BackgroundThe gastrointestinal peptide hormone ghrelin was discovered in 1999 as the endogenous ligand of the growth hormone secretagogue receptor. Increasing evidence supports more complicated and nuanced roles for the hormone, which go beyond the regulation of systemic energy metabolism.Scope of reviewIn this review, we discuss the diverse biological functions of ghrelin, the regulation of its secretion, and address questions that still remain 15 years after its discovery.Major conclusionsIn recent years, ghrelin has been found to have a plethora of central and peripheral actions in distinct areas including learning and memory, gut motility and gastric acid secretion, sleep/wake rhythm, reward seeking behavior, taste sensation and glucose metabolism.

Synthetic agonists of the growth hormone secretagogue receptor (GHSR) rejuvenate the pulsatile pattern of GH-release in the elderly, and increase lean but not fat mass in obese subjects. Screening of tissue extracts in a cell line engineered to overexpress the GHSR led to the identification of a natural agonist called ghrelin. Paradoxically, this hormone was linked to obesity. However, it had not been directly shown that the GHSR is a physiologically relevant ghrelin receptor. Furthermore, ghrelin's structure is significantly different from the synthetic agonist (MK-0677) used to expression-clone the GHSR. To address whether the GHSR mediates ghrelin's stimulatory effects on GH release and appetite, we generated Ghsr-null mice. In contrast to wild-type mice, acute treatment of Ghsr-null mice with ghrelin stimulated neither GH release nor food intake, showing that the GHSR is a biologically relevant ghrelin receptor. Nevertheless, Ghsr-null mice are not dwarfs; their appetite and body composition are comparable to that of wild-type littermates. Furthermore, in contrast to suggestions that ghrelin regulates leptin and insulin secretion, fastinginduced changes in serum levels of leptin and insulin are identical in wild-type and null mice. Serum insulin-like growth factor 1 levels and body weights of mature Ghsr-null mice are modestly reduced compared to wild-type littermates, which is consistent with ghrelin's property as an amplifier of GH pulsatility and its speculated role in establishing an insulin-like growth factor 1 set-point for maintaining anabolic metabolism. Our results suggest that chronic treatment with ghrelin antagonists will have little effect on growth or appetite.

Pharmacological studies show that ghrelin stimulates growth hormone release, appetite, and fat deposition, but ghrelin's physiological role in energy homeostasis has not been established. Ghrelin was also proposed to regulate leptin and insulin release and to be important for the normal function of stomach, heart, kidney, lung, testis, and placenta. To help determine a definable physiological role for ghrelin, we generated ghrelin-null mice. In contrast to predictions made from the pharmacology of ghrelin, ghrelin-null mice are not anorexic dwarfs; their size, growth rate, food intake, body composition, reproduction, gross behavior, and tissue pathology are indistinguishable from wild-type littermates. Fasting produces identical decreases in serum leptin and insulin in null and wild-type mice. Ghrelin-null mice display normal responses to starvation and diet-induced obesity. As in wild-type mice, the administration of exogenous ghrelin stimulates appetite in null mice. Our data show that ghrelin is not critically required for viability, fertility, growth, appetite, bone density, and fat deposition and not likely to be a direct regulator of leptin and insulin. Therefore, antagonists of ghrelin are unlikely to have broad utility as antiobesity agents.Ghrelin is an endogenous ligand for the growth hormone secretagogue receptor (GHS-R). GHS-R was first characterized, cloned, and identified as the receptor for a family of synthetic ligands that restore the age-related decline in pulse amplitude of growth hormone (GH) release by activating hypothalamic neurons (14,29,30). To identify an endogenous ligand for the GHS-R, cell lines overexpressing the GHS-R were prepared and used to assay fractionated tissue extracts for activators of the GHS-R. Two natural agonists were identified: ghrelin in stomach extracts and adenosine in hypothalamic extracts (15,28,36). Like ghrelin, adenosine shows agonist activity on the GHS-R, stimulates appetite (17), and exhibits cross-desensitization with the synthetic ligands (28, 36). However, in contrast to ghrelin and the synthetic GHS-R agonists, adenosine fails to stimulate GH release from pituitary cells. Hence, ghrelin, as a new hormone and a closer mimetic of the synthetic GHS-R ligands, became the major focus of subsequent research.Overwhelming attention to ghrelin's role in obesity was initiated by the localization of this peptide in the stomach. Ghrelin levels in plasma are influenced by nutritional status and are believed to regulate GH, appetite, and fat deposition (12,20,21,35,40). Most intriguing was the observation that low levels of circulating ghrelin correlate with sustained weight loss and reduced appetite in obese humans after gastric bypass surgery (6). However, whether these beneficial changes are a result of reduced ghrelin, rather than alterations in other gut peptides involved in regulation of appetite, is still unclear. The association of ghrelin with obesity was surprising because chronic administration of a synthetic ghrelin agonist, MK-0677, to obese humans pro...

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.

-Cardiac dysfunction is a major component of sepsis-induced multi-organ failure in critical care units. Changes in cardiac autophagy and its role during sepsis pathogenesis have not been clearly defined. Targeted autophagy-based therapeutic approaches for sepsis are not yet developed. -Beclin-1-dependent autophagy in the heart during sepsis and the potential therapeutic benefit of targeting this pathway were investigated in a mouse model of lipopolysaccharide (LPS)-induced sepsis. -LPS induced a dose-dependent increase in autophagy at low doses, followed by a decline that was in conjunction with mTOR activation at high doses. Cardiac-specific overexpression of Beclin-1 promoted autophagy, suppressed mTOR signaling, improved cardiac function, and alleviated inflammation and fibrosis after LPS challenge. Haplosufficiency for resulted in opposite effects. Beclin-1 also protected mitochondria, reduced the release of mitochondrial DAMPs, and promoted mitophagy via PINK1-Parkin but not adaptor proteins in response to LPS. Injection of a cell-permeable Tat-Beclin-1 peptide to activate autophagy improved cardiac function, attenuated inflammation, and rescued the phenotypes caused by deficiency in LPS-challenged mice. -These results suggest that Beclin-1 protects the heart during sepsis and that the targeted induction of Beclin-1 signaling may have important therapeutic potential.