PROJECT SUMMARY
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 ß-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. We also find that the expression of other
components of the NP signaling system, such as phosphodiesterase-9 and the peptidase neprilysin are also
decreased in response to cold and ßAR agonists The overall objective of this project is to: define the
transcriptional regulatory mechanisms of the Nprc, Pde9 and Mme genes 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.