AMPK regulates macrophage polarization in adipose tissue inflammation and NASH

Individuals who are obese are frequently insulin resistant, putting them at increased risk of developing type 2 diabetes and its associated adverse health conditions. The accumulation in adipose tissue of macrophages in an inflammatory state is a hallmark of obesity-induced insulin resistance. Here, we reveal a role for AMPK beta 1 in protecting macrophages from inflammation under high lipid exposure. Genetic deletion of the AMPK beta 1 subunit in mice (referred to herein as,61(-/-) mice) reduced macrophage AMPK activity, acetyl-CoA carboxylase phosphorylation, and mitochondrial content, resulting in reduced rates of fatty acid oxidation. 131(-/-) macrophages displayed increased levels of diacylglycerol and markers of inflammation, effects that were reproduced in WT macrophages by inhibiting fatty acid oxidation and, conversely, prevented by pharmacological activation of AMPK)beta 1-containing complexes. The effect of AMPK beta 1 loss in macrophages was tested in vivo by transplantation of bone marrow from WT or)81(-/-) mice into WT recipients. When challenged with a high-fat diet, mice that received 31(-/-) bone marrow displayed enhanced adipose tissue macrophage inflammation and liver insulin resistance compared with animals that received WT bone marrow. Thus, activation of AMPK beta 1 and increasing fatty acid oxidation in macrophages may represent a new therapeutic approach for the treatment of insulin resistance.