The long-term objective of this grant has been to determine the role of glucose transport in adipose tissue and muscle in whole body glucose homeostasis and insulin sensitivity, with the goal of finding new therapeutic targets for type 2 diabetes. We demonstrated an important role for adipocytes in insulin sensitivity and the pathogenesis of type 2 diabetes. We showed that the down regulation of Glut4 in adipocytes that occurs in obesity and type 2 diabetes plays an important role in the insulin resistance in these states. We discovered that adipose expression and serum levels of retinol binding protein 4 (RBP4) are increased in insulin resistant states in humans and rodents In the next cycle, the overall goals will continue to be to determine 1) the physiologic, cellular and molecular mechanisms by which RBP4 causes insulin resistance and 2) whether increased retention of RBP4 is an important mechanism for its serum elevation in insulin resistant states, and the mechanisms underlying this.
Aim 1 is to determine the mechanisms for RBP4-induced insulin resistance. Using complementary in vivo and in vitro approaches, we will investigate the intracellular signaling pathways that appear to be involved and the "inflammatory" effects.
Aim 2 is to determine whether the mechanism(s) by which elevation of RBP4 causes insulin resistance are retinoid-dependent or retinoid-independent.
Aim 3 is to determine the role of STRA6 in RBP4-induced metabolic effects.
Aim 4 is to determine whether increased retention of RBP4 is an important mechanism for RBP4 elevation in serum in insulin-resistant states and whether this results from post-translational modifications of transthyretin. Understanding the mechanisms by which elevated RBP4 contributes to insulin resistance, metabolic syndrome and risk of diabetes and cardiovascular disease could lead to new insights into the pathogenesis of these disorders. In addition, understanding the mechanisms by which RBP4 becomes elevated in these states could lead to new therapeutic approaches. These studies will elucidate novel mechanisms underlying the inter-tissue communication that plays an important role in the pathogenesis of type 2 diabetes.
Fat cells are important regulators of metabolism and diabetes risk. Fat cells and liver secrete retinol binding protein 4 (RBP4) which carries vitamin A in the blood. RBP4 is elevated in serum of insulin resistant people with obesity and type 2 diabetes. This may contribute to the insulin resistance and risk for diabetes. We will investigate the mechanisms by which RBP4 regulates insulin/glucose balance and diabetes risk.
|Moraes-Vieira, Pedro M; Yore, Mark M; Dwyer, Peter M et al. (2014) RBP4 activates antigen-presenting cells, leading to adipose tissue inflammation and systemic insulin resistance. Cell Metab 19:512-26|
|Zemany, Laura; Kraus, Bettina J; Norseen, Julie et al. (2014) Downregulation of STRA6 in adipocytes and adipose stromovascular fraction in obesity and effects of adipocyte-specific STRA6 knockdown in vivo. Mol Cell Biol 34:1170-86|
|Yore, Mark M; Syed, Ismail; Moraes-Vieira, Pedro M et al. (2014) Discovery of a class of endogenous mammalian lipids with anti-diabetic and anti-inflammatory effects. Cell 159:318-32|
|Sun, Qi; Jiménez, Monik C; Townsend, Mary K et al. (2014) Plasma levels of fetuin-A and risk of coronary heart disease in US women: the Nurses' Health Study. J Am Heart Assoc 3:e000939|
|Guzman, Johanna; Jauregui, Alexandra N; Merscher-Gomez, Sandra et al. (2014) Podocyte-specific GLUT4-deficient mice have fewer and larger podocytes and are protected from diabetic nephropathy. Diabetes 63:701-14|
|Kraus, Daniel; Yang, Qin; Kong, Dong et al. (2014) Nicotinamide N-methyltransferase knockdown protects against diet-induced obesity. Nature 508:258-62|
|Wu, Ning; Zheng, Bin; Shaywitz, Adam et al. (2013) AMPK-dependent degradation of TXNIP upon energy stress leads to enhanced glucose uptake via GLUT1. Mol Cell 49:1167-75|
|Sun, Qi; Kiernan, Urban A; Shi, Ling et al. (2013) Plasma retinol-binding protein 4 (RBP4) levels and risk of coronary heart disease: a prospective analysis among women in the nurses' health study. Circulation 127:1938-47|
|Lin, Qun; Huang, Yan; Booth, Carmen J et al. (2013) Activation of hypoxia-inducible factor-2 in adipocytes results in pathological cardiac hypertrophy. J Am Heart Assoc 2:e000548|
|Norseen, Julie; Hosooka, Tetsuya; Hammarstedt, Ann et al. (2012) Retinol-binding protein 4 inhibits insulin signaling in adipocytes by inducing proinflammatory cytokines in macrophages through a c-Jun N-terminal kinase- and toll-like receptor 4-dependent and retinol-independent mechanism. Mol Cell Biol 32:2010-9|
Showing the most recent 10 out of 30 publications