The Role of Adipocyte Connexin-43 in Mediating Adipose Tissue Inflammation and Dysfunction in Obesity

Introduction:
Obesity is a leading global health concern and a major risk factor for type-2 diabetes. Thus, identifying mechanisms linking obesity to insulin resistance is of great importance. Chronic low-grade inflammation of the adipose tissue (AT) has been shown as an important pathophysiological link between obesity and the development of systemic insulin resistance. Gap junction (GJ) intercellular-communication, primarily composed of connexin-(Cx)43, has recently been reported to have immunomodulatory roles in various tissues, with increased Cx43 expression and GJ activity implicated in the response of various tissues to chronic stress.

Aim:
To study the role of Cx43 in shaping the AT adaptive or maladaptive response to the cellular insults of obesity.

Methods:
We have used a diet-induced obesity (DIO) mouse model to study the effect of obesity on Cx43 expression and the role of Cx43 in the AT response to obesity, by using wild-type (WT) and adipocyte-specific Cx43 knock-out (AdCx43KO) mice.

Results:
DIO resulted in increased AT Cx43 expression, primarily attributed to increased Cx43 expression in adipocytes. In AdCx43KO mice, we observed increased macrophage infiltration to the AT as compared to WT mice, accompanied by morphologic changes in the AT and increased variability in adipocyte size. While AdCx43KO mice did not significantly differ from WT mice in body weight, adiposity or food intake, they demonstrated reduced whole-body insulin sensitivity assessed by insulin tolerance test. Mechanistically, we observed that adipocytes can interact directly with neighboring adipocytes and macrophages via Cx43-composed GJ.

Conclusions:
Our results suggest an immunomodulatory role for adipocyte-Cx43 in obesity.