The role of AMPK and SIK isoforms in human adipose tissue and diabetes pathogenesis

Insulin resistance in adipose tissue, and its inability to adequately store excess energy, are major factors underlying systemic insulin resistance and type 2 diabetes (T2D). Our overall aim is to increase the molecular understanding of how lipid storage is controlled and why adipocytes become insulin resistant. We will do this by exploring regulation and function of the anti-diabetic drug target AMP-activated protein kinase (AMPK) and its relative salt-inducible kinase (SIK) -2 in human adipocytes. We have shown that SIK2 is down-regulated in obesity, and is important to maintain insulin sensitivity in adipocytes. The project is organized around several questions, the most outstanding being: How do novel AMPK activators affect adipocyte metabolism? Why is SIK2 attenuated in obesity/insulin resistance? How does SIK2 promote insulin signalling? Which other processes are regulated by SIK2? To address these, we will use a range of techniques to modulate and monitor SIK and AMPK in primary human adipocytes – our main model. Readouts include insulin signalling, glucose transport, anti-lipolysis, lipid synthesis and autophagy. AMPK projects will run in parallel y1-4, studies of autophagy and insulin action y1-2, transcriptional regulation of/by SIKs in y2-5, and in vivo SIK inhibition in y2.
Our proposed research is important because it will improve the molecular understanding of how insulin resistance develops and evaluate if SIKs and AMPK are useful targets for treatment of T2D.