The protective role of fat specific protein 27 (FSP27) against interleukin-1 beta and interleukin-6 induced lipolysis and insulin resistance in human adipocytes

The global rise in the prevalence of obesity has been labeled a pandemic. The increasing rates of overweight and obese persons across the world is discerning, as obesity is a risk factor for many life-threatening and debilitating diseases including type two diabetes mellitus (T2DM), a disease that decreases insulin sensitivity of skeletal muscle, adipose tissue and liver, and insulin secretion in pancreatic beta cells. Despite its pervasiveness, the mechanism by which obesity causes T2DM remains elusive. Adipose tissue is known to contribute to whole body glucose metabolism and as a result has been implicated in T2DM. Obesity causes changes in the physiology of adipose tissue, including hypertrophy of adipocytes, rendering them stressed and dysfunctional. The result is an increase in free fatty acids in the blood, due to increased lipolysis and decreased triglyceride storage. Free fatty acids have been shown to cause insulin resistance in insulin sensitive tissues. It has also been observed that in some patients, obesity results in inflammation of adipose tissue. As adipocytes enlarge, they not only secrete increasing amounts of free fatty acids, they also secrete chemoattractant proteins like MCP-1, which attract macrophages. These macrophages secrete inflammatory cytokines such as Tumor Necrosis Factor- alpha, Interleukin-1beta and Interleukin-6, among others, which have been shown to alter adipose tissue metabolism by increasing lipolysis and decreasing triglyceride storage. In addition, inflammatory cytokines have been suspected to play a role in insulin resistance, although the exact mechanisms remain elusive. The present study explored the possibility that Interleukin-1beta and Interleukin-6 affect insulin signaling in human adipocytes by increasing lipolysis, thus increasing free fatty acids in the blood. Recent studies have emphasized the role of fat specific protein 27 (FSP27) in the regulation of lipolysis in adipocytes whereby, FSP27 controls lipolysis by regulating the lipolytic capacity as well as transcription of the primary lipase ATGL. In the present study we used FSP27 as a tool to investigate if managing lipolysis could protect human adipocytes from the impairment of insulin signaling caused by the presence of inflammatory cytokines. We found that Interleukin-1beta and Interleukin-6 increase lipolysis in human adipocytes by depression of endogenous FSP27 protein levels and that the rate of lipolysis can be rescued by adenoviral expression of FSP27. In addition, we found that interleukin-1beta decreased insulin signaling by decreasing phosphorylation of AKT and that adenoviral expression of FSP27 has a protective effect over Interleukin-1beta - induced impairment of insulin signaling in human adipocytes. Our experiments regarding the effect of Interleukin-6 on insulin signaling were inconclusive and need further experimentation. These results suggest that the inflammatory cytokine Interleukin-1beta indirectly suppresses insulin signaling, by increasing lipolysis and that maintenance of FSP27 protein levels in obese patients could prevent patients from developing insulin resistance and T2DM