Molecular Mechanisms of Roux-en-Y Gastric Bypass

Many of the beneficial effects of Roux-en-Y gastric bypass (RYGB), including improved glucose homeostasis, require the actions of melanocortin-4 receptors (MC4Rs) on autonomic neurons, according to the March issue of Gastroenterology.

Fasting glycemia often improves within days of RYGB (see below figure), which produces greater improvements in glucose homeostasis than weight loss from calorie restriction or other restrictive bariatric procedures.

The digestive pathway following RYGB.

The digestive pathway following RYGB.

One mechanism by which RYGB causes resolution of diabetes appears to involve MC4Rs, which are important regulators of body weight—people and mice with genetic alterations that affect the function of these receptors can become severely obese.

MC4Rs function in the hypothalamus and hindbrain to reduce food intake and increase energy expenditure in response to hormonal and other signals. MC4Rs are also present on autonomic neurons, including cholinergic preganglionic motor neurons (sympathetic and parasympathetic) and parasympathetic vagal sensory neurons. They therefore make important connections between the central nervous system and autonomic outputs to the abdominal viscera and brown adipose tissue.

Juliet Zechner et al. investigated the contribution of MC4Rs to effects of RYGB in mice with diet-induced obesity and in obese patients.

In obese mice, RYGB reduced body weight by 27% compared with sham surgeries; fat mass was reduced by 65% and lean mass was reduced by 11%. The authors observed that RYGB did not reduce food intake or increase physical activity—instead, it increased energy expenditure to cause weight loss. A daily calorie restriction of 27% was required to match the body weights of a separate group of sham-operated mice to the mice that underwent RYGB.

RYBG also reduced hyperglycemia and hyperinsulinemia in the obese mice, increased glucose tolerance, and improved insulin sensitivity.

However, in MC4R-null obese mice, RYGB reduced body weight by only 10%, because it failed to increase energy expenditure; nor was RYGB fat mass reduced to the same extent in the MC4R-null mice, compared with controls. MC4R was also required for improved glucose homeostasis following RYGB.

MC4R mutations have been detected in 1%–6% of severely obese people. Interestingly, carriers of these variants lost equivalent amounts of weight as noncarriers after RYGB.

However, 89% of patients with a specific gene variant,  MC4R(I251L), no longer required diabetes medications by 2 weeks after RYGB, compared with 50% of patients with the rare, obesity-associated variants in MC4R, and 66% patients without these gene variants. The authors conclude that RYGB confers weight-independent early diabetes remission in all subjects, and that carriers of MC4R(I251L) have the highest rate of resolution.

How does MC4R control energy expenditure and glucose homeostasis? Zechner et al. identified a neuronal mechanism whereby the effects of RYGB on glucose homeostasis diverged from its effects on energy expenditure and body weight.

They found that MC4Rs in autonomic brainstem neurons (including the parasympathetic dorsal motor vagus) mediate the improvements in glucose homeostasis following RYGB, independently of changes in body weight. In contrast, MC4Rs in cholinergic preganglionic motor neurons (sympathetic and parasympathetic) mediate the ability of RYGB to increase energy expenditure.

The authors propose that these observations could account for the early, weight-independent effects of RYGB on diabetes in humans.

In an editorial that accompanies the article, Andrew Butler and Robert O’Rourke say that these findings are an important step in identifying genetic factors that affect outcomes after bariatric surgery.

Read the article online.
Zechner ZF, Mirshahi UL, Satapati S, et al. Weight-independent effects of roux-en-Y gastric bypass on glucose homeostasis via melanocortin-4 receptors in mice and humans. Gastroenterology 2013;144:580-590.e7.

Read the accompanying editorial.
Butler AA, O’Rourke RW. Bariatric surgery in the era of personalized medicine. Gastroenterology 2013;144:497-500.

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About Kristine Novak, PhD, Science Editor

Dr. Kristine Novak is the science editor for Gastroenterology and Clinical Gastroenterology and Hepatology, both published by the American Gastroenterological Association. She has worked as an editor at biomedical research journals and as a science writer for more than 12 years, covering advances in gastroenterology, hepatology, cancer, immunology, biotechnology, molecular genetics, and clinical trials. She has a PhD in cell biology and an interest in all areas of medical research.
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