Agonist-independent Gαz activity negatively regulates beta-cell compensation in a diet-induced obesity model of type 2 diabetes

Michael D Schaid,Cara L Green,Darby C Peter,Shannon J Gallagher,Erin Guthery,Kathryn A Carbajal,Jeffrey M Harrington,Grant M Kelly,Austin Reuter,Molly L Wehner,Allison L Brill,Joshua C Neuman,Dudley W Lamming,Michelle E Kimple

doi:10.1074/jbc.ra120.015585

Michael D Schaid, Cara L Green + Show 12 more

Open Access

https://doi.org/10.1074/jbc.ra120.015585

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Abstract

The inhibitory G protein alpha-subunit (Gαz) is an important modulator of beta-cell function. Full-body Gαz-null mice are protected from hyperglycemia and glucose intolerance after long-term high-fat diet (HFD) feeding. In this study, at a time point in the feeding regimen where WT mice are only mildly glucose intolerant, transcriptomics analyses reveal islets from HFD-fed Gαz KO mice have a dramatically altered gene expression pattern as compared with WT HFD-fed mice, with entire gene pathways not only being more strongly upregulated or downregulated versus control-diet fed groups but actually reversed in direction. Genes involved in the “pancreatic secretion” pathway are the most strongly differentially regulated: a finding that correlates with enhanced islet insulin secretion and decreased glucagon secretion at the study end. The protection of Gαz-null mice from HFD-induced diabetes is beta-cell autonomous, as beta cell–specific Gαz-null mice phenocopy the full-body KOs. The glucose-stimulated and incretin-potentiated insulin secretion response of islets from HFD-fed beta cell–specific Gαz-null mice is significantly improved as compared with islets from HFD-fed WT controls, which, along with no impact of Gαz loss or HFD feeding on beta-cell proliferation or surrogates of beta-cell mass, supports a secretion-specific mechanism. Gαz is coupled to the prostaglandin EP3 receptor in pancreatic beta cells. We confirm the EP3γ splice variant has both constitutive and agonist-sensitive activity to inhibit cAMP production and downstream beta-cell function, with both activities being dependent on the presence of beta-cell Gαz.

Highlights

A crucial factor in the development of type 2 diabetes (T2D) is failure of beta cells to adapt their secretory phenotype and/ or mount a compensatory increase in mass in the face of peripheral insulin resistance [1]
We have previously shown that male B6N mice deficient in a protein-coding exon of Gnaz, the gene encoding for G protein alpha-subunit (Gαz), are fully protected from hyperglycemia and glucose intolerance, even after up to 26 to 30 weeks of consuming a 45 kcal% fat diet (HFD) starting at 11 weeks of age [8]
After 16 weeks of control diet (CD) or high-fat diet (HFD) feeding, both HFD-fed groups were significantly heavier than CD-fed groups, and there were no differences in the body weight by genotype (Fig. 1C)

Summary

Introduction

A crucial factor in the development of type 2 diabetes (T2D) is failure of beta cells to adapt their secretory phenotype and/ or mount a compensatory increase in mass in the face of peripheral insulin resistance [1]. The resistance of Gαz KO mice to HFD-induced glucose intolerance appears due to enhanced insulin secretory capacity and not a primary effect of Gαz loss on beta-cell replication.

Results

Conclusion