270-OR: Adipocyte Integrin-Linked Kinase Is Necessary for the Development of Diet-Induced Adipose Insulin Resistance

Abstract

The remodeling of the extracellular matrix (ECM) in tissues including adipose tissue, and the expression of collagen binding integrin α2β1 have been associated with the development of insulin resistance. Integrin-linked Kinase (ILK), an adaptor protein and a key component of the IPP (ILK-Parvin-PINCH) complex mediates integrins linking the ECM with intracellular signalling. This study determines the role of ILK in adipose function and insulin resistance in chow and high fat (HF)-fed mice. HF feeding increased adipose ILK expression in mice (2.7 ±0.62 vs. 1±0.23; p=0.01). Adipocyte-specific deletion of ILK resulted in a decrease in fat mass (21.6±1.6% vs. 27.3±1.4%; p=0.009) and epididymal tissue weight (eWAT) (1.04±0.07g vs. 1.62±0.11g; p<0.001) in HF-fed mice, but not in chow-fed mice. During the hyperinsulinemic-euglycemic clamp, HF-fed ILK deficient mice showed increased glucose uptake (66.22±p=0.028) in the brown adipose tissue (BAT) compared with the wild type littermate controls. Increased glucose uptake in BAT is associated with increased phosphorylation of AKT (1.96±0.16 vs. 1±0.28 fold change; p=0.01), and decreased phosphorylation of p38 and JNK (0.23 ± 0.17 vs. 1±0.48; p=0.024 and 0.41 ±0.12 vs. 1±0.17; p=0.025 respectively). The inhibition of lipolysis by insulin was also improved in HF-fed ILK deficient mice determined by plasma NEFA level during the clamp. This could be attributed to decreased cell size (0.85±0.042 vs. 1±0.06; p=0.0001), decreased collagen deposition (22.8±0.98 vs. 30.28± 2.05; p=0.01) and a trend increase in vascularization (3.47±1.26 vs. 1±0.23; p=0.07) in the eWAT. These data suggest that adipocyte ILK plays an important role in regulating adipocyte morphology, signaling and glucose and lipid homeostasis, therefore representing a potential target for obesity, insulin resistance and diabetes. Disclosure A. Bugler-Lamb: None. C. Hennayake: None. A. Hasib: None. M.L. Ashford: None. L. Kang: None. Funding Diabetes UK; Diabetes Research & Wellness Foundation