AbstractWith decreased physical activity and increased energy intake, obesity and T2DM are steadily becoming a global health threat. Both these diseases can be associated to physiological disorders such as impaired glucose tolerance and insulin sensitivity. Although there is a wide range of treatments for T2DM, the majority of these cause adverse effects in patients. Therefore, there is a need to identify novel therapeutic targets for the prevention or treatment of T2DM.
It has previously been shown that increased deposition of the extracellular matrix (ECM) in adipose tissue during obesity contributes to insulin resistance. The integrin receptors transmit changes in the extracellular environment to the cell, causing corresponding intracellular adaptations. Integrin-linked-kinase (ILK), an adaptor protein, is a central hub for intracellular signalling of integrins. Previous studies have shown that ILK in skeletal muscle and liver is necessary for the development of insulin resistance in high fat (HF) diet- fed mice.
In this study, we set out to determine the role of ILK in adipose tissue function and insulin resistance. Adipose tissue ILK protein expression was increased by HF diet feeding in mice and in visceral fat of morbidly obese humans. To investigate its pathogenic role in obesity and insulin resistance, adipocyte-specific ILK deficient mice (ILKlox/lox Cre+) were studied. The HF fed ILKlox/lox Cre+ mice displayed reduced fat mass and improved glucose tolerance relative to HF-fed wildtype (WT) littermates (ILKlox/loxCre-). During a hyperinsulinemic-euglycemic clamp, HF-fed ILKlox/lox Cre+ mice exhibited a mild improvement in insulin sensitivity in their adipose tissue. Lipolysis was suppressed to greater extent by insulin and glucose uptake in brown adipose tissue (BAT) was increased. The improved anti-lipolytic action may be attributed to increased vascularization in the epididymal white adipose tissue (eWAT), while increased glucose uptake in BAT was associated with increased AKT phosphorylation and P38/JNK de-phosphorylation. ILK did not impact inflammation within the eWAT on either diet. Both the eWAT and BAT showed a significant reduction in PGC-1 α gene expression in the HF-fed ILKlox/lox Cre+ mice. Moreover, the eWAT of the ILKlox/lox Cre+ mice had reduced CD36 gene expression, potentially indicative of reduced lipid uptake. Finally, the deletion of ILK in 3T3-L1 cells resulted in a decrease in PPARγ and C/EBPα and a failure to differentiate into mature adipocytes.
These data demonstrate that the pathogenic overexpression of ILK in adipose tissue may contribute to insulin resistance in mice challenged on HF diet. Additionally, in this study we demonstrated that ILK is important in regulating adipocyte functions such as adipogenesis and lipid uptake.
|Date of Award||2020|
|Sponsors||Wellcome Trust & Carnegie Trust for the Universities of Scotland|
|Supervisor||Li Kang (Supervisor) & Michael Ashford (Supervisor)|