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

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.

• Authors: 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 Beutler, Joachim Herz, Philipp E Scherer
• Journal: The Journal of clinical investigation (J Clin Invest) Vol. 128 Issue 3 Pg. 1178-1189 (03 01 2018) ISSN: 1558-8238 [Electronic] United States
• PMID: 29457786 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Blood Glucose
• Insulin
• Low Density Lipoprotein Receptor-Related Protein-1
• Lrp1 protein, mouse
• PPAR gamma
• Receptors, LDL
• Sphingolipids
• Tumor Suppressor Proteins
• Glucose

Topics

• 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, metabolism)
• Insulin-Secreting Cells (metabolism)
• Lipid Metabolism
• Low Density Lipoprotein Receptor-Related Protein-1
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Obesity (metabolism)
• PPAR gamma (metabolism)
• Receptors, LDL (metabolism)
• Sphingolipids (metabolism)
• Transcription, Genetic
• Tumor Suppressor Proteins (metabolism)