Patients with rare defects in the gene encoding proopiomelanocortin (POMC) have extreme early-onset obesity, hyperphagia, hypopigmentation, and hypocortisolism, resulting from the lack of the proopiomelanocortin-derived peptides melanocyte-stimulating hormone and corticotropin. In such patients, adrenal insufficiency must be treated with hydrocortisone early in life. No effective pharmacologic treatments have been available for the hyperphagia and obesity that characterize the condition. In this investigator-initiated, open-label study, two patients with proopiomelanocortin deficiency were treated with setmelanotide, a new melanocortin-4 receptor agonist. The patients had a sustainable reduction in hunger and substantial weight loss (51.0 kg after 42 weeks in Patient 1 and 20.5 kg after 12 weeks in Patient 2).

Genetic defects underlying the melanocortin-4 receptor (MC4R) signaling pathway lead to severe obesity. Three severely obese LEPR-deficient individuals were administered the MC4R agonist setmelanotide, resulting in substantial and durable reductions in hyperphagia and body weight over an observation period of 45-61 weeks. Compared to formerly developed and tested MC4R agonists, setmelanotide has the unique capability of activating nuclear factor of activated T cell (NFAT) signaling and restoring function of this signaling pathway for selected MC4R variants. Our data demonstrate the potency of setmelanotide in treatment of individuals with diverse MC4R-related pathway deficiencies.

Adiponectin affects lipid metabolism and insulin sensitivity. However, adiponectin circulates in three different oligomers that may also have distinct biological functions. We aimed to analyze the role of these oligomers in obesity and lipid metabolism after weight reduction. A total of 17 obese volunteers (15 women and 2 men) participated in a weight reduction program. Individuals were characterized before and after 6 months of a balanced diet. Adiponectin was determined by enzyme-linked immunosorbent assay, and oligomers were detected by nondenaturating Western blot. BMI decreased (35.1 ؎ 1.2 to 32.8 ؎ 1.1 kg/m 2 , P < 0.001), which was associated with an improved metabolite profile. Total adiponectin increased from 5.3 ؎ 0.5 to 6.1 ؎ 0.6 g/ml (P ‫؍‬ 0.076). High (HMW) and medium molecular weight (MMW) adiponectin oligomers significantly increased during weight reduction (HMW: 0.37 ؎ 0.07 to 0.4 ؎ 0.08 g/ml, P ‫؍‬ 0.042; MMW: 2.3 ؎ 0.2 to 2.9 ؎ 0.3 g/ml, P ‫؍‬ 0.007), while low molecular weight (LMW) did not significantly change. Body weight inversely correlated with HMW (r ‫؍‬ ؊0.695, P ‫؍‬ 0.002) and positively with LMW (r ‫؍‬ 0.579, P ‫؍‬ 0.015). Interestingly, HDL cholesterol and HMW were strongly correlated (r ‫؍‬ 0.665, P ‫؍‬ 0.007). Indeed, HMW and free fatty acids before weight reduction predicted ϳ60% of HDL changes during intervention. In conclusion, weight reduction results in a relative increase of HMW/MMW adiponectin and a reduction of LMW adiponectin. Total adiponectin and especially HMW adiponectin are related to circulating HDL cholesterol. Diabetes 54: 2712-2719, 2005