The role of ghrelin in the control of energy balance.

Ghrelin is the only potent orexigenic peptide in circulation. It stimulates food intake and leads to positive energy balance, adipogenesis, and body weight gain. However, the physiological significance of ghrelin in the regulation of energy homeostasis is controversial, since loss of ghrelin function in rodents does not necessarily lead to anorexia and weight loss. In this chapter, we discuss the metabolic function of ghrelin and are highlighting recent findings including the discovery and function of ghrelin-acylating enzyme ghrelin O-acyltransferase (GOAT). Based on available published data, we conclude that ghrelin is a principally important endogenous regulator of energy balance, which however may affect both food intake and systemic metabolism via independent mechanisms. Importantly, ghrelin, when acylated by GOAT, might represent a key molecular link between the sensing of consumed calories and the neuroendocrine control of energy homeostasis. Thus, agents antagonizing the action of ghrelin may have therapeutic potential in the therapy of obesity

Ghrelin in the control of energy, lipid, and glucose metabolism.

The discovery of ghrelin as the endogenous ligand for the growth hormone secretagogue receptor (GHS-R) led to subsequent studies characterizing the endogenous action of this gastrointestinal hormone. Accordingly, exogenous administration of ghrelin was found to increase food intake and adiposity in a variety of species, including rodents, nonhuman primates, and humans. Later work supported these findings and confirmed that ghrelin acts through hypothalamic neurons to mediate its effects on energy metabolism. Ghrelin acts specifically through GHS-R to promote a positive energy balance as demonstrated by loss of ghrelin action after pharmacological blockade or genetic deletion of GHS-R. More recently, ghrelin was found to be a mediator of glucose metabolism and acts to inhibit insulin secretion from pancreatic β-cells. Together, the literature highlights a predominant role of ghrelin in regulating energy and glucose metabolism

Ablation of ghrelin O-acyltransferase does not improve glucose intolerance or body adiposity in mice on a leptin-deficient ob/ob background.

Type 2 Diabetes is a global health burden and based on current estimates will become an even larger problem in the future. Developing new strategies to prevent and treat diabetes is a scientific challenge of high priority. The stomach hormone ghrelin has been associated with playing a role in the regulation of glucose homeostasis. However, its precise mechanism and impact on whole glucose metabolism remains to be elucidated. This study aims to clarify the role of the two ghrelin isoforms acyl- and desacyl ghrelin in regulating glucose homeostasis. Therefore ghrelin activating enzyme Ghrelin-O-acyltransferase (GOAT) was ablated in leptin-deficient ob/ob mice to study whether specific acyl ghrelin deficiency or desacyl ghrelin abundance modifies glucose tolerance on a massively obese background. As targeted deletion of acyl ghrelin does not improve glucose homeostasis in our GOAT-ob/ob mouse model we conclude that neither acyl ghrelin nor the increased ratio of desacyl/acyl ghrelin is crucial for controlling glucose homeostasis in the here presented model of massive obesity induced by leptin deficiency

The role of ghrelin-octanoyl-acyl-transferase in thermoregulation.

BACKGROUND: Ghrelin is a gastrointestinal peptide that promotes a positive energy balance. The enzyme ghrelin O-acyltransferase (GOAT) esterifies an n-octanoic acid to the peptide, thereby enabling ghrelin to bind and activate the ghrelin receptor. Although ghrelin has previously been implicated in the control and maintenance of body core temperature (BCT), the role that this acylation may play in thermoregulation has not been examined. AIM: We aimed to investigate the endogenous role of ghrelin acylation in thermoregulation. METHODS: In this study, we exposed mice lacking the enzyme GOAT as well as wild type (WT) control mice to cold temperatures under ad libitum and fasting conditions. Additionally, we investigated the role of GOAT in metabolic adaptation to cold temperatures by analyzing BCT and energy metabolism in mice with and without GOAT that were progressively exposed to low ambient temperatures (31-7°C). RESULTS: We find that regardless of nutritional status, mice lacking GOAT maintain a similar BCT as their WT counterparts during an 8 h cold exposure. Furthermore, mice lacking GOAT maintain a similar BCT and metabolic adaptation as WT controls during acclimatization to low ambient temperatures. CONCLUSIONS: We conclude that the absence of the enzyme GOAT does not play a significant role in maintenance of BCT or metabolic adaptation during exposure to low external temperatures

Both acyl and des-acyl ghrelin regulate adiposity and glucose metabolism via CNS ghrelin receptors.

Ghrelin receptors (GHSRs) in the central nervous system (CNS) mediate hyperphagia and adiposity induced by acyl ghrelin (AG). Evidence suggests that des-acyl ghrelin (dAG) has biological activity through GHSR independent mechanisms. We combined in vitro and in vivo approaches to test possible GHSR-mediated biological activity of dAG. Both AG (100nM) and dAG (100nM) significantly increased IP3 formation in HEK-293 cells transfected with human GHSR. As expected, intracerebroventricular (icv) infusion of AG in mice increased fat mass (FM), in comparison with the saline-infused controls. Icv-dAG also increased FM at the highest dose tested (5 nmol/day). Chronic icv infusion of AG or dAG increased glucose-stimulated insulin secretion (GSIS). Subcutaneously infused AG regulated FM and GSIS in comparison to saline-infused control mice, whereas dAG failed to regulate these parameters even with doses that were efficacious when delivered icv. Furthermore, icv-dAG failed to regulate FM and induce hyperinsulinemia in GHSR deficient (Ghsr-/-) mice. In addition, a hyperinsulinemic-euglycemic clamp suggests that icv-dAG impairs glucose clearance without affecting endogenous glucose production. Taken together, these data demonstrate that dAG is an agonist of GHSR and regulates body adiposity and peripheral glucose metabolism through a CNS GHSR-dependent mechanism

Duodenal nutrient exclusion improves metabolic syndrome and stimulates villus hyperplasia.

OBJECTIVE: Surgical interventions that prevent nutrient exposure to the duodenum are among the most successful treatments for obesity and diabetes. However, these interventions are highly invasive, irreversible and often carry significant risk. The duodenal-endoluminal sleeve (DES) is a flexible tube that acts as a barrier to nutrient-tissue interaction along the duodenum. We implanted this device in Zucker Diabetic Fatty (ZDF) rats to gain greater understanding of duodenal nutrient exclusion on glucose homeostasis. DESIGN: ZDF rats were randomised to four groups: Naive, sham ad libitum, sham pair-fed, and DES implanted. Food intake, body weight (BW) and body composition were measured for 28 days postoperatively. Glucose, lipid and bile acid metabolism were evaluated, as well as histological assessment of the upper intestine. RESULTS: DES implantation induced a sustained decrease in BW throughout the study that was matched by pair-fed sham animals. Decreased BW resulted from loss of fat, but not lean mass. DES rats were also found to be more glucose tolerant than either ad libitum-fed or pair-fed sham controls, suggesting fat mass independent metabolic benefits. DES also reduced circulating triglyceride and glycerol levels while increasing circulating bile acids. Interestingly, DES stimulated a considerable increase in villus length throughout the upper intestine, which may contribute to metabolic improvements. CONCLUSIONS: Our preclinical results validate DES as a promising therapeutic approach to diabetes and obesity, which offers reversibility, low risk, low invasiveness and triple benefits including fat mass loss, glucose and lipid metabolism improvement which mechanistically may involve increased villus growth in the upper gut