Melanocortin-4 receptor signaling is required for weight loss after gastric bypass surgery

Abstract

Context: Roux-en-Y gastric bypass (RYGB) is one of the most effective long-term therapies for the treatment of severe obesity. Recent evidence indicates that RYGB effects weight loss through multiple physiological mechanisms, including changes in energy expenditure, food intake, food preference, and reward pathways.

Objective: Because central melanocortin signaling plays an important role in the regulation of energy homeostasis, we investigated whether genetic disruption of the melanocortin-4 receptor (MC4R) in rodents and humans affects weight loss after RYGB.

Methods and results: Here we report that MC4R(-/-) mice lost substantially less weight after surgery than wild-type animals, indicating that MC4R signaling is necessary for the weight loss effects of RYGB in this model. Mice heterozygous for MC4R remain fully responsive to gastric bypass. To determine whether mutations affect surgically induced weight loss in humans, we sequenced the MC4R gene in 972 patients undergoing RYGB. Patients heterozygous for MC4R mutations exhibited the same magnitude and distribution of postoperative weight loss as patients without such mutations, suggesting that although two normal copies of the MC4R gene are necessary for normal weight regulation, a single normal copy of the MC4R gene is sufficient to mediate the weight loss effects of RYGB.

Conclusions: MC4R is the first gene identified that is required for the sustained effects of bariatric surgery. The need for MC4R signaling for the weight loss effects of RYGB in mice underscores the physiological mechanisms of action of this procedure and demonstrates that RYGB both influences and is dependent on the normal pathways that regulate energy balance.

Fig. 1.

Body weight change over time in WT, MC4R^+/− heterozygous (Het), and MC4R^−/− null (KO) mice before and after gastric bypass surgery. A, Body weight (grams) of WT mice on a C57BL/6J background after RYGB-H (dashed green line and open green circles; n = 5) or SO (solid green line and circles; n = 5). B, MC4R^−/− mice on a 129 background after RYGB-H (dashed blue line and open blue circles; n = 3) or SO (solid blue line and circles; n = 3). C, MC4R^−/− mice on a 129/C57BL6 mixed background after RYGB (dashed blue line and open blue circles; n = 3) or SO (solid blue line and circles; n = 3). D, WT (green), Het (red), and MC4R^−/− (blue) mice on a C57BL/6J background after RYGB-C (dashed lines and open circles; n = 3, n = 4, and n = 7, respectively) or SO (solid lines and circles; n = 3, n = 6, and n = 3, respectively). E, Change in body weight (grams) from postoperative wk 4 to postoperative wk 8 in RYGB-C and SO mice. F, Body weight (grams) 8 wk after surgery in WT (left), Het (center), and MC4R^−/− (right) mice on a C57BL/6J background. Dark gray bars indicate muscle mass. White bars indicate fat mass. G, Body weight (grams) growth curves of untouched WT, Het, and MC4R^−/− mice. Error bars, sem.

Fig. 1.

Body weight change over time in WT, MC4R^+/− heterozygous (Het), and MC4R^−/− null (KO) mice before and after gastric bypass surgery. A, Body weight (grams) of WT mice on a C57BL/6J background after RYGB-H (dashed green line and open green circles; n = 5) or SO (solid green line and circles; n = 5). B, MC4R^−/− mice on a 129 background after RYGB-H (dashed blue line and open blue circles; n = 3) or SO (solid blue line and circles; n = 3). C, MC4R^−/− mice on a 129/C57BL6 mixed background after RYGB (dashed blue line and open blue circles; n = 3) or SO (solid blue line and circles; n = 3). D, WT (green), Het (red), and MC4R^−/− (blue) mice on a C57BL/6J background after RYGB-C (dashed lines and open circles; n = 3, n = 4, and n = 7, respectively) or SO (solid lines and circles; n = 3, n = 6, and n = 3, respectively). E, Change in body weight (grams) from postoperative wk 4 to postoperative wk 8 in RYGB-C and SO mice. F, Body weight (grams) 8 wk after surgery in WT (left), Het (center), and MC4R^−/− (right) mice on a C57BL/6J background. Dark gray bars indicate muscle mass. White bars indicate fat mass. G, Body weight (grams) growth curves of untouched WT, Het, and MC4R^−/− mice. Error bars, sem.

Fig. 2.

Structure of the MC4R protein and location of mutations present in a cohort of 970 men and women undergoing RYGB. Positions of the mutations identified in this cohort are indicated in purple. Mutations shown to be pathogenic are shaded orange; nonpathogenic mutations are shaded blue.

Fig. 3.

Weight loss after RYGB among 847 men and women who underwent RYGB by type of heterozygous MC4R mutation. A, Distribution of percent excess weight loss after RYGB in patients with no mutations (upper panel), heterozygous nonpathogenic mutations (middle panel), or heterozygous pathogenic mutations (bottom panel). B, Weight loss curves over time in patients with no mutations (solid black line), nonpathogenic mutations (dashed black line), or pathogenic mutations (solid gray line) %EBWL, Percent excess body weight loss.