Gene expression of both GPR A and
Gene expression of both GPR109A and GPR81 in adipocytes has been linked to PPARγ activation . Treatment with the thiazolidinedione (TZD) PPARγ agonist, rosiglitazone, increases GPR109A and GPR81 expression, and knockdown of PPARγ suppresses receptor expression in fully differentiated human multipotent adipose-derived stem cells and in 3T3-L1 adipocytes . Increased GPR109A and GPR81 expression in response to TZD treatment may reduce circulating free fatty Amsacrine australia levels and perhaps ameliorate insulin resistance . In support of these cell culture findings, we observed a positive correlation between PPARγ gene expression and GPR109A and GPR81 gene expression in the mouse epididymal fat pads.
There is an obvious discrepancy between the effects we observed for HFD-induced obesity to decrease receptor expression in vivo and acute inflammatory stimulus to increase receptor expression in vitro. This may be due to the duration of the HFD feeding. Initially, in response to HFD-induced obesity, the adipose tissue becomes very inflamed. While inflammation persists throughout the course of obesity, a remodeling process takes place with prolonged HFD, leading to a state of adipose tissue repair and a partial resolution of inflammation . If the mice had been fed a HFD for a shorter time period, it is possible that we may have seen an upregulation of receptor expression in the adipose tissue due increased adipose tissue inflammation. At 11weeks, the adipose tissue may begin to adapt to the HFD, and decrease receptor expression in order to prevent excessive lipolysis, when it is in a remodeling stage. The mechanism by which HFD reduces GPR109A and GPR81 expression remains to be elucidated. However, the current and previous investigations indicate that inflammation may play a key role in regulation of receptor expression.
Other highly expressed adipose tissue receptors that give the adipocyte metabolic sensing abilities are GPR43, GPR84, and GPR120, all of which are receptors for endogenous free fatty acids , , . Cornall et al. demonstrated HFD increased GPR43 gene expression in the skeletal muscle and liver, while GPR120 expression was increased in the skeletal muscle and cardiac tissue . They did not examine receptor expression in the adipose tissue. However, others have reported increased adipose tissue expression of GPR43 and GPR120 in response to HFD , . Additionally, Nagasaki et al. reported that GPR84, a receptor for medium-chain fatty acids, is upregulated in the adipose tissue of mice in response to five weeks on a HFD . They also demonstrated that co-culture of 3T3-L1 adipocytes with RAW 264.7 macrophages enhances GPR84 expression in 3T3-L1 adipocytes. We treated RAW 264.7 macrophages and 3T3-L1 adipocytes with CM from the opposing cells and found that treatment with CM from cells treated with LPS significantly increased GPR109A expression in 3T3-L1 adipocytes and enhanced GPR109A expression in RAW 264.7 macrophages, but did not affect GPR81. Thus, the ability of different cell types to affect receptor expression is not dependent on direct contact with the opposing cells, but rather on secreted products. While we did not conduct studies to investigate what that secreted product may be, Nagasaki et al. demonstrated that TNF-α secreted from macrophages enhanced GPR84 expression in adipocytes. Additionally, others have reported that treatment of 3T3-L1 adipocytes with TNF-α increases GPR109A gene expression . TNF-α is secreted by both adipocytes and macrophages, making it a likely candidate for the effects on GPR109A that we observed.
Introduction Hyperglycemia and diabetes mellitus are leading causes of mortality and morbidity worldwide, and it is estimated 347 million people have diabetes globally, mostly type 2 DM (Clement et al, 2004, Danaei et al, 2011). In addition to hyperglycemia, abnormal lipid profiles with increased circulating total and LDL-cholesterol and triglycerides, or hyperlipidemia, are frequently found in severe diabetic patients (Abbate and Brunzell, 1990). The major clinical outcome of hyperlipidemia is atherosclerosis, which is the leading cause of death in the United States and other Western countries (Murray and Lopez, 1997).