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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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Research Article Metabolism Article has an altmetric score of 6

Hematopoietic AMPK β1 reduces mouse adipose tissue macrophage inflammation and insulin resistance in obesity

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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 5

Hematopoietic deletion of AMPK β1 results in macrophage recruitment and inflammatory activation of adipose tissue macrophages.

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Hematopoietic deletion of AMPK β1 results in macrophage recruitment and ...
(A) PCR genotyping of genomic DNA from liver, white adipose tissue (WAT), and skeletal muscle (Sk mus), with WT- or β1-specific primers. (B) mRNA expression of macrophage markers Emr1 (F4/80) and Cd68 in WAT and liver of HFD-fed WTBMT and β1–/–BMT mice (dotted line indicates expression in chow-fed WTBMT mice). Immunohistochemical staining and quantification of F4/80 in (C) WAT and (D) liver (original magnification, ×200). Adipose tissue macro­phage (ATM) mRNA expression of (E) Arg1 and iNos, (F) Itgax (Cd11c), (G) inflammatory cytokines Ccl2, Tnfa, Il6, Il1b, and Il10, and (H) markers of mitochondrial density Pgc1a, Cs, and Hadh. (I) Correlation analysis between expression of Cs and Arg1. All data presented are mean ± SEM; n = 8–10. *P < 0.05, **P < 0.01 compared with WTBMT, within dietary treatment, where the relative expression was normalized to Actb.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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Referenced in 4 patents
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