title: Long term exendin-4 treatment reduces food intake and body weight and alters expression of brain homeostatic and reward markers.
abstract: Repeated administration of the long-acting glucagon-like peptide 1 receptor agonist exendin-4 (EX-4) has been shown to reduce food intake and body weight and do so without a rebound increase in food intake after treatment termination. The current study examines the neural mechanisms underlying these actions. After 6 weeks of maintenance on a standard chow or a high-fat (HF) diet, male Sprague Dawley rats were treated with EX-4 (3.2 μg/kg, i.p., twice a day) or vehicle for 9 consecutive days. Food intake and body weight (BW) were monitored daily. Expression of the genes for the hypothalamic arcuate nucleus (ARC) peptides proopiomelanocortin (POMC), neuropeptide Y (NPY), and agouti gene-related protein was determined. Expression of the dopamine precursor tyrosine hydroxylase (TH) gene in the ventral tegmental area and genes for dopamine receptors 1 (D1R) and dopamine receptor 2 in the nucleus accumbens were also determined. Pair-fed groups were included to control for the effects of reduced food intake and BW. Treatment with EX-4 significantly decreased food intake and BW over the 9-day period in both the standard chow and HF groups. HF feeding decreased POMC without changing NPY/agouti gene-related protein gene expression in the ARC. Treatment with EX-4 increased POMC and decreased NPY expression independent of the reduction of food intake and BW. Mesolimbic TH and D1R gene expression were decreased significantly in chronic HF diet-fed rats, and these changes were reversed in both EX-4 and pair-fed conditions. These results suggest a role for increased POMC and decreased NPY expression in the ARC in the effects of EX-4 on food intake and BW. Our findings also suggest that EX-4 induced the recovery of mesolimbic TH and D1R expression in HF diet-fed rats may be secondary to HF intake reduction and/or weight loss.
authors.affiliation: Department of Endocrinology (Y.Y.), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China; Department of Psychiatry and Behavioral Sciences (Y.Y., A.A.M., Z.A.C., T.H.M.), Johns Hopkins University School of Medicine, Baltimore, Maryland 21205; and Department of Psychology (N.C.L.), University of Illinois-Urbana Champaign, Champaign, Illinois 61820.
authors.forename: Yan
authors.initials: Y
authors.lastname: Yang
authors.forename: Alexander A
authors.initials: AA
authors.lastname: Moghadam
authors.forename: Zachary A
authors.initials: ZA
authors.lastname: Cordner
authors.forename: Nu-Chu
authors.initials: NC
authors.lastname: Liang
authors.forename: Timothy H
authors.initials: TH
authors.lastname: Moran
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D001835:Body Weight / Q000187:drug effects*; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D004435:Eating / Q000187:drug effects*; D000077270:Exenatide; D006706:Homeostasis / Q000187:drug effects; D006801:Humans; D008297:Male; D009478:Neuropeptide Y / Q000235:genetics / Q000378:metabolism; D009765:Obesity / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D010455:Peptides / Q000008:administration & dosage*; D011333:Pro-Opiomelanocortin / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D014688:Venoms / Q000008:administration & dosage*
chemical_list: D015415:Biomarkers; D009478:Neuropeptide Y; D010455:Peptides; D014688:Venoms; D011333:Pro-Opiomelanocortin; D000077270:Exenatide