Fat Factors Controlling Adiponectin Expression

The epidemic of obesity has become among the most serious health problems worldwide because the weight gain carries a high risk of developing life-threatening diseases such as type 2 diabetes, hypertension, coronary artery disease, and heart failure. Recent work has highlighted the key role of adipokines in the adverse clinical consequences of excessive fat mass. The increase in circulating levels of leptin and other adipocyte-derived factors, resulting from the expansion of adipose tissue, has been shown to promote insulin resistance, inflammation, hypertension, and endothelial dysfunction.1,2 Unlike many other adipokines whose circulating levels increase in obesity, the circulating levels of adiponectin decrease in obese subjects, particularly among patients with excess visceral adiposity (Figure). 1 Clinical studies suggest that the attendant hypoadiponectinemia that occurs in obesity correlates with the development of hyperglycemia and type 2 diabetes, hypertension, coronary artery disease, sympathetic nerve activation, and impaired vasoreactivity.1,3 Consistent with this, adiponectin null mice have impaired glucose homeostasis and severe insulin resistance.3 Adiponectin has beneficial effects on biological processes that are relevant to the pathogenesis of diabetes and cardiovascular diseases including an improvement in insulin sensitivity (Figure). 3,4 In endothelial cells, adiponectin stimulates the activity of endothelial nitric oxide synthase and increases production of NO.5 Moreover, administration of adiponectin decreases arterial pressure and renal sympathetic nerve outflow in rats.6 Together, these findings implicate dysregulated production of adiponectin in obesity as a potential mediator of the metabolic and cardiovascular abnormalities associated with this condition. Therefore, understanding the mechanisms that regulate the expression and production of adiponectin is critical. Transcriptional regulation of the adiponectin gene is complex involving a number of ubiquitously expressed and cell-specific transcription factors. Among these are peroxisome proliferator-activated receptor , C/EBP, and SREBP1c, each of which plays an important role in adipogenesis, metabolism, and the regulation of a wide array of adiposespecific genes (reviewed elsewhere7). Binding sites for each of these transcription factors are present in the adiponectin promoter. In addition, the proximal 1 kb of the adiponectin promoter contains 3 E-boxes. E-boxes carry the consensus sequence CANNTG (where N is any nucleotide), which is recognized as the binding site for class I basic helix–loop– helix (bHLH) proteins, also known as E-proteins, such as the founding member of the family E2A. The E2A gene encodes 2 separate bHLH transcription factors, 1 of which is E47. E-proteins are expressed in many cell types but can gain functional specificity by forming heterodimers with other classes of bHLH proteins that exhibit greater cell specificity. SREBP-1c is a member of another class of bHLH proteins which also contains an adjacent leucine zipper domain (bHLHLZ). Leucine zippers are formed between 2 proteins that have evenly spaced leucine residues on parallel -helices. SREBPs are synthesized as membrane bound precursors that undergo posttranslational processing in response to cues induced by cholesterol depletion (reviewed elsewhere8). The amino-terminal segment of the protein then enters the nucleus, where it can bind to response elements in the promoter region of target genes. SREBPs exhibit an interesting DNA specificity in that they can recognize both sterol response elements (SRE) containing the sequence TCACNCCAC and E-boxes. This is interesting because in addition to 3 E-boxes, the adiponectin promoter contains 2 SREs. The bHLH factors are important regulators of differentiation and development. Their role in lymphocyte development, for example, has been extensively studied (reviewed elsewhere9). Their function can be modulated by yet another class of HLH proteins called “inhibitors of differentiation” (Ids). Ids such as Id3 have a HLH structure but lack the basic residues required for DNA binding. Consequently, as their name implies, Ids inhibit the activity of E-proteins by directly binding to them, thus preventing their association with DNA. Because the Id proteins do not themselves bind to DNA, they act dominant negatively by sequestering their targets (ie, E47). As a member of bHLHLZ family, SREBP may also be subjected to regulation by Id proteins. Moldes et al10 have reported a direct interaction between Id2 and Id3 with SREBP-1c, and Id2 and Id3 inhibited SREBP-1c–mediated activation of the fatty acid synthase promoter. In this issue of Circulation Research, McNamara and colleagues11 examined the importance of the E-box sequences present in the adiponectin promoter and their interaction with E-proteins, Id proteins, and SREBP-1c, focusing primarily on E47 and Id3. The authors first confirmed that Id3 acts as an The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association. From the Departments of Internal Medicine (K.R., C.D.S.) and Molecular Physiology and Biophysics (C.D.S.) and Center for Functional Genomics of Hypertension (K.R., C.D.S.), Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City. Correspondence to Curt D. Sigmund, PhD, Roy J. Carver Chair in Hypertension Research, Departments of Internal Medicine and Molecular Physiology and Biophysics, 3181B Medical Education and Biomedical Research Facility, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA 52242. E-mail curt-sigmund@ uiowa.edu (Circ Res. 2008;103:565-567.) © 2008 American Heart Association, Inc.