Inhibition of cisplatin-induced lipid catabolism and weight loss by ghrelin in male mice.

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 ß-oxidation in liver and WAT and suppressed lipogenesis in liver, WAT, and muscle. Ghrelin prevented the imbalance between lipolysis, ß-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 ß-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.

Central and peripheral roles of ghrelin on glucose homeostasis.

Ghrelin, an acylated 28-amino-acid peptide, is an endogenous ligand of the growth hormone secretagogue type 1a (GHS-R1a). Ghrelin is best known for its hypothalamic actions on growth hormone-releasing hormone neurons and neuropeptide Y/agouti-related peptide neurons; however, ghrelin affects multiple organ systems and the complexity of its functions is only now being realized. Although ghrelin is mainly produced in the stomach, it is also produced in low levels by the hypothalamus and by most peripheral tissues. GHS-R1a is expressed predominantly in the anterior pituitary gland, at lower levels in the brain including hypothalamic neurons that regulate feeding behavior and glucose sensing, and at even lower levels in the pancreas. A reciprocal relationship exists between ghrelin and insulin, suggesting that ghrelin regulates glucose homeostasis. Ablation of ghrelin in mice increases glucose-induced insulin secretion, and improves peripheral insulin sensitivity. This review focuses on the newly emerging role of ghrelin in glucose homeostasis and exploration of whether ghrelin is a potential therapeutic target for diabetes.

Studies of cocaine- and amphetamine-regulated transcript (CART) knockout mice.

CART (cocaine- and amphetamine-regulated transcript) peptides are neuropeptides expressed throughout the central nervous system and have been implicated in a variety of physiological processes. Research on the many physiological processes involving CART peptide have been somewhat limited by the lack of an identified CART antagonist. Development of CART peptide deficient mice has allowed scientists to further explore the many functions of CART peptide. This review briefly summarizes recent findings in the literature characterizing CART peptide deficient mice.

Ablation of ghrelin improves the diabetic but not obese phenotype of ob/ob mice.

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.

Growth hormone secretagogues: prospects and potential pitfalls.

The growth hormone secretagogues (GHSs) are the first well-characterised agents that rejuvenate the growth hormone (GH)/insulin-like growth factor (IGF-1) axis. This property was discovered during investigations of the underlying causative mechanisms of age-related endocrine changes. Chronic administration of the long acting GHS, MK-0677, reverses the age-related decline in pulse-amplitude of GH secretion and restores IGF-1 levels producing profiles typical of young adults. This restoration is accompanied by improvements in body composition in frail elderly subjects. When given acutely, the GHSs also increase appetite. Following cloning and characterisation of the GHS-receptor (GHS-R) an endogenous ligand, ghrelin, was isolated and identified. Ghrelin shares the GH releasing and orexigenic properties of the GHSs. Studies using Ghsr-null mice confirmed that the GHS-R was the ghrelin-receptor; hence, the GHSs should be considered to be 'ghrelin mimetics.' Ghrelin levels are reported to decline during ageing, therefore long-acting GHSs are ideal candidates for ghrelin replacement therapy.

Vasoactive intestinal polypeptide/pituitary adenylate cyclase-activating peptide receptor 2 deficiency in mice results in growth retardation and increased basal metabolic rate.

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.

Targeted disruption of the melanin-concentrating hormone receptor-1 results in hyperphagia and resistance to diet-induced obesity.

The hypothalamic neuropeptide melanin-concentrating hormone (MCH) has been implicated in a variety of physiological functions including the regulation of feeding and energy homeostasis. Two MCH receptors (MCHR1 and MCHR2) have been identified so far. To decipher the functional role of the MCH receptors, we have generated and phenotypically characterized mice rendered deficient in MCHR1 expression by homologous recombination. Inactivation of MCHR1 results in mice (MCHR1-/-) that are resistant to diet-induced obesity. With a high-fat diet, body fat mass is significantly lower in both male (4.7 +/- 0.6 g vs. 9.6 +/- 1.2 g) and female (3.9 +/- 0.2 vs. 5.8 +/- 0.5 g) MCHR1-/- mice than that of the wild-type control (P < 0.01), but the lean mass remains constant. When normalized to body weight, female mice are hyperphagic, and male mice are hyperphagic and hypermetabolic, compared with wild-type mice. Consistent with the lower fat mass, both leptin and insulin levels are significantly lower in male MCHR1-/- mice than in the wild-type controls. Our data firmly establish MCHR1 as a mediator of MCH effects on energy homeostasis and suggest that inactivation of MCHR1 alone is capable to counterbalance obesity induced by a high-fat diet.