Pharmacologic approaches to the treatment of obesity

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Obesity is a huge and increasing medical problem, with inadequate therapeutic options. One approach to the treatment of obesity is long-term pharmacotherapy. One modestly effective drug, orlistat, has been marketed in the United States since 1999. More recently four other drugs have been approved by the FDA: lorcaserin and Qsymia (a combination of phentermine and topiramate) in 2012 and Contrave (a combination of buproprion and naltrexone) and liraglutide (high dose) in 2014. The limited efficacy of single agents has led to the idea that additional agents and combination therapy are required. Progress in FY2017 includes the following: We wrote an editorial highlighting a remarkable study showing that treatment of patients with genetic deficiency of POMC (proopiomelanocortin) had their massive obesity revered by treatment with a melanocortin agonist, setmelanotide 1. We also wrote a commentary on a series of papers that individually appear well-done and convincing, yet fundamentally disagree. One group reported that interleukin-4 (IL-4) does not increase adipose thermogenesis and that activated macrophages do not synthesize catecholamines. This contrasts with prior findings that IL-4 activation of macrophages has been proposed to have a pivotal role in cold-induced thermogenesis by stimulating macrophage catecholamine production to recruit thermogenic beige or brite fat 2. We contributed to a study (in press) that examined the effect of a drug, JD5037, that is peripheral-acting (not acting in the brain) blocker of the endocannabinoid/CB1 receptor. The results demonstrated that peripheral CB1R blockade in diet-induced obese mice restored sensitivity to endogenous leptin. Thus, the leptin as able to elicit hypophagia via the activation of melanocortin signaling in the arcuate nucleus of the hypothalamus.