The epidemic of cardiometabolic disease occurring throughout the world is taking a heavy toll on individuals' quality of life, along with a huge economic impact Excess caloric intake leading to obesity is a major driver of the cardiometabolic syndrome. Brown adipose tissue (BAT) evolved in homeotherms as a mean to maintain body temperature by generating heat from stored calories. Brown adipocytes are highly enriched in mitochondria and express a unique protein called uncoupling protein-1 (UCP1). UCP1 `uncouples' the mitochondrial proton gradient from ATP production, thus avidly consuming glucose and fatty acids with the result being net energy expenditure. Active brown fat is present in adult humans and its amount is significantly correlated with reduced body fat and circulating triglycerides, greater insulin sensitivity, and lowered incidence of Type II diabetes. Increasing brown adipocyte amount and activity could reduce the risk of cardiometabolic disease. The sympathetic nervous system (SNS)-derived catecholamine norepinephrine, which act through ?-adrenergic receptors and cAMP, is a well-established activator of BAT and the recruitment of UCP1-positive cells in white adipose tissue (WAT) depots (a process termed `browning' or `beiging'). We have shown in prior work that the cardiac hormones atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP) also stimulate a similar `browning' program in mouse and human adipocytes, and protect against obesity-associated insulin resistance, hepatic steatosis and inflammation. This suggests that increasing NP signaling in adipose tissues is metabolically beneficial. NP activation of NP receptor A (NPRA) leads to cGMP production, while the NP `clearance receptor' NPRC removes NPs from circulation, and the ratio of NPRA to NPRC determines NP signaling capacity. Clinical studies show that compared to lean individuals, obese individuals have lower circulating NP level, increased NPRC level in adipose tissue, and blunted lipolytic responses to NPs. We observed similar patterns of receptor expression and physiological responses in mice. It has been postulated that higher adipose NPRC levels increases NP clearance, thus reducing NP availability in the circulation and efficacy in target tissues, resulting in a so-called `natriuretic handicap'. On the other hand, conditions such as fasting and cold temperature exposure reduce the level of NPRC expression, resulting in an increased NPRA/NPRC ratio and thus NP/cGMP signaling. Our studies with mouse models further support these observations. However, little is known about the regulation of the Npra and Nprc genes in either rodents or humans. The overall objective of this project is to: define the transcriptional regulatory mechanisms of the Nprc gene in human and mouse adipocytes; determine whether increased levels of NPRC in obesity serves as a `sink' to remove NPs from circulation, thus creating the `natriuretic handicap', and test the effects of selective NP ligands to modulate insulin sensitivity.
The goal of this project is to (i) establish the molecular mechanisms regulating the expression of the natriuretic peptide receptor-C (Nprc) gene in adipocytes and adipose tissue, (ii) test the hypothesis that elevated NPRC expression in adipose tissue results in excessive uptake of the peptides ANP and BNP from the circulation, (iii) and to test in mouse models the efficacy and utility of a longer-acting ANP analogue to increase brown/beige adipocyte amount and activity, thus raising energy expenditure and protecting from obesity-induced insulin. The goal is to understand the mechanics of this pathway to ultimately find molecules that can selectively increase fat burning to fight obesity.
