Ghrelin and leptin are suggested to regulate energy homeostasis as mutual antagonists on hypothalamic neurons that regulate feeding behavior. We employed reverse genetics to investigate the interplay between ghrelin and leptin. Leptin-deficient mice (ob/ob) are hyperphagic, obese, and hyperglycemic. Unexpectedly, ablation of ghrelin in ob/ob mice fails to rescue the obese hyperphagic phenotype, indicating that the ob/ob phenotype is not a consequence of ghrelin unopposed by leptin. Remarkably, deletion of ghrelin augments insulin secretion in response to glucose challenge and increases peripheral insulin sensitivity; indeed, the hyperglycemia exhibited by ob/ob mice is markedly reduced when ob/ob mice are bred onto the ghrelin(-/-) background. We further demonstrate that ablation of ghrelin reduces expression of Ucp2 mRNA in the pancreas, which contributes toward enhanced glucose-induced insulin secretion. Hence, chronically, ghrelin controls glucose homeostasis by regulating pancreatic Ucp2 expression and insulin sensitivity.

Cachexia, defined as an involuntary weight loss ≥ 5%, is a serious and dose-limiting side effect of chemotherapy that decreases survival in cancer patients. Alterations in lipid metabolism are thought to cause the lipodystrophy commonly associated with cachexia. Ghrelin has been proposed to ameliorate the alterations in lipid metabolism due to its orexigenic and anabolic properties. However, the mechanisms of action through which ghrelin could potentially ameliorate chemotherapy-associated cachexia have not been elucidated. The objectives of this study were to identify mechanisms by which the chemotherapeutic agent cisplatin alters lipid metabolism and to establish the role of ghrelin in reversing cachexia. Cisplatin-induced weight and fat loss were prevented by ghrelin. Cisplatin increased markers of lipolysis in white adipose tissue (WAT) and of β-oxidation in liver and WAT and suppressed lipogenesis in liver, WAT, and muscle. Ghrelin prevented the imbalance between lipolysis, β-oxidation, and lipogenesis in WAT and muscle. Pair-feeding experiments demonstrated that the effects of cisplatin and ghrelin on lipogenesis, but not on lipolysis and β-oxidation, were due to a reduction in food intake. Thus, ghrelin prevents cisplatin-induced weight and fat loss by restoring adipose tissue functionality. An increase in caloric intake further enhances the anabolic effects of ghrelin.

Vasoactive intestinal polypeptide (VIP) and pituitary adenylate cyclase-activating peptide (PACAP) are two closely related peptides that bind two homologous G protein-coupled receptors, VIP/PACAP receptor 1 (VPAC1R) and VIP/PACAP receptor II (VPAC2R), with equally high affinity. Recent reports suggest that VPAC2R plays a role in circadian rhythm and T cell functions. To further elucidate the functional activities of VPAC2R, we generated VPAC2R-deficient mice by deleting exons VIII-X of the VPAC2R gene. The VPAC2R-deficient mice showed retarded growth and had reduced serum IGF-I levels compared with gender-matched, wild-type siblings. The mutant mice appeared healthy and fertile at a young adult age. However, older male mutant mice exhibited diffuse seminiferous tubular degeneration with hypospermia and reduced fertility rate. The mutant mice appeared to have an increase in insulin sensitivity. VPAC2R-deficient mice had increased lean mass and decreased fat mass with reduced serum leptin levels. Indirect calorimetry experiments showed that the respiratory quotient values immediately following the transition into the dark cycle were significantly higher in male knockout mice for about 4 h. Additionally, male and female VPAC2R-deficient mice presented an increased basal metabolic rate (23% and 10%, respectively) compared with their wild-type siblings. Our results suggest that VPAC2R plays an important role in growth, basal energy expenditure, and male reproductive functions.