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Publication
Weight-independent effects of roux-en-Y gastric bypass on glucose homeostasis
via melanocortin-4 receptors in mice and humans.
Authors Zechner JF, Mirshahi UL, Satapati S, Berglund ED, Rossi J, Scott MM, Still CD,
Gerhard GS, Burgess SC, Mirshahi T, Aguirre V
Submitted By Submitted Externally on 8/18/2017
Status Published
Journal Gastroenterology
Year 2013
Date Published 3/1/2013
Volume : Pages 144 : 580 - 590.e7
PubMed Reference 23159449
Abstract 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 also might 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., 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 surgeries. We also sequenced the MC4R locus
in patients undergoing RYGB to investigate diabetes resolution in carriers of
rare MC4R variants., 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, the 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 noncarriers. 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 noncarriers, indicating a role
for MC4Rs in the effects of RYGB., MC4Rs in autonomic neurons mediate beneficial
effects of RYGB, including weight-independent improved glucose homeostasis, in
mice and humans.






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