intake in preclinical models. The cannabinoid receptor 1 (CB1) is present in brain regions known to control food intake. Cannabinoid-induced feeding can be antagonized by the use of CB1 antagonists and starvation-induced feeding can be reduced by the administration of CB1 antagonists. Interestingly, CB1 knockout mice are leaner than wild-type controls primarily due to decreased food intake and lipogenesis in white fat during early postnatal development. In older animals, increased peripheral energy expenditure appears to be the predominant defense against increased adiposity in the knockout animals. The CB1 receptor is expressed within the key hypothalamic peptidergic systems that regulate appetite, including neurons containing corticotropin-releasing factor (CRF) in the paraventricular nucleus, cocaine- and amphetamine-related transcript (CART) in the arcuate nucleus, and MCH and orexin in the lateral hypothalamus and perifornical regions. Therefore, it is likely that endocannabinoids, through the CB1 receptor, influence these peptidergic systems to regulate both food intake and peripheral storage of energy.

Delta-9-tetrahydrocannabidiol

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