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

IJ Hatoum, N Stylopoulos, AM Vanhoose… - The Journal of …, 2012 - academic.oup.com
IJ Hatoum, N Stylopoulos, AM Vanhoose, KL Boyd, DP Yin, KLJ Ellacott, LL Ma, K Blaszczyk…
The Journal of Clinical Endocrinology & Metabolism, 2012academic.oup.com
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 …
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.
Oxford University Press