Intracellular lipid metabolism impairs β cell compensation during diet-induced obesity

J Clin Invest. 2018 Mar 1;128(3):1178-1189. doi: 10.1172/JCI97702. Epub 2018 Feb 19.

Abstract

The compensatory proliferation of insulin-producing β cells is critical to maintaining glucose homeostasis at the early stage of type 2 diabetes. Failure of β cells to proliferate results in hyperglycemia and insulin dependence in patients. To understand the effect of the interplay between β cell compensation and lipid metabolism upon obesity and peripheral insulin resistance, we eliminated LDL receptor-related protein 1 (LRP1), a pleiotropic mediator of cholesterol, insulin, energy metabolism, and other cellular processes, in β cells. Upon high-fat diet exposure, LRP1 ablation significantly impaired insulin secretion and proliferation of β cells. The diminished insulin signaling was partly contributed to by the hypersensitivity to glucose-induced, Ca2+-dependent activation of Erk and the mTORC1 effector p85 S6K1. Surprisingly, in LRP1-deficient islets, lipotoxic sphingolipids were mitigated by improved lipid metabolism, mediated at least in part by the master transcriptional regulator PPARγ2. Acute overexpression of PPARγ2 in β cells impaired insulin signaling and insulin secretion. Elimination of Apbb2, a functional regulator of LRP1 cytoplasmic domain, also impaired β cell function in a similar fashion. In summary, our results uncover the double-edged effects of intracellular lipid metabolism on β cell function and viability in obesity and type 2 diabetes and highlight LRP1 as an essential regulator of these processes.

Keywords: Beta cells; Diabetes; Endocrinology; Metabolism; Obesity.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alleles
  • Animals
  • Blood Glucose / metabolism
  • Cell Proliferation
  • Crosses, Genetic
  • Cytoplasm / metabolism
  • Diet*
  • Female
  • Gene Expression Profiling
  • Gene Expression Regulation
  • Glucose / metabolism
  • Glucose Tolerance Test
  • Insulin / blood
  • Insulin / metabolism
  • Insulin-Secreting Cells / metabolism*
  • Lipid Metabolism*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Obesity / metabolism*
  • PPAR gamma / metabolism
  • Receptors, LDL / metabolism*
  • Sphingolipids / metabolism
  • Transcription, Genetic
  • Tumor Suppressor Proteins / metabolism*

Substances

  • Blood Glucose
  • Insulin
  • Lrp1 protein, mouse
  • PPAR gamma
  • Receptors, LDL
  • Sphingolipids
  • Tumor Suppressor Proteins
  • Glucose