Defining theDefining the Role of Diabetes-associated Transcription Factor Glis3 in Macrophage Activation and Atherogenes

Project: Research


  • Yisheng Yang (PI)


Individuals with diabetes have a high risk of developing atherosclerosis and vascular complications, the underlying mechanisms are poorly understood. A chronic, low-grade inflammation is a key pathogenic factor providing the environment that supports the development of these metabolic disorders. Accumulating evidence highlights the contrasting roles of two subsets of macrophages termed proinflammatory (classical, M1) and anti-inflammatory (alternative, M2) in the development of chronic inflammation. It is widely accepted that macrophages play central roles in each stage of atherogenesis. Recent genome-wide association studies (GWAS) in adult populations identified the Krppel-like transcription factor GLIS family zinc finger 3 (GLIS3) as a candidate gene for type 1 diabetes , and as a gene associated with type 2 diabetes (T2DM) . We have determined the crucial functions of Glis3 in controlling fetal islet differentiation and mature beta cell function as well as beta cell mass maintenance . Unexpectedly, we recently found that Glis3+/− mice develop accelerated diabetes upon high fat diet (HFD) feeding with impaired insulin sensitivity. Furthermore we observed that myeloid-specific, but not liver-specific or adipocyte-specific, Glis3 deficient mice phenocopied the Glis3+/− mice in terms of insulin resistance, with elevated plasma inflammatory cytokines, such as interleukin-6 (IL-6) and IL-1beta. The mRNA expression of suppressor of cytokine signaling (Socs)1 and Socs3 is upregulated by Glis3 forced overexpression in macrophages. Based on these novel findings, we hypothesize that Glis3 is indispensable for maintaining normal macrophage function by regulating Socs family genes, whose impairment leads to classical macrophage activation and insulin resistance that underlies subsequent pathophysiologicial events including diabetes and atherogenesis. We propose the following aims to test this hypothesis. Aim 1: To determine the molecular mechanisms whereby Glis3 regulates macrophage function and hepatic insulin sensitivity. Aim 2: To analyze the roles and mechanisms of Glis3 in the development of atherogenesis.
Award amount$308,000.00
Award date07/01/2013
Program typeScientist Development Grant
Award ID13SDG17090096
Effective start/end date07/01/201306/30/2017