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.

Figure 1.

RYGB weight loss is independent of 5-HT2CR signaling. Body weight (A) and percentage change in body weight (B) in diet-induced obese male mice after RYGB or sham operations. Average daily food intake (C) measured during postoperative weeks 6–8. Body weight was measured at postoperative week 13 (D). Fat mass (E) and lean mass (F) were measured by Bruker Minispec at postoperative week 13 (n = 4–6 per group). *, P < .05; **, P < .01; ***, P < .001. Values represent the mean ± SEM.

Figure 2.

RYGB improves glucose regulation independent of 5-HT2CR signaling. Fasted glucose (A), fed glucose (B), fasted insulin (C), fed insulin concentrations (D), and HOMA-IR (E) measures in diet-induced obese WT and 5-HT2CR-deficient mice 10–11 weeks after RYGB or sham operations (n = 4–6 per group). *, P < .05; **, P < .01; ***, P < .001. Values represent the mean ± SEM.

Figure 3.

RYGB improves glucose tolerance independent of 5-HT2CR signaling. Oral glucose tolerance test (1g/kg BW glucose) (A) and area under the curve calculations (B) in diet-induced obese WT and 5-HT2CR-deficient mice 9 weeks after RYGB or sham operations. Glucose-stimulated insulin secretion after an oral gavage of (1g/kg BW) glucose (C) and area under the curve calculations (D) 11 weeks after RYGB or sham operations (n = 4–6 per group). *, P < .05; **, P < .01. Values represent the mean ± SEM.

Figure 4.

The nonspecific serotonergic agent fenfluramine selectively decreases body weight after RYGB. Body weight change (A and B) and placebo-subtracted percentage body weight change (C and D) in sham and RYGB mice over 3 weeks of daily ip treatment with fenfluramine (10 mg/kg), topiramate (40 mg/kg), or saline (5 μL/g BW) (n = 4–6 per group). *, P < .05 with repeated-measures, two-way ANOVA. Values represent the mean ± SEM. WL, weight loss.

Figure 5.

Topiramate and fenfluramine decrease food intake in sham mice. Cumulative food intake during 3 weeks of treatment with ip fenfluramine (10 mg/kg), topiramate (40 mg/kg), or saline in sham-operated (A) and RYGB-operated (B) mice. *, P < .05 with unpaired Student's t test. Values represent the mean ± SEM.

Figure 6.

Short-term treatment with the 5-HT2CR agonist mCPP decreased body weight and food intake after RYGB. Percentage body weight change (A) and cumulative food intake (B) in sham and RYGB mice during infusion of mCPP (36 mg/kg · d) or saline via a sc osmotic pump (n = 4 per group). *, P < .05. Values represent the mean ± SEM.