PKCζ-Regulated Inflammation in the Nonhematopoietic Compartment Is Critical for Obesity-Induced Glucose Intolerance

SummaryObesity-induced inflammation is critical for the development of insulin resistance. Here, we show that genetic inactivation of PKCζ in vivo leads to a hyperinflammatory state in obese mice that correlates with a higher glucose intolerance and insulin resistance. Previous studies implicated PKCζ in the regulation of type 2 inflammatory responses in T cells. By using ex vivo and in vivo experiments, we demonstrate that although PKCζ is involved in the alternative (M2) activation of macrophages, surprisingly, PKCζ ablation in the nonhematopoietic compartment but not in the hematopoietic system is sufficient to drive inflammation and IL-6 synthesis in the adipose tissue, as well as insulin resistance. Experiments using PKCζ/IL-6 double-knockout mice demonstrated that IL-6 production accounts for obesity-associated glucose intolerance induced by PKCζ deficiency. These results establish PKCζ as a critical negative regulator of IL-6 in the control of obesity-induced inflammation in adipocytes.

Graphical AbstractFigure optionsDownload high-quality image (99 K)Download as PowerPoint slideHighlights
► PKCζ−/− mice display insulin resistance and hepatic steatosis on a high-fat diet
► High-fat-fed PKCζ−/− mice have increased IL-6 and adipose-macrophage infiltration
► PKCζ−/− deficiency in the nonhematopoietic compartment enhances insulin resistance
► In vivo deletion of IL-6 restores glucose tolerance in high-fat-fed PKCζ−/− mice