Hypertriglyceridemia is a major component of the metabolic syndrome and a strong risk factor for atherosclerosis and coronary artery disease. Adiponectin is an adipose-derived hormone that promotes insulin sensitization and plays an important role in energy metabolism. However, adiponectin gene expression and plasma adiponectin concentrations are paradoxically reduced in obesity. Hypertriglyceridemia usually accompanies adiposity. Previous human and animal studies have clearly shown that circulating adiponectin protein levels correlate inversely with triglyceride concentrations, indicating that adiponectin regulates triglyceride metabolism. However, the mechanism by which adiponectin regulates triglyceride metabolism is largely unknown. Our long term goal is to elucidate the underlying mechanisms of obesity-induced dyslipidemia. Using adenovirus-mediated in vivo gene transduction, we have shown that elevated plasma adiponectin reduces serum triglyceride levels without significantly changing hepatic very low density lipoprotein (VLDL)-triglyceride production. Interestingly, postheparin plasma lipoprotein lipase (LPL) activity, as well as LPL and VLDL receptor gene expression in skeletal muscle, was significantly increased in mice with elevated plasma adiponectin. LPL is a rate-limiting enzyme for VLDL-triglyceride hydrolysis, and the VLDL receptor enhances LPL activity. Our studies have also found that the expression of PPAR? co-activator-1a (PGC-1a) was robustly increased by adiponectin in both skeletal muscle and cultured myotubes. PGC-1a plays a pivotal role in skeletal muscle mitochondrial biogenesis and fatty acids oxidation. Therefore, we hypothesize that adiponectin reduces plasma triglyceride concentration by increasing VLDL-triglyceride catabolism in skeletal muscle and that PGC-1a mediates the regulatory effects of adiponectin by increasing LPL and VLDLr gene expression. This project will address two main specific aims.
In specific aim 1, we will investigate the mechanism by which adiponectin stimulates VLDL-triglyceride catabolism and the roles of skeletal muscle LPL and the VLDLr in this regulation. This will be accomplished in part using skeletal muscle tissue-specific LPL deficient or VLDLr deficient mice.
In specific aim 2, we will use the PGC-1a deficient mouse model and molecular techniques to determine the mechanisms by which PGC-1a mediates adiponectin-induced VLDL-triglyceride catabolism in skeletal muscle. This study is expected to reveal a new mechanism and concept about how an adipose derived hormone adiponectin regulates lipid and lipoprotein metabolism. It will also shed light on a novel mechanism that integrates adipose and skeletal muscle tissues in the context of lipoprotein metabolism. These studies may lead to new prevention or therapeutic strategies for obesity and the metabolic syndrome, which impose a serious health problem world wide. This study is expected to reveal a new mechanism and concept about how an adipose-derived hormone adiponectin regulates lipid and lipoprotein metabolism. It will also shed light on a novel mechanism that integrates adipose and skeletal muscle tissues in the context of lipoprotein metabolism. These studies may lead to new prevention or therapeutic strategies for obesity and the metabolic syndrome, which impose a serious health problem world wide.
|Lee, Bonggi; Qiao, Liping; Lu, Min et al. (2014) C/EBPÎ± regulates macrophage activation and systemic metabolism. Am J Physiol Endocrinol Metab 306:E1144-54|
|Lee, Bonggi; Shao, Jianhua (2014) Adiponectin and energy homeostasis. Rev Endocr Metab Disord 15:149-56|
|Qiao, Liping; Yoo, Hyung sun; Bosco, Chris et al. (2014) Adiponectin reduces thermogenesis by inhibiting brown adipose tissue activation in mice. Diabetologia 57:1027-36|
|Yoo, Hyung Sun; Qiao, Liping; Bosco, Chris et al. (2014) Intermittent cold exposure enhances fat accumulation in mice. PLoS One 9:e96432|
|Lee, Bonggi; Qiao, Liping; Kinney, Brice et al. (2014) Macrophage depletion disrupts immune balance and energy homeostasis. PLoS One 9:e99575|
|Qiao, Liping; Yoo, Hyung Sun; Madon, Alysha et al. (2012) Adiponectin enhances mouse fetal fat deposition. Diabetes 61:3199-207|
|Qiao, Liping; Kinney, Brice; Yoo, Hyung Sun et al. (2012) Adiponectin increases skeletal muscle mitochondrial biogenesis by suppressing mitogen-activated protein kinase phosphatase-1. Diabetes 61:1463-70|
|Qiao, Liping; Kinney, Brice; Schaack, Jerome et al. (2011) Adiponectin inhibits lipolysis in mouse adipocytes. Diabetes 60:1519-27|
|Qiao, Liping; Lee, Bonggi; Kinney, Brice et al. (2011) Energy intake and adiponectin gene expression. Am J Physiol Endocrinol Metab 300:E809-16|
|Kinney, Brice P; Qiao, Liping; Levaugh, Justin M et al. (2010) B56alpha/protein phosphatase 2A inhibits adipose lipolysis in high-fat diet-induced obese mice. Endocrinology 151:3624-32|
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