Secreted proteins are important metabolic regulators that function in healthy and disease states. Our objective was to identify those secreted proteins that are important regulators of pancreatic islet function in obesity. To facilitate this, we used Weighted Gene Co-Expression Network Analysis-based approach on the expression data that was obtained from the pancreatic islets of lean and obese mice to identify gene modules that enriched with obesity. Subsequently, filtering the data for transcripts expressing secreted protein based on the intramodular connectivity, module membership, and differential expression identified complement-1q-like-3 (C1ql3) secreted protein as a top candidate to affect islet function. Co-expression network, hierarchal clustering, and gene-ontology based approaches identified C1ql3 to affect ‘secretory processes’ in islets. Biological validation showed that C1ql3 is expressed in human and mouse islets, and inhibits insulin secretion from pancreatic β-cells. Its expression in islets is increased by >32-fold with obesity. Moreover, C1ql3 in the islet β-cells specifically reduced the expression of genes that are critical for regulating insulin secretion. These findings demonstrate a streamlined approach to screen for the putative novel secreted protein regulators that function in an autocrine/paracrine manner to affect islet function in obesity. Herein, we have identified a critical role of C1ql3 in β-cells and propose that the increased secretion of C1ql3 from islets during obesity contributes to the reduced β-cell function in a paracrine/autocrine-dependent pathway to increase the susceptibility to type 2 diabetes.
J. Koltes: None. I. Arora: None. R. Gupta: None. D.C. Nguyen: None. S. Bhatnagar: None.
American Diabetes Association (1-18-PDF-103 to R.G.)