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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

Aims/hypothesis

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/interpretation

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.

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Abbreviations

HGP:

Hepatic glucose production

IR:

Insulin receptor

IRkd:

Insulin receptor knockdown

RYGB:

Roux-en-Y gastric bypass

VMH:

Ventromedial hypothalamus

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Funding

This work was supported by National Institutes of Health grants DK 20495 and P30 DK 45735 (R. S. Sherwin) and DK080899 (A. Hajnal) as well as a pilot grant from the Diabetes Endocrinology Research Center (S. A. Paranjape).

Duality of interest

The authors declare that there is no duality of interest associated with this manuscript.

Contribution statement

SAP and OC were involved in the conception and design of the study, acquisition of data, or analysis and interpretation of data, drafting of the article and final approval of the version to be published. AH, AMR and RSS were involved in the conception and design of the study, analysis and interpretation of data, drafting and revision of the article, and final approval of the version to be published. NKA and WZ were involved in the acquisition of data, drafting of the article and final approval of the version to be published.

Author information

Correspondence to S. A. Paranjape.

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Paranjape, S.A., Chan, O., Zhu, W. et al. Improvement in hepatic insulin sensitivity after Roux-en-Y gastric bypass in a rat model of obesity is partially mediated via hypothalamic insulin action. Diabetologia 56, 2055–2058 (2013). https://doi.org/10.1007/s00125-013-2952-7

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Keywords

  • Gastric bypass surgery
  • Hypothalamus
  • Insulin