Hematopoietic AMPK β1 reduces mouse adipose tissue macrophage inflammation and insulin resistance in obesity
Sandra Galic, … , Bruce E. Kemp, Gregory R. Steinberg
Sandra Galic, … , Bruce E. Kemp, Gregory R. Steinberg
Published November 14, 2011
Citation Information: J Clin Invest. 2011;121(12):4903-4915. https://doi.org/10.1172/JCI58577.
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Hematopoietic AMPK β1 reduces mouse adipose tissue macrophage inflammation and insulin resistance in obesity

Abstract

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 β1 in protecting macrophages from inflammation under high lipid exposure. Genetic deletion of the AMPK β1 subunit in mice (referred to herein as β1–/– mice) reduced macrophage AMPK activity, acetyl-CoA carboxylase phosphorylation, and mitochondrial content, resulting in reduced rates of fatty acid oxidation. β1–/– 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 β1–containing complexes. The effect of AMPK β1 loss in macrophages was tested in vivo by transplantation of bone marrow from WT or β1–/– mice into WT recipients. When challenged with a high-fat diet, mice that received β1–/– bone marrow displayed enhanced adipose tissue macrophage inflammation and liver insulin resistance compared with animals that received WT bone marrow. Thus, activation of AMPK β1 and increasing fatty acid oxidation in macrophages may represent a new therapeutic approach for the treatment of insulin resistance.

Authors

Sandra Galic, Morgan D. Fullerton, Jonathan D. Schertzer, Sarah Sikkema, Katarina Marcinko, Carl R. Walkley, David Izon, Jane Honeyman, Zhi-Ping Chen, Bryce J. van Denderen, Bruce E. Kemp, Gregory R. Steinberg

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Figure 3

Mitochondrial fatty acid oxidation and β1-specific activation of AMPK suppresses JNK phosphorylation in WT but not β1–/– macrophages.

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Mitochondrial fatty acid oxidation and β1-specific activation of AMPK su...
(A) WT and β1–/– BMDMs were treated with 0.5 mM palmitate (0.5 μCi/ml 14C-palmitate) for 4 hours in the presence of A769662 (100 μM), etomoxir (50 μM), and/or rotenone (50 μM) before determination of fatty acid oxidation. (B) BMDMs were incubated as described above with 0.5 mM palmitate and immunoblotted for p-JNK/JNK (T183/Y185) and p-ACC (S79)/ACC as a measure of AMPK activation. Treatment of WT BMDMs with ethidium bromide (Eth Br) (0.4 μg/ml) in the presence or absence of A769662 (100 μM) (C) reduces fatty acid oxidation and increases (D) JNK phosphorylation, blocking the effects of A769662. β1–/– BMDMs were treated with or without dinitrophenol (DNP) (500 μM), and (E) fatty acid oxidation and (F) p-JNK/JNK levels were determined. Data are expressed as mean ± SEM; n = 3–5 from at least 2 independent experiments. *P < 0.05, **P < 0.01, ***P < 0.001 compared with WT; #P < 0.05 compared with WT basal; and †P < 0.05 compared with β1–/– basal. For expression of total JNK, duplicate gels were used.