Salt-inducible kinases in adipose tissue

Abstract: Obesity, insulin resistance and type 2 diabetes (T2D) are metabolic diseases that increase rapidly in the modern society. The underlying mechanisms are complex and involve both environmental and genetic factors. Adipose tissue is an important organ for maintaining whole body energy homeostasis. In response to nutrient overload (as observed in obesity), adipocytes become hypertrophic and dysfunctional, which contribute to the development of systemic insulin resistance. AMP-activated protein kinase (AMPK) is described as a master regulator of whole body energy homeostasis. The salt-inducible kinases (SIKs) are related to AMPK. SIK2 displays abundant expression in adipose tissue and has been reported to be increased in adipose tissue in obese diabetic (db/db) mice, suggesting that SIK2 is potentially involved in the development of obesity and T2D. Taken together, this makes the SIKs, and SIK2 in particular, interesting to study in adipose tissue in the context of obesity and insulin resistance. This thesis has addressed the expression, regulation and biological role of SIKs, in particular SIK2, in adipose tissue. So far, studies on SIKs in adipose tissue have exclusively been performed in rodents. This thesis focuses on studying the role of SIKs in humans.We demonstrate that the transcriptional regulators CRTC2, CRTC3 and HDAC4 are direct downstream substrates of SIK2 in adipocytes. Moreover, we demonstrate that the expression of SIK2 and SIK3 is markedly downregulated in adipose tissue from obese or insulin-resistant individuals. Furthermore, the expression of SIK2 and SIK3 in adipose tissue is regulated in response to weight change and inflammation (TNF-α). SIKs are involved in promoting glucose uptake in adipocytes and the underlying mechanism(s) involves direct, and positive, effects on the insulin signalling pathway. We also identify a novel regulatory pathway of SIK2 in adipocytes through insulin-induced phosphorylation at Thr484. From a functional aspect, insulin stimulation appears to be important to increase SIK2 protein stability. Taken together, our data suggest that insulin resistance might be a causal factor underlying the downregulation of SIK2 in human adipose tissue. Given these findings, SIK2 might provide an attractive therapeutic target for the treatment of metabolic diseases in the future. Importantly, our findings on SIK2 expression in human obesity and insulin resistance are in contrast to what was previously identified in mice, and demonstrates that interspecies differences exist with regard to the regulation of SIK2 in metabolic disease. Furthermore, this emphasise the importance to study SIKs in human adipocytes.