IKK/NF-κB-regulated Inflammatory Pathway in Human Adipocytes: Implication in Subsequent Contribution to Insulin Resistance and Atherosclerosis

Abstract

Obesity is associated with a state of chronic inflammation that is thought to be major contributor to disease and atherosclerosis. Many inflammatory pathways that contribute to the development of insulin resistance and atherosclerosis are regulated by IKK- NF-κB signaling. Several studies during the past two decades have highlighted the key role of the IKK/NF-κB pathway in the induction and maintenance of the state of inflammation that underlies metabolic diseases. We addressed the stipulated role of IKKβ to produce proinflammatory cytokines in cultured human adipocytes using small molecule inhibitor. We hypothesized that IKK/NF-kB signaling plays a critical role in inflammatory pathway in human adipocytes which may subsequently contribute to insulin resistance and atherosclerosis. We have developed an effective protocol for deriving adipocytes from in vitro culture of pre-adipocytes and demonstrated upregulation of proinflammatory cytokines in this system. Our results show that IKK inhibition abrogates inflammatory cytokine secretion during adipogenesis and mature adipocytes in dose dependent manner. In conclusion, this study provides the critical role of IKK/NF-kB-mediated inflammatory pathways in human adipocytes; and represents proof of concept for use of appropriate IKK inhibitor as an innovative therapeutic strategy to treat obesity and cardiometabolic diseases. Importance of this work: Obesity is a rapidly growing epidemic representing a serious threat to the health of the population in almost every country around the world. There is an imperative need to understand the mechanisms underlying the obesity and associated cardiometabolic disorders. In this thesis, we have shown that inhibition with specific small molecular inhibitor of IKK abrogated the proinflammatory cytokine release. This study provides a foundation for targeting the IKK NF-kB signaling as therapeutic strategy for metabolic diseases.