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

Risheng Ye, Ruth Gordillo, Mengle Shao, Toshiharu Onodera, Zhe Chen, Shiuhwei Chen, Xiaoli Lin, Jeffrey A. SoRelle, Xiaohong Li, Miao Tang, Mark P. Keller, Regina Kuliawat, Alan D. Attie, Rana K Gupta, William L Holland, Bruce A Beutler, Joachim Herz, Philipp E Scherer

Research output: Contribution to journalArticle

13 Scopus citations

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 glucoseinduced, 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.

Original languageEnglish (US)
Pages (from-to)1178-1189
Number of pages12
JournalJournal of Clinical Investigation
Volume128
Issue number3
DOIs
StatePublished - Mar 1 2018

ASJC Scopus subject areas

  • Medicine(all)

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    Ye, R., Gordillo, R., Shao, M., Onodera, T., Chen, Z., Chen, S., Lin, X., SoRelle, J. A., Li, X., Tang, M., Keller, M. P., Kuliawat, R., Attie, A. D., Gupta, R. K., Holland, W. L., Beutler, B. A., Herz, J., & Scherer, P. E. (2018). Intracellular lipid metabolism impairs β cell compensation during diet-induced obesity. Journal of Clinical Investigation, 128(3), 1178-1189. https://doi.org/10.1172/JCI97702