Impaired Glucose and Insulin Modulation of Ghrelin Secretion in Obese Mice

Presentation Number: SUN 582
Date of Presentation: April 2nd, 2017

Bader Nasser Alamri*1, Fatima Imran2 and Younes Anini3
1Dalhousie University, Halifax, NS, CANADA, 2Dalhousie University, 3Dalhousie University, Halifax, NS, Canada

Abstract

The stomach-derived hormone, ghrelin, acts as a key regulator of appetite and energy homeostasis by stimulating food intake and promoting adiposity. Typically, ghrelin levels peak during fasting and reach a nadir during fed state. Despite obesity being generally associated with increased food intake, obese individuals have low basal ghrelin levels and a blunted postprandial suppression, suggesting that obesity may be associated with dysregulation of ghrelin secretion. The goal of the present study was to investigate the putative mechanisms underlying dysregulation of ghrelin secretion in obesity using the diet-induced obesity (DIO) mouse model.

C57BL/6 mice fed high fat diet (HFD) for 8 weeks (DIO mice) had higher body weights and impaired glucose tolerance compared to those fed standard rodent chow (lean mice). We investigated the effect of oral glucose (75 mg) on ghrelin secretion. In lean mice, overnight fasting resulted in increased acylated ghrelin plasma levels (520.3 ± 32 pM). Administering oral glucose significantly reduced ghrelin levels to 60% at 30 min and 70% at 60 min (p<0.001, p<0.001 respectively, n=6) before increasing slightly at 120 min. While fasting ghrelin level was lower in HDF mice compared to low fat diet (LFD) (462 ± 28 pM, P<0.05), glucose-induced suppression of ghrelin secretion was significantly reduced compared to LFD-fed mice and was only different from the fasting level at 60 min (p<0.05, n=6). These results indicate that ghrelin secretion is impaired in obesity.

We previously showed that insulin inhibited both basal and norepinephrine-stimulated ghrelin secretion through phosphorylated serine-threonine kinase (AKT) (Gagnon et al. Endocrinology 2012). The direct effect of insulin on ghrelin secretion was further tested in primary cultures of dispersed gastric mucosal cells generated from either lean or DIO mice. In preparations from lean mice, 10 nM insulin reduced acyl-ghrelin secretion by 40% (P< 0.05, n=6). In contrast, the effects of insulin was lost in gastric mucosal cells derived from DIO mice (n =6). Western blotting relative densitometry of pAKT/AKT was examined after 15 min of treatment with 10 nm insulin in primary cultures of dispersed gastric mucosal cells generated from lean mice and DIO mice. In lean mice, insulin significantly increased pAKT levels relative to total AKT (6.4 ± 2.1-fold of control, P < 0.01), while insulin had no significant effect on Akt phosphorylation in primary cultures of dispersed gastric mucosal cells generated from DIO mice.

In summary, our findings demonstrate that postprandial ghrelin suppression is impaired in obesity and in part due to impaired insulin signaling in ghrelin cells.

 

Nothing to Disclose: BNA, FI, YA