Weight Cycling Impairs Pancreatic Insulin Secretion but Does Not Perturb Whole-Body Insulin Action in Mice With Diet-Induced Obesity

Author:

Winn Nathan C.1ORCID,Cottam Matthew A.1,Bhanot Monica1,Caslin Heather L.1,Garcia Jamie N.1,Arrojo e Drigo Rafael1ORCID,Hasty Alyssa H.12ORCID

Affiliation:

1. 1Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN

2. 2VA Tennessee Valley Healthcare System, Nashville, TN

Abstract

In the setting of obesity and insulin resistance, glycemia is controlled in part by β-cell compensation and subsequent hyperinsulinemia. Weight loss improves glycemia and decreases hyperinsulinemia, whereas weight cycling worsens glycemic control. The mechanisms responsible for weight cycling–induced deterioration in glucose homeostasis are poorly understood. Thus, we aimed to pinpoint the main regulatory junctions at which weight cycling alters glucose homeostasis in mice. Using in vivo and ex vivo procedures we show that despite having worsened glucose tolerance, weight-cycled mice do not manifest impaired whole-body insulin action. Instead, weight cycling reduces insulin secretory capacity in vivo during clamped hyperglycemia and ex vivo in perifused islets. Islets from weight-cycled mice have reduced expression of factors essential for β-cell function (Mafa, Pdx1, Nkx6.1, Ucn3) and lower islet insulin content, compared with those from obese mice, suggesting inadequate transcriptional and posttranscriptional response to repeated nutrient overload. Collectively, these data support a model in which pancreatic plasticity is challenged in the face of large fluctuations in body weight resulting in a mismatch between glycemia and insulin secretion in mice.

Funder

National Cancer Institute

American Heart Association

National Institute of Diabetes and Digestive and Kidney Diseases

U.S. Department of Veterans Affairs

Publisher

American Diabetes Association

Subject

Endocrinology, Diabetes and Metabolism,Internal Medicine

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