The evidence of metabolic-improving effect of metformin in Ay/a mice with genetically-induced melanocortin obesity and the contribution of hypothalamic mechanisms to this effect.

In diet-induced obesity, metformin (MF) has weight-lowering effect and improves glucose homeostasis and insulin sensitivity. However, there is no information on the efficiency of MF and the mechanisms of its action in melanocortin-type obesity. We studied the effect of the 10-day treatment with MF at the doses of 200, 400 and 600 mg/kg/day on the food intake and the metabolic and hormonal parameters in female C57Bl/6J (genotype Ay/a) agouti-mice with melanocortin-type obesity, and the influence of MF on the hypothalamic signaling in obese animals at the most effective metabolic dose (600 mg/kg/day). MF treatment led to a decrease in food intake, the body and fat weights, the plasma levels of glucose, insulin and leptin, all increased in agouti-mice, to an improvement of the lipid profile and glucose sensitivity, and to a reduced fatty liver degeneration. In the hypothalamus of obese agouti-mice, the leptin and insulin content was reduced and the expression of the genes encoding leptin receptor (LepR), MC3- and MC4-melanocortin receptors and pro-opiomelanocortin (POMC), the precursor of anorexigenic melanocortin peptides, was increased. The activities of AMP-activated kinase (AMPK) and the transcriptional factor STAT3 were increased, while Akt-kinase activity did not change from control C57Bl/6J (a/a) mice. In the hypothalamus of MF-treated agouti-mice (10 days, 600 mg/kg/day), the leptin and insulin content was restored, Akt-kinase activity was increased, and the activities of AMPK and STAT3 were reduced and did not differ from control mice. In the hypothalamus of MF-treated agouti-mice, the Pomc gene expression was six times higher than in control, while the gene expression for orexigenic neuropeptide Y was decreased by 39%. Thus, we first showed that MF treatment leads to an improvement of metabolic parameters and a decrease of hyperleptinemia and hyperinsulinaemia in genetically-induced melanocortin obesity, and the specific changes in the hypothalamic signaling makes a significant contribution to this effect of MF.

Melanotan-induced priapism: a hard-earned tan.

Melanocortin analogues, such as melanotan, are illegally used for artificial tanning. They have also been suggested as possible therapeutic agents in the treatment of erectile dysfunction. This case study presents a patient attending the accident and emergency department, in a tertiary urology centre, with acute priapism after abdominal subcutaneous injection of melanotan. The priapism was diagnosed as 'low-flow' and managed with cavernosal aspiration, irrigation and subsequent intracavernosal injection of phenylephrine. The patient avoided requiring surgical shunting but had not yet recovered erectile function at 4-week follow-up. Acute priapism is an unreported side effect of melanocortin analogue use and this case report presents a patient managed without surgical intervention. Future therapeutic application of these agents will need to take this potential life altering complication into consideration.