Weight-Independent Effects of Roux-en-Y Gastric Bypass on Glucose Homeostasis via Melanocortin-4 Receptors in Mice and Humans

Abstract

Background & Aims Roux-en-Y gastric bypass (RYGB) improves glucose homeostasis independently of changes in body weight by unknown mechanisms. Melanocortin-4 receptors (MC4R) have weight-independent effects on glucose homeostasis, via autonomic neurons, and might also contribute to weight loss after RYGB. We investigated whether MC4Rs mediate effects of RYGB, such as its weight-independent effects on glucose homeostasis, in mice and humans. Methods We studied C57BL/6 mice with diet-induced obesity, MC4R-deficient mice, and mice that re-express MC4R specifically in autonomic neurons after RYGB or Sham operations. We also sequenced the MC4R locus in patients undergoing RYGB, to investigate diabetes resolution in carriers of rare MC4R variants. Results MC4Rs in autonomic brainstem neurons (including the parasympathetic dorsal motor vagus) mediated improved glucose homeostasis independent of changes in body weight. In contrast, MC4Rs in cholinergic preganglionic motor neurons (sympathetic and parasympathetic) mediated RYGB-induced increased energy expenditure and weight loss. Increased energy expenditure after RYGB is the predominant mechanism of weight loss and confers resistance to weight gain from a high-fat diet, effects of which are MC4R-dependent. MC4R-dependent effects of RYGB still occurred in mice with Mc4r haplosufficiency, and early-stage diabetes resolved at a similar rate in patients with rare variants of MC4R and non-carriers. However, carriers of MC4R (I251L), a rare variant associated with increased weight loss after RYGB and increased basal activity in vitro, were more likely to have early and weight-independent resolution of diabetes than non-carriers, indicating a role for MC4Rs in the effects of RYGB. Conclusions MC4Rs in autonomic neurons mediate beneficial effects of RYGB, including weight-independent improved glucose homeostasis, in mice and humans.

Roux-en-Y gastric bypass: effects on feeding behavior and underlying mechanisms

“…Interestingly, a study employing intracerebroventricular administration of a specific MC4R antagonist in RYGBP and sham-operated rats demonstrated that while central MC4R blockade led to doubling of food intake and weight regain, the reduction in meal size produced by RYGBP was unaffected (123). Restoration of MC4R in key preganglionic autonomic motor neurons of Mc4r-null mice demonstrated that MC4R expression in these neurons was important for RYGBP-induced reductions in food intake, but the effect was greater for RYGBP effects on energy expenditure (124). While these studies highlight the critical role of the melanocortin pathway in regulation of energy intake, they establish that central melanocortin signaling is not the critical mechanism responsible for the anorectic effects of RYGBP, in particular, the RYGBP-induced reduction in meal size, which is clearly central to the feeding changes observed in humans after RYGBP (41).…”

The physiology underlying Roux-en-Y gastric bypass: a status report

“…Most of the recent animal studies and some studies in humans have examined the role of the melanocortin system, which seems to be central to many peripheral and brain-derived stimuli that control eating and body weight (55,92,93,157). In humans, the sufficiency of one functional MC4r gene for effective RYGB outcome was indicated in some studies, including RYGB or VSG-operated humans (157).…”

“…Most of the recent animal studies and some studies in humans have examined the role of the melanocortin system, which seems to be central to many peripheral and brain-derived stimuli that control eating and body weight (55,92,93,157). In humans, the sufficiency of one functional MC4r gene for effective RYGB outcome was indicated in some studies, including RYGB or VSG-operated humans (157). However, the important role of the melanocortin system was supported by findings in humans with a specific variant of the MC4 gene [MC4r(I251L)], which is associated with a better metabolic status; in fact, carriers of this variant had improved surgery outcome (92,157).…”

“…In humans, the sufficiency of one functional MC4r gene for effective RYGB outcome was indicated in some studies, including RYGB or VSG-operated humans (157). However, the important role of the melanocortin system was supported by findings in humans with a specific variant of the MC4 gene [MC4r(I251L)], which is associated with a better metabolic status; in fact, carriers of this variant had improved surgery outcome (92,157).…”

Does gastric bypass surgery change body weight set point?

“…79 However, because all these vagal lesions did not differentiate between afferents and efferents, the conclusions are limited and await more selective vagal manipulations such as targeted genetic deletions in mouse models of RYGB. 37,80 CONCLUSIONS Studies using forced over-or under-feeding paradigms in rodents clearly demonstrate defense of a new body weight set point after RYGB and sleeve gastrectomy, but the underlying mechanisms have not yet been fully revealed. Specifically, it is not clear what signals are generated in the re-arranged gut, how they reach the brain, and where exactly in the brain they act to evade a state of hunger and hypo-metabolism that is typically encountered with dieting-induced weight loss.…”