Obestatin as a key regulator of metabolism and cardiovascular function with emerging therapeutic potential for diabetes

Abstract

*These two authors contributed equally to this work.Obestatin is a 23-amino acid C-terminally amidated gastrointestinal peptide derived from preproghrelin and which forms an α helix. Although obestatin has a short biological half-life and is rapidly degraded, it is proposed to exert wide-ranging pathophysiological actions. Whilst the precise nature of many of its effects is unclear, accumulating evidence supports positive actions on both metabolism and cardiovascular function. For example, obestatin has been reported to inhibit food and water intake, body weight gain and gastrointestinal motility and also to mediate promotion of cell survival and prevention of apoptosis. Obestatin-induced increases in beta cell mass, enhanced adipogenesis and improved lipid metabolism have been noted along with up-regulation of genes associated with beta cell regeneration, insulin production and adipogenesis. Furthermore, human circulating obestatin levels generally demonstrate an inverse association with obesity and diabetes, whilst the peptide has been shown to confer protective metabolic effects in experimental diabetes, suggesting that it may hold therapeutic potential in this setting. Obestatin also appears to be involved in blood pressure regulation and to exert beneficial effects on endothelial function, with experimental studies indicating that it may also promote cardioprotective actions against, for example, ischaemia-reperfusion injury. This review will present a critical appraisal of the expanding obestatin research area and discuss the emerging therapeutic potential of this peptide for both metabolic and cardiovascular complications of diabetes. AbbreviationsBK Ca , large conductance calcium-activated potassium channel; CART, cocaine-and amphetamine-related transcript; CCK, cholecystokinin; CRF, corticotrophin-releasing factor; GI, gastrointestinal; GLP-1, glucagon-like peptide-1; GLUT-4, glucose transporter type 4; HOMA-IR, homeostatic model assessment of insulin resistance; NPY, neuropeptide Y; PEG, polyethylene glycol; PI3K, phosphoinositide 3-kinase; POMC, proopiomelanocortin; SK6l, ribosomal protein s6 kinase; T1DM, type 1 diabetes mellitus; T2DM, type 2 diabetes mellitus; WAT, white adipose tissue.

The Neuroendocrine Regulation of Food Intake in Fish: A Review of Current Knowledge

“…Obestatin, a gastrointestinal peptide discovered in 2005, is derived from the same precursor as ghrelin and inhibits food intake in mammals (Cowan et al, 2016). In grass carp, although IP injections of an obestatin-like peptide alone do not affect food intake or the expression levels of NPY, CART, or POMC, when co-injected with ghrelin, it blocks ghrelin-induced stimulation of appetite and up-regulation of expressions of NPY and NPY receptors (Yuan et al, 2015), suggesting that obestatin might inhibit the ghrelin system in Cypriniformes.…”

Serum Obestatin: A Biomarker of Cardiovascular and All-Cause Mortality in Hemodialysis Patients

“…Several mechanisms may explain the possible link between obestatin and clinical outcomes in our population, while most of them supported by experimental studies indicate potential cardio-protective properties of obestatin [19, 20]. Obestatin was found to be beneficial in cardiomyocyte injury induced by ischemia-reperfusion in vivo and in vitro [8, 9].…”

Vascular Effects of Obestatin in Lean and Obese Subjects

“…Even though these effects on feeding behavior and gastrointestinal motion have been subsequently disputed and the precise identity of its cognate receptor(s) is still a matter of debate (5), obestatin indisputably exerts a variety of effects in different cell types, including pancreatic b-cells, where it increases survival and proliferation by inhibiting apoptosis and inflammation (6,7). In line with these actions, other favorable effects of obestatin have been observed on glucose and lipid metabolism, such as increased glucose uptake and insulin sensitivity as well as inhibition of lipolysis in human adipocytes (7,8).Interestingly, in addition to its helpful metabolic properties, obestatin has been shown to provide vascular benefits in experimental models. Thus, in rat aorta and the superior mesenteric artery, Agnew et al (9) have demonstrated that obestatin favorably affects endothelial function, inducing nitric oxide (NO)-dependent relaxation via an adenylate cyclase-linked GPCR.…”

“…Even though these effects on feeding behavior and gastrointestinal motion have been subsequently disputed and the precise identity of its cognate receptor(s) is still a matter of debate (5), obestatin indisputably exerts a variety of effects in different cell types, including pancreatic b-cells, where it increases survival and proliferation by inhibiting apoptosis and inflammation (6,7). In line with these actions, other favorable effects of obestatin have been observed on glucose and lipid metabolism, such as increased glucose uptake and insulin sensitivity as well as inhibition of lipolysis in human adipocytes (7,8).…”