The metabolic syndrome is a collection of metabolic abnormalities, including obesity, insulin resistance and atherosclerosis, with chronic inflammation as a causative underlying mechanism. Inflammatory responses in obesity can be activated by altered nutrient metabolism (e.g. excess lipids and modified lipoprotein particles). The studies proposed here aim to determine cellular mechanisms linking nutrient metabolism to inflammation, atherosclerosis and insulin resistance. AMP-activated protein kinase (AMPK) is an evolutionally conserved cellular energy sensor that regulates metabolic pathways in lipid, cholesterol and glucose metabolism. AMPK signaling and expression are down-regulated in macrophages and adipose tissue by inflammatory stimuli and in nutrient-rich conditions, such as exposure to lipopolysaccharide (LPS), free fatty acids (FFAs), oxidized low- density lipoprotein (oxLDL) particles, and in diet-induced obesity. In addition, activation of macrophage AMPK signaling significantly suppresses LPS-, FFAs- and oxLDL-induced inflammation, as well as macrophage chemotaxis and adhesion, important processes in the development of atherosclerosis. This effect is exerted primarily through the 11AMPK isoform in macrophages. Therefore, the overall hypothesis is that macrophage AMPK is a key signaling molecule linking cellular nutrient metabolism to inflammatory responses, and activating macrophage AMPK protects against both atherosclerosis and insulin resistance through suppression of macrophage inflammation. Mice with macrophage-specific over-expression of dominant negative (loss-of- function) or constitutively active (gain-of-function) 11AMPK (DN-11 and CA-11, respectively) have been newly generated and will be used to determine specifically the role of macrophage AMPK in antagonizing obesity- induced inflammation, atherosclerosis and insulin resistance.
Specific aim 1 will determine the protective effects of macrophage AMPK against atherosclerosis using macrophage-specific CA-11 or DN-11 mice crossed with LDL receptor (LDLR) knockout mice. The development of atherosclerosis and the infiltration of macrophages into atherosclerotic lesions at both early and more advanced disease stages will be determined in these mice on an atherogenic diet.
Specific aim 2 will determine the protective effects of macrophage AMPK against obesity-induced inflammation and insulin resistance using macrophage-specific CA-11 or DN-11 mice. The insulin sensitivity and adipose tissue inflammation will be determined in these mice on either chow or high fat diet. Completing these studies will provide novel perspectives in the studying of obesity and associated metabolic syndrome. That is, AMPK serves as a signaling link between cellular nutrient metabolism and inflammation;activating macrophage AMPK significantly suppresses macrophage inflammation in obesity, which have protective effects on both atherosclerosis and insulin resistance;and the therapeutic effects of AMPK to reduce atherosclerosis and insulin resistance may be through reduction of obesity-induced inflammation.

Public Health Relevance

The goal of this project is to understand AMPK as a key signaling molecule linking cellular nutrient metabolism to inflammatory responses and to identify macrophage AMPK as a therapeutic target in the protection against both atherosclerosis and insulin resistance through suppression of macrophage inflammation.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Atherosclerosis and Inflammation of the Cardiovascular System Study Section (AICS)
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Hasan, Ahmed AK
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Georgia State University
Schools of Arts and Sciences
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Shin, Hyunsu; Ma, Yinyan; Chanturiya, Tatyana et al. (2017) Lipolysis in Brown Adipocytes Is Not Essential for Cold-Induced Thermogenesis in Mice. Cell Metab 26:764-777.e5
Chen, Yii-Shyuan; Wu, Rui; Yang, Xiaosong et al. (2016) Inhibiting DNA methylation switches adipogenesis to osteoblastogenesis by activating Wnt10a. Sci Rep 6:25283
Cui, Xin; Nguyen, Ngoc Ly T; Zarebidaki, Eleen et al. (2016) Thermoneutrality decreases thermogenic program and promotes adiposity in high-fat diet-fed mice. Physiol Rep 4:
Li, Fenfen; Wu, Rui; Cui, Xin et al. (2016) Histone Deacetylase 1 (HDAC1) Negatively Regulates Thermogenic Program in Brown Adipocytes via Coordinated Regulation of Histone H3 Lysine 27 (H3K27) Deacetylation and Methylation. J Biol Chem 291:4523-36
Cao, Qiang; Cui, Xin; Wu, Rui et al. (2016) Myeloid Deletion of ?1AMPK Exacerbates Atherosclerosis in LDL Receptor Knockout (LDLRKO) Mice. Diabetes 65:1565-76
Xie, Ping; Kadegowda, Anil K G; Ma, Yinyan et al. (2015) Muscle-specific deletion of comparative gene identification-58 (CGI-58) causes muscle steatosis but improves insulin sensitivity in male mice. Endocrinology 156:1648-58
Li, Jing Jing; Ferry Jr, Robert J; Diao, Shiyong et al. (2015) Nedd4 haploinsufficient mice display moderate insulin resistance, enhanced lipolysis, and protection against high-fat diet-induced obesity. Endocrinology 156:1283-91
Zha, Lin; Li, Fenfen; Wu, Rui et al. (2015) The Histone Demethylase UTX Promotes Brown Adipocyte Thermogenic Program Via Coordinated Regulation of H3K27 Demethylation and Acetylation. J Biol Chem 290:25151-63
Miao, Hongming; Ou, Juanjuan; Ma, Yinyan et al. (2014) Macrophage CGI-58 deficiency activates ROS-inflammasome pathway to promote insulin resistance in mice. Cell Rep 7:223-35
Xie, Ping; Zhu, Hongling; Jia, Lin et al. (2014) Genetic demonstration of intestinal NPC1L1 as a major determinant of hepatic cholesterol and blood atherogenic lipoprotein levels. Atherosclerosis 237:609-17

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