title: Calorie-induced ER stress suppresses uroguanylin satiety signaling in diet-induced obesity.
abstract: OBJECTIVE
  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).
  
  
  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-ER(T2)-Rosa-STOP(loxP/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.
authors.affiliation: Department of Pharmacology and Experimental Therapeutics, Thomas Jefferson University, Philadelphia, PA, USA.
authors.forename: G W
authors.initials: GW
authors.lastname: Kim
authors.affiliation: Department of Pharmacology and Experimental Therapeutics, Thomas Jefferson University, Philadelphia, PA, USA.
authors.forename: J E
authors.initials: JE
authors.lastname: Lin
authors.affiliation: Department of Pharmacology and Experimental Therapeutics, Thomas Jefferson University, Philadelphia, PA, USA.
authors.forename: A E
authors.initials: AE
authors.lastname: Snook
authors.affiliation: Department of Pharmacology and Experimental Therapeutics, Thomas Jefferson University, Philadelphia, PA, USA.
authors.forename: A S
authors.initials: AS
authors.lastname: Aing
authors.affiliation: Department of Pharmacology and Experimental Therapeutics, Thomas Jefferson University, Philadelphia, PA, USA.
authors.forename: D J
authors.initials: DJ
authors.lastname: Merlino
authors.affiliation: Department of Pathology, Stanford University, Stanford, CA, USA.
authors.forename: P
authors.initials: P
authors.lastname: Li
authors.affiliation: Department of Pharmacology and Experimental Therapeutics, Thomas Jefferson University, Philadelphia, PA, USA.
authors.forename: S A
authors.initials: SA
authors.lastname: Waldman
mesh_terms: D000818:Animals; D001111:Arcuate Nucleus of Hypothalamus / Q000378:metabolism; D031204:Caloric Restriction; D004032:Diet; D059865:Endoplasmic Reticulum Stress / Q000502:physiology*; D002149:Energy Intake; D005234:Fatty Liver / Q000628:therapy; D005786:Gene Expression Regulation; D020868:Gene Silencing; D018149:Glucose Intolerance / Q000628:therapy; D020249:Hormone Replacement Therapy; D007413:Intestinal Mucosa / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D008822:Mice, Transgenic; D045265:Natriuretic Peptides / Q000097:blood / Q000378:metabolism*; D009765:Obesity / Q000503:physiopathology* / Q000628:therapy; D019518:Postprandial Period; D000074261:Receptors, Enterotoxin; D050705:Receptors, Guanylate Cyclase-Coupled / Q000235:genetics / Q000378:metabolism; D018000:Receptors, Peptide / Q000235:genetics / Q000378:metabolism; D012527:Satiation; D015398:Signal Transduction; D013655:Taurochenodeoxycholic Acid / Q000494:pharmacology; D014415:Tunicamycin / Q000494:pharmacology
chemical_list: D045265:Natriuretic Peptides; D018000:Receptors, Peptide; D014415:Tunicamycin; C084362:uroguanylin; D013655:Taurochenodeoxycholic Acid; C031655:ursodoxicoltaurine; C000613655:Gucy2c protein, mouse; D000074261:Receptors, Enterotoxin; D050705:Receptors, Guanylate Cyclase-Coupled