PPAR-ALPHA

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Our clinical endeavors this past year have focused on adiponectin receptors expressed in human adipose tissue. The fat-derived protein adiponectin enhances insulin action in rodents. Its circulating levels are reduced in obesity and type 2 diabetes mellitus, and increased by thiazolidinediones in concert with improved insulin action. Adiponectin overexpression in transgenic mice caused abnormal enlargement of certain fat depots (Endocrinology 145:367, 2004), suggesting that adiponectin exerts direct effects on fat tissue. While a recent report confirmed the expression of two recently discovered adiponectin receptors in many human tissues, no fat tissues were examined (Nature 423:762, 2003). Gene expression was quantified in subcutaneous and omental adipose tissue from twelve nondiabetic patients undergoing elective abdominal surgery. In a subgroup, adipocytes and stromal cells were immediately separated by collagenase digestion. RNA copy numbers (plasmid standard curves, normalized to GAPDH) of AdipoR1 were universally 10-fold higher than AdipoR2, and expression of both receptors was similar in subcutaneous and omental tissue. While adiponectin gene expression was specific to adipocytes, the receptors were expressed in both adipocytes and stromal cells. There was no association between BMI and receptor expression levels. To determine the effects of thiazolidinediones on adipose tissue gene expression, fat was biopsied in 8 diabetic subjects after pioglitazone 45 mg or placebo for 21 days. While pioglitazone increased adiponectin expression 2-fold, changes in AdipoR1 and AdipoR2 were minimal. Both adiponectin receptor subtypes are expressed in human fat, with AdipoR1 being much more abundant. Unlike adiponectin, the receptors are expressed in both adipocytes and stromal adipose cells and are minimally affected by thiazolidinediones. Further study to determine the physiologic significance of these receptors in humans is warranted.