title: Improvement in hepatic insulin sensitivity after Roux-en-Y gastric bypass in a rat model of obesity is partially mediated via hypothalamic insulin action.
abstract: OBJECTIVE
  Roux-en-Y gastric bypass (RYGB) surgery, an effective treatment for morbid obesity, commonly leads to near complete resolution of type 2 diabetes. The underlying mechanisms, however, remain unclear and factors other than weight loss alone may be involved.
  
  
  METHODS
  To determine whether increased hypothalamic insulin sensitivity after RYGB drives the rapid improvement in glucose metabolism, high-fat-fed rats received either an insulin receptor (IR) antisense vector or a control lentiviral vector that was microinjected into the ventromedial hypothalamus (VMH). Six weeks later, rats underwent RYGB or control gastrointestinal surgery.
  
  
  RESULTS
  Four weeks after surgery, weight loss was comparable in RYGB and surgical controls. Nevertheless, only RYGB rats that received the control vector demonstrated both improved hepatic and peripheral insulin sensitivity. Insulin suppressed hepatic glucose production (HGP) by 50% (p < 0.05) with RYGB, whereas the effect of insulin on HGP was completely absent in VMH IR knockdown (IRkd) rats. By contrast, both RYGB groups displayed an identical twofold increase in insulin-stimulated peripheral glucose uptake. The animals that underwent control gastrointestinal surgery failed to show any improvement in either hepatic or peripheral insulin sensitivity; VMH IRkd did not influence the magnitude of insulin resistance.
  
  
  CONCLUSIONS
  Our findings demonstrate that RYGB surgery in high-fat-fed obese rats enhances hepatic and peripheral insulin sensitivity independently of weight loss. The improved hepatic, but not the peripheral, response to insulin is mediated centrally at the level of the VMH. These data provide direct evidence that the metabolic benefits of RYGB surgery are not simply a consequence of weight loss but likely in part involve the central nervous system.
authors.affiliation: Department of Internal Medicine, Yale School of Medicine, New Haven, CT 06520, USA. sachinparanjape379@yahoo.com
authors.forename: S A
authors.initials: SA
authors.lastname: Paranjape
authors.forename: O
authors.initials: O
authors.lastname: Chan
authors.forename: W
authors.initials: W
authors.lastname: Zhu
authors.forename: N K
authors.initials: NK
authors.lastname: Acharya
authors.forename: A M
authors.initials: AM
authors.lastname: Rogers
authors.forename: A
authors.initials: A
authors.lastname: Hajnal
authors.forename: R S
authors.initials: RS
authors.lastname: Sherwin
mesh_terms: D000818:Animals; D015390:Gastric Bypass; D007031:Hypothalamus / Q000378:metabolism*; D015151:Immunoblotting; D007328:Insulin / Q000378:metabolism*; D008099:Liver / Q000378:metabolism*; D008297:Male; D009765:Obesity / Q000378:metabolism* / Q000601:surgery*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D007328:Insulin