Calorie-induced ER stress suppresses uroguanylin satiety signaling in diet-induced obesity.

J E Lin,P Li,A E Snook,G W Kim,S A Waldman,D J Merlino,A S Aing

doi:10.1038/nutd.2016.18

Abstract

Background/Objectives:The uroguanylin-GUCY2C gut–brain axis has emerged as one component regulating feeding, energy homeostasis, body mass and metabolism. Here, we explore a role for this axis in mechanisms underlying diet-induced obesity (DIO).Subjects/Methods:Intestinal uroguanylin expression and secretion, and hypothalamic GUCY2C expression and anorexigenic signaling, were quantified in mice on high-calorie diets for 14 weeks. The role of endoplasmic reticulum (ER) stress in suppressing uroguanylin in DIO was explored using tunicamycin, an inducer of ER stress, and tauroursodeoxycholic acid (TUDCA), a chemical chaperone that inhibits ER stress. The impact of consumed calories on uroguanylin expression was explored by dietary manipulation. The role of uroguanylin in mechanisms underlying obesity was examined using Camk2a-Cre-ERT2-Rosa-STOPloxP/loxP-Guca2b mice in which tamoxifen induces transgenic hormone expression in brain.Results:DIO suppressed intestinal uroguanylin expression and eliminated its postprandial secretion into the circulation. DIO suppressed uroguanylin through ER stress, an effect mimicked by tunicamycin and blocked by TUDCA. Hormone suppression by DIO reflected consumed calories, rather than the pathophysiological milieu of obesity, as a diet high in calories from carbohydrates suppressed uroguanylin in lean mice, whereas calorie restriction restored uroguanylin in obese mice. However, hypothalamic GUCY2C, enriched in the arcuate nucleus, produced anorexigenic signals mediating satiety upon exogenous agonist administration, and DIO did not impair these responses. Uroguanylin replacement by transgenic expression in brain repaired the hormone insufficiency and reconstituted satiety responses opposing DIO and its associated comorbidities, including visceral adiposity, glucose intolerance and hepatic steatosis.Conclusions:These studies reveal a novel pathophysiological mechanism contributing to obesity in which calorie-induced suppression of intestinal uroguanylin impairs hypothalamic mechanisms regulating food consumption through loss of anorexigenic endocrine signaling. The correlative therapeutic paradigm suggests that, in the context of hormone insufficiency with preservation of receptor sensitivity, obesity may be prevented or treated by GUCY2C hormone replacement.

Highlights

Obesity is a global pandemic and 41.5 billion adults are overweight, 500 million of whom are obese.[1,2,3] Within the United States, 69% of adults are overweight and 35% are obese, a figure that has doubled over 20 years.[4]
diet-induced obesity (DIO) was associated with a commensurate reduction (43.1 ± 11.4%; P o 0.001) in phosphorylation of vasodilator-stimulated phosphoprotein (VASP), a reporter of GUCY2C-cyclic guanosine monophosphate (cGMP) signaling,[15] in jejunal epithelium (Figure 1d)
The uroguanylin-GUCY2C gut–brain axis has emerged as a regulator of feeding, energy homeostasis, body mass and metabolism in normal physiology in rodents.[6,7,8]

Summary

Introduction

Obesity is a global pandemic and 41.5 billion adults are overweight (body mass index 425 kg m − 2), 500 million of whom are obese (body mass index 430 kg m − 2).[1,2,3] Within the United States, 69% of adults are overweight and 35% are obese, a figure that has doubled over 20 years.[4]. These uroguanylin responses oppose the development of diet-induced obesity (DIO) and the metabolic syndrome.[6,7,8]

Methods

Results

Conclusion