Adiponectin is an adipokine that we first identified in the mid-90's that has gained significant attention due to its insulin sensitizing and anti-inflammatory properties. Many papers have belabored the function of adiponectin in the widest spectrum of clinical and preclinical settings, yet there is no unifying mechanism of action available. Here, we would like to build upon our current data and develop further the mechanistic aspects of adiponectin action. We would like to approach this with the following questions: SA 1) What is the mechanism for the potent anti-apoptotic properties exerted by adiponectin on a number of cell types? We have generated a series of mouse models that allow us to provide an inducible pro-apoptotic insult to specific cell types. These "ATTAC" mice ("Apoptosis Through Triggered Activation of Caspase-8") are available for pancreatic ? cells, cardiac myocytes, podocytes and several other critical cell types. We have preliminary genetic data highlighting the potent adiponectin-dose dependent effects on survival of cardiac myocytes in this model. We will extend these studies to ? cells and podocytes. The basis for these observations is a reduction of local ceramides and/or an increase in the local sphingosine-1-P levels due to activation of the adiponectin receptors by adiponectin. We will extend our preliminary data and believe that the ceramide-lowering effects of adiponectin mediated by the adiponectin receptors AdipoR1 and AdipoR2 offers the first unifying mechanism of action by which adiponectin achieves its remarkable effects systemically on a wide variety of cells. SA 2) Determine whether there is an "intracrine" mechanism of action for adiponectin within the adipocyte by which it enhances the metabolic flexibility of adipose tissue. Adiponectin overexpression from the liver is dramatically different from adiponectin overexpression from the adipocyte. In order to achieve the remarkable degree of "metabolic flexibility" that adipocyte-specific overexpression achieves, we postulate that there is an intracellular mechanism of action that ensures enhanced differentiation potential, increased glyceroneogenesis, improvements in vascularization and enhanced susceptibility to ?3 adrenergic action. Using a combination of novel transgenic models and in vitro biochemistry we will put this hypothesis to a test. SA 3) Identify additional intracellular steps that lead to the assembly/maturation of adiponectin and effective release from adipocytes. We have identified Erp44 and Ero1 as critical factors for the assembly of adiponectin. We would like to identify additional critical players in this complex set of reactions, and establish the role of the Unfolded Protein Response (a process frequently upregulated in obese adipose tissue) in the maturation process. Combined, these studies should provide significant new insights into the physiology of this protein. The proposed lowering of ceramide levels is an attractive novel mechanism with the potential to explain the insulin-sensitizing, anti-apoptotic, pro-angiogenic and anti-inflammatory properties that have been attributed to adiponectin.
Adiponectin is an adipocyte-derived factor exerting a vast array of beneficial effects on metabolically active cells. Even though we appreciate the strong correlations of elevated adiponectin levels with improvements in insulin-sensitivity, reduced inflammation and enhanced survival of many cell types, there is no known unifying mechanism that can explain the underlying principles leading to the metabolic enhancements generally seen with elevated adiponectin levels. A better understanding of this mechanism will highlight novel therapeutic avenues for the treatment of obesity, diabetes and cardiovascular disease.
|Liu, Chen; Bookout, Angie L; Lee, Syann et al. (2014) PPAR? in vagal neurons regulates high-fat diet induced thermogenesis. Cell Metab 19:722-30|
|Williams, Kevin W; Liu, Tiemin; Kong, Xingxing et al. (2014) Xbp1s in Pomc neurons connects ER stress with energy balance and glucose homeostasis. Cell Metab 20:471-82|
|Rutkowski, Joseph M; Scherer, Philipp E (2014) Isolation and quantitation of adiponectin higher order complexes. Methods Enzymol 537:243-59|
|Asterholm, Ingrid W; Rutkowski, Joseph M; Fujikawa, Teppei et al. (2014) Elevated resistin levels induce central leptin resistance and increased atherosclerotic progression in mice. Diabetologia 57:1209-18|
|Rutkowski, Joseph M; Halberg, Nils; Wang, Qiong A et al. (2014) Differential transendothelial transport of adiponectin complexes. Cardiovasc Diabetol 13:47|
|Berglund, Eric D; Liu, Tiemin; Kong, Xingxing et al. (2014) Melanocortin 4 receptors in autonomic neurons regulate thermogenesis and glycemia. Nat Neurosci 17:911-3|
|Zhu, Hong; Guariglia, Sara; Li, Wenjing et al. (2014) Role of extracellular signal-regulated kinase 5 in adipocyte signaling. J Biol Chem 289:6311-22|
|Wang, Zhao V; Deng, Yingfeng; Gao, Ningguo et al. (2014) Spliced X-box binding protein 1 couples the unfolded protein response to hexosamine biosynthetic pathway. Cell 156:1179-92|
|Sun, Kai; Kusminski, Christine M; Luby-Phelps, Kate et al. (2014) Brown adipose tissue derived VEGF-A modulates cold tolerance and energy expenditure. Mol Metab 3:474-83|
|Wernstedt Asterholm, Ingrid; Tao, Caroline; Morley, Thomas S et al. (2014) Adipocyte inflammation is essential for healthy adipose tissue expansion and remodeling. Cell Metab 20:103-18|
Showing the most recent 10 out of 127 publications