title: Gastric Bypass Surgery Recruits a Gut PPAR-α-Striatal D1R Pathway to Reduce Fat Appetite in Obese Rats.
abstract: Bariatric surgery remains the single most effective long-term treatment modality for morbid obesity, achieved mainly by lowering caloric intake through as yet ill-defined mechanisms. Here we show in rats that Roux-en-Y gastric bypass (RYGB)-like rerouting of ingested fat mobilizes lower small intestine production of the fat-satiety molecule oleoylethanolamide (OEA). This was associated with vagus nerve-driven increases in dorsal striatal dopamine release. We also demonstrate that RYGB upregulates striatal dopamine 1 receptor (D1R) expression specifically under high-fat diet feeding conditions. Mechanistically, interfering with local OEA, vagal, and dorsal striatal D1R signaling negated the beneficial effects of RYGB on fat intake and preferences. These findings delineate a molecular/systems pathway through which bariatric surgery improves feeding behavior and may aid in the development of novel weight loss strategies that similarly modify brain reward circuits compromised in obesity.
authors.affiliation: Integrated Research and Treatment Centre for Adiposity Diseases, Department of Medicine, Universität Leipzig, Liebigstraße 21, 04103 Leipzig, Germany.
authors.forename: Mohammed K
authors.initials: MK
authors.lastname: Hankir
authors.affiliation: Department of General and Visceral, Vascular, and Paediatric Surgery, University of Würzburg, 97070 Würzburg, Germany.
authors.forename: Florian
authors.initials: F
authors.lastname: Seyfried
authors.affiliation: Integrated Research and Treatment Centre for Adiposity Diseases, Department of Medicine, Universität Leipzig, Liebigstraße 21, 04103 Leipzig, Germany.
authors.forename: Constantin A
authors.initials: CA
authors.lastname: Hintschich
authors.affiliation: Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3B Building 18.5, 2200 Copenhagen, Denmark.
authors.forename: Thi-Ai
authors.initials: TA
authors.lastname: Diep
authors.affiliation: Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Jagtvej 160, 1165 Copenhagen, Denmark.
authors.forename: Karen
authors.initials: K
authors.lastname: Kleberg
authors.affiliation: Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research, Permoserstraße 15, 04318 Leipzig, Germany.
authors.forename: Mathias
authors.initials: M
authors.lastname: Kranz
authors.affiliation: Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research, Permoserstraße 15, 04318 Leipzig, Germany.
authors.forename: Winnie
authors.initials: W
authors.lastname: Deuther-Conrad
authors.affiliation: John B. Pierce Laboratory and Departments of Psychiatry and Physiology, Yale University, New Haven, CT 06519, USA.
authors.forename: Luis A
authors.initials: LA
authors.lastname: Tellez
authors.affiliation: Department of Nuclear Medicine, Universität Leipzig, Liebigstraße 18, 04109 Leipzig, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Rullmann
authors.affiliation: Department of Nuclear Medicine, Universität Leipzig, Liebigstraße 18, 04109 Leipzig, Germany.
authors.forename: Marianne
authors.initials: M
authors.lastname: Patt
authors.affiliation: Rudolf Boehm Institute of Pharmacology and Toxicology, Clinical Pharmacology, Universität Leipzig, Härtelstraße 16-18, 04107 Leipzig, Germany.
authors.forename: Jens
authors.initials: J
authors.lastname: Teichert
authors.affiliation: Integrated Research and Treatment Centre for Adiposity Diseases, Department of Medicine, Universität Leipzig, Liebigstraße 21, 04103 Leipzig, Germany; Department of Nuclear Medicine, Universität Leipzig, Liebigstraße 18, 04109 Leipzig, Germany.
authors.forename: Swen
authors.initials: S
authors.lastname: Hesse
authors.affiliation: Integrated Research and Treatment Centre for Adiposity Diseases, Department of Medicine, Universität Leipzig, Liebigstraße 21, 04103 Leipzig, Germany; Department of Nuclear Medicine, Universität Leipzig, Liebigstraße 18, 04109 Leipzig, Germany.
authors.forename: Osama
authors.initials: O
authors.lastname: Sabri
authors.affiliation: Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research, Permoserstraße 15, 04318 Leipzig, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Brust
authors.affiliation: Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Jagtvej 160, 1165 Copenhagen, Denmark.
authors.forename: Harald S
authors.initials: HS
authors.lastname: Hansen
authors.affiliation: John B. Pierce Laboratory and Departments of Psychiatry and Physiology, Yale University, New Haven, CT 06519, USA.
authors.forename: Ivan E
authors.initials: IE
authors.lastname: de Araujo
authors.affiliation: Rudolf Boehm Institute of Pharmacology and Toxicology, Universität Leipzig, Härtelstraße 16-18, 04107 Leipzig, Germany. Electronic address: ute.kruegel@medizin.uni-leipzig.de.
authors.forename: Ute
authors.initials: U
authors.lastname: Krügel
authors.affiliation: Integrated Research and Treatment Centre for Adiposity Diseases, Department of Medicine, Universität Leipzig, Liebigstraße 21, 04103 Leipzig, Germany. Electronic address: wiebkekristin.fenske@medizin.uni-leipzig.de.
authors.forename: Wiebke K
authors.initials: WK
authors.lastname: Fenske
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001066:Appetite / Q000187:drug effects*; D001835:Body Weight / Q000187:drug effects; D059305:Diet, High-Fat; D004041:Dietary Fats / Q000494:pharmacology*; D004298:Dopamine / Q000378:metabolism; D063388:Endocannabinoids / Q000378:metabolism; D005247:Feeding Behavior / Q000187:drug effects; D005518:Food Preferences / Q000187:drug effects; D015390:Gastric Bypass; D041981:Gastrointestinal Tract / Q000187:drug effects / Q000378:metabolism*; D007421:Intestine, Small / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D008820:Mice, Obese; D008954:Models, Biological; D017072:Neostriatum / Q000187:drug effects / Q000378:metabolism*; D009765:Obesity / Q000378:metabolism* / Q000503:physiopathology*; D009829:Oleic Acids / Q000378:metabolism; D047493:PPAR alpha / Q000378:metabolism*; D017208:Rats, Wistar; D017447:Receptors, Dopamine D1 / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D014630:Vagus Nerve / Q000187:drug effects / Q000378:metabolism; D015431:Weight Loss / Q000187:drug effects
chemical_list: D004041:Dietary Fats; D063388:Endocannabinoids; D009829:Oleic Acids; D047493:PPAR alpha; D017447:Receptors, Dopamine D1; C488250:oleoylethanolamide; D004298:Dopamine
keywords: D1R signaling; OEA; PPAR-alpha; [11C] SCH 23390; altered nutrient preference; dopamine system; fat appetite; gastric bypass surgery