Abstract
Secreted proteins are important metabolic regulators. Identifying and characterizing the role of secreted proteins from small tissue depots such as islets of Langerhans, which are required for the proper control of whole-body energy metabolism, remains challenging. Our objective was to identify islet-derived secreted proteins that affect islet function in obesity. Lean and obese mouse islet expression data were analyzed by weighted gene co-expression network analysis (WGCNA) to identify trait-associated modules. Subsequently, genes within these modules were filtered for transcripts that encode for secreted proteins based on intramodular connectivity, module membership, and differential expression. Complement 1q like-3 (C1ql3) secreted protein was identified as a hub gene affecting islet function in obesity. Co-expression network, hierarchal clustering, and gene-ontology based approaches identified a putative role for C1ql3 in regulating β-cell insulin secretion. Biological validation shows that C1ql3 is expressed in β-cells, it inhibits insulin secretion and key genes that are involved in β-cell function. Moreover, the increased expression of C1ql3 is correlated with the reduced insulin secretion in islets of obese mice. Herein, we demonstrate a streamlined approach to effectively screen and determine the function of secreted proteins in islets, and identified C1ql3 as a putative contributor to reduced insulin secretion in obesity, linking C1ql3 to an increased susceptibility to type 2 diabetes.
Highlights
Secreted proteins reflect the dynamic changes that occur in tissues and serve as within- and across-tissue metabolic regulators[1]
Co-expression network analysis along with data filtering approaches of gene expression data obtained from islets of lean and obese mice identified C1ql[3] as a hub gene affecting islet function in obesity
Functional validation shows C1ql[3] is expressed in β-cells and it inhibits insulin secretion and the mRNA abundance of genes that are important in regulating pancreatic β-cell function
Summary
Secreted proteins reflect the dynamic changes that occur in tissues and serve as within- and across-tissue metabolic regulators[1]. The expression of secreted proteins can be affected by a wide array of stimuli, including development, maturation, environmental, physiological, and pathological states. Upon secretion, these proteins relay the metabolic status of their tissue of origin via endocrine, paracrine, or autocrine signaling to impart a regulatory effect on their target tissue. Increased metabolic stress due to obesity and its commonly-associated inflammation and peripheral insulin resistance causes islet cells to functionally adapt by altering their hormone secretion to maintain blood glucose levels[13,14,15]. Identifying signaling pathways within islets that control the adaptation of the islet cells in response to obesity will provide insights into the mechanisms underlying T2D
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
