title: Weight Loss After RYGB Is Independent of and Complementary to Serotonin 2C Receptor Signaling in Male Mice.
abstract: Roux-en-Y gastric bypass (RYGB) typically leads to substantial, long-term weight loss (WL) and diabetes remission, although there is a wide variation in response to RYGB among individual patients. Defining the pathways through which RYGB works should aid in the development of less invasive anti-obesity treatments, whereas identifying weight-regulatory pathways unengaged by RYGB could facilitate the development of therapies that complement the beneficial effects of surgery. Activation of serotonin 2C receptors (5-HT2CR) by serotonergic drugs causes WL in humans and animal models. 5-HT2CR are located on neurons that activate the melanocortin-4 receptors, which are essential for WL after RYGB. We therefore sought to determine whether 5-HT2CR signaling is also essential for metabolic effects of RYGB or whether it is a potentially complementary pathway, the activation of which could extend the benefits of RYGB. Diet-induced obese male mice deficient for the 5-HT2CR and their wild-type littermates underwent RYGB or sham operation. Both groups lost similar amounts of weight after RYGB, demonstrating that the improved metabolic phenotype after RYGB is 5-HT2CR independent. Consistent with this hypothesis, wild-type RYGB-treated mice lost additional weight after the administration of the serotonergic drugs fenfluramine and meta-chlorophenylpiperazine but not the nonserotonergic agent topiramate. The fact that RYGB does not depend on 5-HT2CR signaling suggests that there are important WL mechanisms not fully engaged by surgery that could potentially be harnessed for medical treatment. These results suggest a rational basis for designing medical-surgical combination therapies to optimize clinical outcomes by exploiting complementary physiological mechanisms of action.
authors.affiliation: Obesity, Metabolism, and Nutrition Institute and Gastrointestinal Unit (J.S.C., N.N.A., S.M., S.L., L.M.K.), Massachusetts General Hospital, Boston, Massachusetts 02114; and Department of Medicine (J.S.C., N.N.A., S.M., L.M.K.), Harvard Medical School, Boston, Massachusetts 02115.
authors.forename: Jill S
authors.initials: JS
authors.lastname: Carmody
authors.affiliation: Obesity, Metabolism, and Nutrition Institute and Gastrointestinal Unit (J.S.C., N.N.A., S.M., S.L., L.M.K.), Massachusetts General Hospital, Boston, Massachusetts 02114; and Department of Medicine (J.S.C., N.N.A., S.M., L.M.K.), Harvard Medical School, Boston, Massachusetts 02115.
authors.forename: Nadia N
authors.initials: NN
authors.lastname: Ahmad
authors.affiliation: Obesity, Metabolism, and Nutrition Institute and Gastrointestinal Unit (J.S.C., N.N.A., S.M., S.L., L.M.K.), Massachusetts General Hospital, Boston, Massachusetts 02114; and Department of Medicine (J.S.C., N.N.A., S.M., L.M.K.), Harvard Medical School, Boston, Massachusetts 02115.
authors.forename: Sriram
authors.initials: S
authors.lastname: Machineni
authors.affiliation: Obesity, Metabolism, and Nutrition Institute and Gastrointestinal Unit (J.S.C., N.N.A., S.M., S.L., L.M.K.), Massachusetts General Hospital, Boston, Massachusetts 02114; and Department of Medicine (J.S.C., N.N.A., S.M., L.M.K.), Harvard Medical School, Boston, Massachusetts 02115.
authors.forename: Scott
authors.initials: S
authors.lastname: Lajoie
authors.affiliation: Obesity, Metabolism, and Nutrition Institute and Gastrointestinal Unit (J.S.C., N.N.A., S.M., S.L., L.M.K.), Massachusetts General Hospital, Boston, Massachusetts 02114; and Department of Medicine (J.S.C., N.N.A., S.M., L.M.K.), Harvard Medical School, Boston, Massachusetts 02115.
authors.forename: Lee M
authors.initials: LM
authors.lastname: Kaplan
mesh_terms: D000818:Animals; D001786:Blood Glucose; D001835:Body Weight; D005247:Feeding Behavior; D005277:Fenfluramine; D015390:Gastric Bypass; D008297:Male; D008810:Mice, Inbred C57BL; D044405:Receptor, Serotonin, 5-HT2C / Q000378:metabolism*; D058826:Serotonin 5-HT2 Receptor Agonists; D015431:Weight Loss
chemical_list: D001786:Blood Glucose; D044405:Receptor, Serotonin, 5-HT2C; D058826:Serotonin 5-HT2 Receptor Agonists; D005277:Fenfluramine