1. Inflammation causes insulin resistance in mice via interferon regulatory factor 3 (IRF3)-mediated reduction in FAHFA levels.
- Author
-
Yan S, Santoro A, Niphakis MJ, Pinto AM, Jacobs CL, Ahmad R, Suciu RM, Fonslow BR, Herbst-Graham RA, Ngo N, Henry CL, Herbst DM, Saghatelian A, Kahn BB, and Rosen ED
- Subjects
- Animals, Male, Mice, Mice, Inbred C57BL, Glucose metabolism, 3T3-L1 Cells, Insulin Resistance, Interferon Regulatory Factor-3 metabolism, Interferon Regulatory Factor-3 genetics, Obesity metabolism, Diet, High-Fat adverse effects, Inflammation metabolism, Mice, Knockout, Adipocytes metabolism
- Abstract
Obesity-induced inflammation causes metabolic dysfunction, but the mechanisms remain elusive. Here we show that the innate immune transcription factor interferon regulatory factor (IRF3) adversely affects glucose homeostasis through induction of the endogenous FAHFA hydrolase androgen induced gene 1 (AIG1) in adipocytes. Adipocyte-specific knockout of IRF3 protects male mice against high-fat diet-induced insulin resistance, whereas overexpression of IRF3 or AIG1 in adipocytes promotes insulin resistance on a high-fat diet. Furthermore, pharmacological inhibition of AIG1 reversed obesity-induced insulin resistance and restored glucose homeostasis in the setting of adipocyte IRF3 overexpression. We, therefore, identify the adipocyte IRF3/AIG1 axis as a crucial link between obesity-induced inflammation and insulin resistance and suggest an approach for limiting the metabolic dysfunction accompanying obesity., (© 2024. The Author(s).)
- Published
- 2024
- Full Text
- View/download PDF