High-fat diet-induced autophagy protects against endoplasmic reticulum stress and death but suppresses insulin secretion in pancreatic beta-cells — ASN Events

High-fat diet-induced autophagy protects against endoplasmic reticulum stress and death but suppresses insulin secretion in pancreatic beta-cells (#104)

Kwan Yi (Connie) Chu 1 , Trevor Biden 1
  1. Garvan Institute of Medical Research, Darlinghurst, NSW, Australia

There is increasing evidence that disruption of basic cell-biological processes contributes to beta-cell failure in Type 2 diabetes. One such process, autophagy, is an important cellular survival mechanism. Our aim here was to address whether high-fat feeding suppresses or enhances autophagy in beta-cells, and define how autophagy impacts on beta cell function in this context.

To assess autophagic flux, GFP-LC3 mice were fed with chow/high-fat diets for 8 weeks and then injected with chloroquine. GFP-LC3 puncta (an autophagy marker) were assessed by fluorescence microscopy of pancreatic sections. Alternatively, autophagic, endoplasmic reticulum (ER) stress and apoptotic markers were detected by western blot following 2h chloroquine treatment of islets from chow/high-fat fed mice. For studying autophagy-deficiency, wildtype or Atg7-knockout mice were employed using tamoxifen to induce deletion of this key autophagy regulator specifically in beta-cells. After 3 weeks, oral glucose tolerance tests were performed; and islets were isolated for assessment of glucose-stimulated insulin secretion.

Autophagic flux was increased in beta-cells after high-fat feeding and chloroquine injection. LC3 levels in isolated mouse islets were also increased by high-fat diet and further enhanced by chloroquine incubation ex vivo. ER stress (CHOP and phospho-eIf2α levels) in isolated islets was not augmented by high-fat feeding, but was induced by chloroquine and further enhanced by the combined condition. Apoptotic markers were also increased by the combined condition. This reveals a reciprocal relationship between ER stress/apoptosis and autophagy in beta-cells. In contrast, high-fat fed autophagy-deficient mice showed improved glucose tolerance and increased plasma insulin versus wildtype littermates. Islets from Atg7 null mice on the high-fat diet also displayed enhanced insulin secretion ex vivo compared to wildtypes.

Autophagy in beta-cells serves dual and opposing roles during high-fat feeding. It protects against apoptosis and ER stress, but this comes at the expense of an inhibition of glucose-stimulated insulin secretion.