title: Weight-independent effects of roux-en-Y gastric bypass on glucose homeostasis via melanocortin-4 receptors in mice and humans.
abstract: OBJECTIVE
  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.
  
  
  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 surgeries. 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, 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.
  
  
  CONCLUSIONS
  MC4Rs in autonomic neurons mediate beneficial effects of RYGB, including weight-independent improved glucose homeostasis, in mice and humans.
authors.affiliation: Center for Hypothalamic Research, Department of Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: Juliet F
authors.initials: JF
authors.lastname: Zechner
authors.forename: Uyenlinh L
authors.initials: UL
authors.lastname: Mirshahi
authors.forename: Santhosh
authors.initials: S
authors.lastname: Satapati
authors.forename: Eric D
authors.initials: ED
authors.lastname: Berglund
authors.forename: Jari
authors.initials: J
authors.lastname: Rossi
authors.forename: Michael M
authors.initials: MM
authors.lastname: Scott
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Still
authors.forename: Glenn S
authors.initials: GS
authors.lastname: Gerhard
authors.forename: Shawn C
authors.initials: SC
authors.lastname: Burgess
authors.forename: Tooraj
authors.initials: T
authors.lastname: Mirshahi
authors.forename: Vincent
authors.initials: V
authors.lastname: Aguirre
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism*; D059329:Cholinergic Neurons / Q000378:metabolism; D059305:Diet, High-Fat / Q000009:adverse effects; D004734:Energy Metabolism; D015390:Gastric Bypass; D006579:Heterozygote; D006706:Homeostasis; D006801:Humans; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009046:Motor Neurons / Q000378:metabolism*; D044105:Receptor, Melanocortin, Type 4 / Q000235:genetics / Q000378:metabolism*; D014630:Vagus Nerve / Q000378:metabolism*; D015431:Weight Loss
chemical_list: D001786:Blood Glucose; D044105:Receptor, Melanocortin, Type 4