Testosterone replacement therapy restores normal ghrelin in hypogonadal men

We recently described a connection between androgens and ghrelin in women affected by the polycystic ovary syndrome. To further investigate the interaction between sex steroids and ghrelin, we investigated circulating ghrelin levels in a group of hypogonadal men before and after therapeutic intervention aiming at normalization low testosterone ( T) concentrations. Seven hypogonadal men were compared with nine overweight/moderately obese men matched for body mass index and body fat distribution parameters, as well as with 10 normal weight controls. Total and free T and plasma ghrelin levels were significantly lower in the hypogonadal men than in the control groups. Hypogonadal men also had a significantly higher insulin resistance state. Ghrelin levels were positively correlated with both total and free T concentrations. A significant correlation was also found between ghrelin and the anthropometric parameters and the insulin resistance indexes. However, in a multiple regression analysis in which a correction for all covariants was performed, only the relationship with total and free T persisted. After the 6-month replacement T therapy, ghrelin levels of hypogonadal patients increased and did not differ significantly in comparison with both control groups. The positive correlation between ghrelin and androgens still persisted after T replacement therapy, after adjusting for confounding variables. These data further indicate that sex hormones modulate circulating ghrelin concentrations in humans. This may be consistent with the concept that ghrelin may exert a relevant role in the endocrine network connecting the control of the reproductive system with the regulation of energy balance

Gut Peptides: Targets for Antiobesity Drug Development?

Gut peptides play multiple roles in the controls of gastrointestinal function and in the initiation and termination of meals. Plasma levels of these peptides are differentially affected by the presence of nutrients in the digestive tract, and the patterns of peptide release are consistent with both their feeding stimulatory and inhibitory actions. A number of these peptide systems have been investigated as potential targets for antiobesity drug development. Progress has been made in developing long-acting peptide analogs and, in some cases, nonpeptide agonists and antagonists. Whether any individual approach will have significant long-term efficacy remains to be demonstrated. Approaches that target multiple systems may hold the most promise

Uncoupling Protein-2 Decreases the Lipogenic Actions of Ghrelin

The exact mechanisms through which ghrelin promotes lipogenesis are unknown. Uncoupling protein (UCP)-2 is a mitochondrial protein important in regulating reactive oxygen species; however, recent research shows that it may play an important role fat metabolism. Given that ghrelin increases UCP2 mRNA in white adipose tissue, we examined whether the lipogenic actions of ghrelin are modulated by UCP2 using ucp2+/+ and ucp2−/− mice. Chronic ghrelin treatment either via osmotic minipumps or daily ip injections induced body weight gain in both ucp2+/+ and ucp2−/− mice; however, body weight gain was potentiated in ucp2−/− mice. Increased body weight gain was completely due to increased body fat as a result of decreased fat oxidation in ucp2−/− mice. Ghrelin treatment of ucp2−/− mice resulted in a gene expression profile favoring lipogenesis. In a calorie-restriction model of negative energy balance, ghrelin to ucp2+/+ mice did not increase body weight; however, ghrelin to ucp2−/− mice still induced body weight. These results show that UCP2 plays an important role in fat metabolism by promoting fat oxidation and restricts ghrelin-induced lipogenesis