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RESEARCH PRODUCT

AMPK regulates macrophage polarization in adipose tissue inflammation and NASH

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Molecular and Translational Medicine, Dept. of Medicine I, University Medical Center, Johannes Gutenberg University Mainz, Langenbeckstrase 1,55116 Mainz, GermanyCOMMENTARY ON:Hematopoietic AMPK beta1 reduces mouse adipose tissue mac-rophage inflammation and insulin resistance in obesity. Galic S,Fullerton MD, Schertzer JD, Sikkema S, Marcinko K, Walkley CR,Izon D, Honeyman J, Chen ZP, van Denderen BJ, Kemp BE, Stein-berg GR. J Clin Invest 2011;121(12):4903–15. Copyright 2011.Reprinted with permission of American Society for ClinicalInvestigation.http://www.ncbi.nlm.nih.gov/pubmed/22080866Abstract: Individuals who are obese are frequently insulin resistant,putting them at increased risk of developing type 2 diabetes and itsassociated adverse health conditions. The accumulation in adiposetissue of macrophages in an inflammatory state is a hallmark ofobesity-induced insulin resistance. Here, we reveal a role for AMPKb1 in protecting macrophages from inflammation under high lipidexposure. Genetic deletion of the AMPK b1 subunit in mice (referredto herein as b1( / ) mice) reduced macrophage AMPK activity,acetyl-CoA carboxylase phosphorylation, and mitochondrial content,resulting in reduced rates of fatty acid oxidation. b1( / ) macro-phages displayed increased levels of diacylglycerol and markers ofinflammation, effects that were reproduced in WT macrophages byinhibiting fatty acid oxidation and, conversely, prevented by phar-macological activation of AMPK b1-containing complexes. The effectof AMPK b1 loss in macrophages was tested in vivo by transplanta-tion of bone marrow from WT or b1( / ) mice into WT recipients.When challenged with a high-fat diet, mice that received b1( / )bone marrowdisplayedenhancedadiposetissue macrophage inflam-mation and liver insulin resistance compared with animals thatreceived WT bone marrow. Thus, activation of AMPK b1 and increas-ing fatty acid oxidation in macrophages may represent a new thera-peutic approach for the treatment of insulin resistance. 2011 European Association for the Study of the Liver. Publishedby Elsevier B.V. All rights reserved.Obesity has long been linked to type 2 diabetes (T2D), but theinvolved metabolic dysregulation is incompletely understood.Galic et al. [1] recently reported that adenosine monophosphatekinase (AMPK) b1 plays a hitherto unknown role in modulatingobesity-induced insulin resistance. AMPK is a central regulatorof energy balance. Decreased cellular energy status, as reflectedby accumulation of AMP, activates AMPK which turns on expres-sion of catabolic enzymes that permit ATP production and shutsdown energy consuming biosynthetic pathways. Thus, AMPK isa central regulator of fatty acid, cholesterol, and glucose homeo-stasis through phosphorylation of metabolism-regulatingenzymes including acetyl-CoA carboxylase (ACC), glycogen syn-thase (GS), glucose transporter 4 (GLUT4), HMG-CoA reductase,hormone-sensitive lipase (HSL), and mammalian target of rapa-mycin (mTOR). AMPK is a heterotrimer of a catalytic