Diet-induced obesity causes peripheral and central ghrelin resistance by promoting inflammation.

Farhana Naznin,Koji Toshinai,Masamitsu Nakazato,Abu Saleh Md Moin,Cherl Namkoong,T M Zaved Waise,Hideyuki Sakoda

doi:10.1530/joe-15-0139

Abstract

Ghrelin, a stomach-derived orexigenic peptide, transmits starvation signals to the hypothalamus via the vagus afferent nerve. Peripheral administration of ghrelin does not induce food intake in high fat diet (HFD)-induced obese mice. We investigated whether this ghrelin resistance was caused by dysfunction of the vagus afferent pathway. Administration (s.c.) of ghrelin did not induce food intake, suppression of oxygen consumption, electrical activity of the vagal afferent nerve, phosphorylation of ERK2 and AMP-activated protein kinase alpha in the nodose ganglion, or Fos expression in hypothalamic arcuate nucleus of mice fed a HFD for 12 weeks. Administration of anti-ghrelin IgG did not induce suppression of food intake in HFD-fed mice. Expression levels of ghrelin receptor mRNA in the nodose ganglion and hypothalamus of HFD-fed mice were reduced. Inflammatory responses, including upregulation of macrophage/microglia markers and inflammatory cytokines, occurred in the nodose ganglion and hypothalamus of HFD-fed mice. A HFD blunted ghrelin signaling in the nodose ganglion via a mechanism involving in situ activation of inflammation. These results indicate that ghrelin resistance in the obese state may be caused by dysregulation of ghrelin signaling via the vagal afferent.

Highlights

Control of food intake in the brain is regulated by the integration of both the neuronal and humoral signals from the periphery
We showed that peripheral ghrelin resistance is associated with inflammation in the nodose ganglia of high fat diet (HFD)-fed mice, resulting in an impairment of the vagal afferent system
We showed that neutralization of ghrelin by the i.c.v. administration of anti-ghrelin IgG failed to suppress natural feeding in Diet-induced obesity (DIO) mice, indicating that endogenous ghrelin did not act as an orexigenic peptide under HFD

Summary

Introduction

Control of food intake in the brain is regulated by the integration of both the neuronal and humoral signals from the periphery. A variety of sensory information derived from the gastrointestinal tract is transmitted to the nucleus of the tractus solitaries (NTS) in the medulla oblongata via the vagal afferent nerve, terminating in hypothalamic nuclei implicated in the control of feeding (Rinaman 2010). The nodose ganglion, located outside the jugular foramen, is a constellation of vagal afferent neurons that synthesize receptors for gut peptides that regulate feeding and energy homeostasis (Zhuo et al 1997, Konturek et al 2004). These receptors are transported to afferent terminals in the gastrointestinal mucosa, which are more optimally positioned to monitor bioactive substances released from gastrointestinal enteroendocrine cells.

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