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: Jill S Carmody, Nadia N Ahmad, Sriram Machineni, Scott Lajoie, Lee M Kaplan
• Journal: Endocrinology (Endocrinology) Vol. 156 Issue 9 Pg. 3183-91 (Sep 2015) ISSN: 1945-7170 [Electronic] United States
• PMID: 26066076 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Blood Glucose
• Receptor, Serotonin, 5-HT2C
• Serotonin 5-HT2 Receptor Agonists
• Fenfluramine

Topics

• Animals
• Blood Glucose
• Body Weight
• Feeding Behavior
• Fenfluramine
• Gastric Bypass
• Male
• Mice, Inbred C57BL
• Receptor, Serotonin, 5-HT2C (metabolism)
• Serotonin 5-HT2 Receptor Agonists
• Weight Loss