CONNEXIN-43 MEDIATED CELL-CELL COMMUNICATION AND PROPAGATION OF ADIPOSE TISSUE ER STRESS IN OBESITY

Obesity, a leading global health burden, is a major contributor to type-2 diabetes mellitus. Cellular dysfunction of the obese adipocytes has been shown as an important pathophysiological link between obesity and the development of insulin resistance and diabetes. The obese adipose tissue is characterized by chronic inflammation and cellular stresses such as endoplasmic-reticulum (ER) stress. However, the adaptive or maladaptive response to these cellular insults at the tissue level is less well understood. Increased gap junction (GJ) activity, primarily composed of Connexin-(Cx)43, has been shown to play a pivotal role in the tissue response to various chronic stress conditions. We observed that ER-stress can cross from `stressed` (or ‘donor’) cells to unstressed (‘recipient’) cells via Cx43-mediated GJ communication, and ER-stress induction increased GJ function in-vitro. In a diet-induced obesity mouse model we demonstrated an increase in Cx43 expression in the intact adipose tissue, which could be primarily attributed to increased Cx43 expression in adipocytes. Moreover, in a preliminary study conducted in high fat diet-fed adipocyte-specific Cx43 knock-out mice, we observed lower fasting glucose levels and improved insulin sensitivity as compared to Cx43 wild type mice, independent of body weight.

Our results suggest that in obesity, adipocyte Cx43 plays a role in the development of adipose tissue dysfunction and consequential impairment of systemic metabolic homeostasis, and may imply Cx43 as a novel therapeutic target for obesity associated metabolic abnormalities.