title: Food-intake dysregulation in type 2 diabetic Goto-Kakizaki rats: hypothesized role of dysfunctional brainstem thyrotropin-releasing hormone and impaired vagal output.
abstract: Thyrotropin-releasing hormone (TRH), a neuropeptide contained in neural terminals innervating brainstem vagal motor neurons, enhances vagal outflow to modify multisystemic visceral functions and food intake. Type 2 diabetes (T2D) and obesity are accompanied by impaired vagal functioning. We examined the possibility that impaired brainstem TRH action may contribute to the vagal dysregulation of food intake in Goto-Kakizaki (GK) rats, a T2D model with hyperglycemia and impaired central vagal activation by TRH. Food intake induced by intracisternal injection of TRH analog was reduced significantly by 50% in GK rats, compared to Wistar rats. Similarly, natural food intake in the dark phase or food intake after an overnight fast was reduced by 56-81% in GK rats. Fasting (48h) and refeeding (2h)-associated changes in serum ghrelin, insulin, peptide YY, pancreatic polypeptide and leptin, and the concomitant changes in orexigenic or anorexigenic peptide expression in the brainstem and hypothalamus, all apparent in Wistar rats, were absent or markedly reduced in GK rats, with hormone release stimulated by vagal activation, such as ghrelin and pancreatic polypeptide, decreased substantially. Fasting-induced Fos expression accompanying endogenous brainstem TRH action decreased by 66% and 91%, respectively, in the nucleus tractus solitarius (NTS) and the dorsal motor nucleus of the vagus (DMV) in GK rats, compared to Wistar rats. Refeeding abolished fasting-induced Fos-expression in the NTS, while that in the DMV remained in Wistar but not GK rats. These findings indicate that dysfunctional brainstem TRH-elicited vagal impairment contributes to the disturbed food intake in T2D GK rats, and may provide a pathophysiological mechanism which prevents further weight gain in T2D and obesity.
authors.affiliation: Research & Development, Department of Veterans Affairs, Greater Los Angeles Health Care System, Los Angeles, CA 90073, USA.
authors.forename: K
authors.initials: K
authors.lastname: Zhao
authors.forename: Y
authors.initials: Y
authors.lastname: Ao
authors.forename: R M
authors.initials: RM
authors.lastname: Harper
authors.forename: V L W
authors.initials: VL
authors.lastname: Go
authors.forename: H
authors.initials: H
authors.lastname: Yang
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D001933:Brain Stem / Q000378:metabolism*; D003924:Diabetes Mellitus, Type 2 / Q000097:blood* / Q000503:physiopathology; D004435:Eating / Q000502:physiology*; D005215:Fasting / Q000097:blood; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D013973:Thyrotropin-Releasing Hormone / Q000502:physiology*; D014630:Vagus Nerve / Q000378:metabolism*
chemical_list: D001786:Blood Glucose; D013973:Thyrotropin-Releasing Hormone
keywords: 2h refed after a 48h fasted; 48h fasted; AP; AgRP; Amb; BW; DMV; DVC; F48h; GHSR; GIP; GK rats; GLAHS; GLP-1; Goto-Kakizaki rats; Greater Los Angeles Healthcare System; IACUC; Institutional Animal Care and Use Committee; LEPR; MC4R; NF; NPY; NTS; PB; POMC; PP; PYY; RF2h; T2D; TRH; TRH receptor; TRHR; VA; VMH; Veterans Affairs; Y2R; agouti-related peptide; area postrema; body weight; brainstem; dorsal motor nucleus of the vagus; dorsal vagal complex; food intake; ghrelin receptor; glucagon-like peptide-1; glucose-dependent insulinotropic polypeptide; ic; intracisternal or intracisternal injection; leptin receptor; melanocortin receptor 4; neuropeptide Y; neuropeptide receptor 2; normally fed; nucleus ambiguus; nucleus tractus solitarius; pancreatic polypeptide; peptide YY; phosphate buffer; proopiomelanocortin; the vagus nerve; thyrotropin-releasing hormone; type 2 diabetes; ventromedial hypothalamic