Obesity and weight gain are associated with increased morbidity and mortality, and affect a sizable and rapidly increasing population in the U.S. and other developed countries. Considerable effort has gone into understanding the changes in adipose tissue that accompany obesity in order to identify therapeutic targets to prevent of treat obesity and related conditions. In spite of progress in this area, few effective strategies have been developed. A central goal of our research, therefore, is to identify new factors and processes that may serve as targets for novel interventional strategies. The research proposed in this application is designed to assess the impact of CREB on the development of fat tissue, its role in mature adipocyte survival, and adipose tissue inflammation. We anticipate that these studies will define the impact of CREB on adipose tissue formation and function in animal models, and highlight CREB and associated factors and processes as potential targets for therapies designed to treat or prevent obesity and other adipose disorders.
Obesity is characterized by an increase in adipose tissue mass due to hypertrophy of existing fat cells and through the generation of new adipocytes (hyperplasia). New adipocytes arise from resident preadipocytes and interstitial mesenchymal stem cells. Conversion of these precursor cells to mature adipocytes requires the temporally orchestrated expression of transcription factors including C/EBPs 1 and 2, and PPAR3, which leads to the expression of factors associated with the mature adipocyte phenotype. Our studies have shown that activation of the transcription factor CREB is also required to induce adipogenic conversion of 3T3-L1 preadipocytes. CREB activation also protects mature adipocytes from apoptosis in vitro. While much has been learned from these in vitro studies, the role of CREB in adipose biology has not been explored in animal models. Recent preliminary studies show that CREB levels are diminished in adipose tissue from obese mice and rats. This may account, in part, for the increased adipocyte apoptosis and suppression of adipogenesis observed in obese individuals. It may also account for the infiltration of fat tissue from obese subjects with macrophages, since inhibition of CREB activity in 3T3-L1 adipocytes not only induces their apoptosis, but also increases expression of intercellular adhesion molecule-1 (ICAM-1), macrophage migration inhibitory factor-1 (MIF-1), macrophage colony stimulating factor-1 (MCSF-1), CXC ligand 13, stromal cell-derived factors -1 (SDF-1) and monocyte chemotactic protein-3 (MCP-3). Our preliminary studies have led us to propose two hypotheses related to CREB function in adipose biology. First, we hypothesize that CREB is required for adipogenesis, adipose tissue development, and adipocyte survival (Fig.1). Second, we hypothesize that loss of CREB in apoptotic adipocytes promotes the recruitment or retention of macrophages in adipose tissue via the upregulation of ICAM-1, MCSF-1, MIF-1, CXCL13, SDF-1 and/or MCP-3.
Four Specific Aims will test these hypotheses using in vivo and in vitro models.
Aim 1 will test whether forced depletion of CREB in preadipocytes inhibits adipogenesis in vivo, and whether forced loss of CREB in adipocytes induces their apoptotic death in vivo.
Aim 2 will investigate the impact of adipocyte- specific CREB depletion on adiposity and whole animal physiology.
Aim 3 will determine whether forced loss of CREB in adipocytes alone or both adipocytes and macrophages promotes macrophage recruitment to adipose tissue.
The fourth Aim will explore the ability of forced CREB depletion in adipocytes to promote macrophage recruitment and/or adhesion to adipocytes in vitro. We anticipate that these studies will define the impact of CREB on adipose tissue formation and function in animal models, and highlight CREB and associated factors and processes as potential targets for therapies designed to treat or prevent obesity and other adipose disorders.
|Garat, Chrystelle V; Crossno Jr, Joseph T; Sullivan, Timothy M et al. (2013) Inhibition of phosphatidylinositol 3-kinase/Akt signaling attenuates hypoxia-induced pulmonary artery remodeling and suppresses CREB depletion in arterial smooth muscle cells. J Cardiovasc Pharmacol 62:539-48|
|McCurdy, Carrie E; Schenk, Simon; Holliday, Michael J et al. (2012) Attenuated Pik3r1 expression prevents insulin resistance and adipose tissue macrophage accumulation in diet-induced obese mice. Diabetes 61:2495-505|
|Garat, Chrystelle V; Crossno Jr, Joseph T; Sullivan, Timothy M et al. (2010) Thiazolidinediones prevent PDGF-BB-induced CREB depletion in pulmonary artery smooth muscle cells by preventing upregulation of casein kinase 2 alpha' catalytic subunit. J Cardiovasc Pharmacol 55:469-80|
|Schauer, Irene E; Knaub, Leslie A; Lloyd, Monique et al. (2010) CREB downregulation in vascular disease: a common response to cardiovascular risk. Arterioscler Thromb Vasc Biol 30:733-41|
|Fox, Keith E; Colton, Lillester A; Erickson, Paul F et al. (2008) Regulation of cyclin D1 and Wnt10b gene expression by cAMP-responsive element-binding protein during early adipogenesis involves differential promoter methylation. J Biol Chem 283:35096-105|
|Schroeder-Gloeckler, Jill M; Rahman, Shaikh Mizanoor; Janssen, Rachel C et al. (2007) CCAAT/enhancer-binding protein beta deletion reduces adiposity, hepatic steatosis, and diabetes in Lepr(db/db) mice. J Biol Chem 282:15717-29|
|Crossno Jr, Joseph T; Majka, Susan M; Grazia, Todd et al. (2006) Rosiglitazone promotes development of a novel adipocyte population from bone marrow-derived circulating progenitor cells. J Clin Invest 116:3220-8|
|Fox, Keith E; Fankell, Dana M; Erickson, Paul F et al. (2006) Depletion of cAMP-response element-binding protein/ATF1 inhibits adipogenic conversion of 3T3-L1 cells ectopically expressing CCAAT/enhancer-binding protein (C/EBP) alpha, C/EBP beta, or PPAR gamma 2. J Biol Chem 281:40341-53|
|Zhang, Jiang-Wen; Klemm, Dwight J; Vinson, Charles et al. (2004) Role of CREB in transcriptional regulation of CCAAT/enhancer-binding protein beta gene during adipogenesis. J Biol Chem 279:4471-8|
|Reusch, Jane E B; Klemm, Dwight J (2003) Cyclic AMP response element-binding protein in the vessel wall: good or bad? Circulation 108:1164-6|
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