Research ArticleMetabolism

Enhancing natriuretic peptide signaling in adipose tissue, but not in muscle, protects against diet-induced obesity and insulin resistance

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Science Signaling  25 Jul 2017:
Vol. 10, Issue 489, eaam6870
DOI: 10.1126/scisignal.aam6870

When fat is more important than muscle

Although natriuretic peptides were originally identified as modifiers of blood pressure, they also exert metabolic effects, and obese individuals have decreased circulating natriuretic peptide concentrations. Wu et al. sought to determine whether these metabolic effects were exerted by signaling in skeletal muscle or adipose tissue. Mice with an adipose tissue–specific deficiency in the natriuretic peptide clearance receptor, which acts to limit natriuretic peptide signaling, were protected from the detrimental metabolic effects of diet-induced obesity, such as insulin resistance, inflammation, and hepatic steatosis. In contrast, mice with a muscle-specific deficiency in the clearance receptor gained weight and developed insulin resistance on a high-fat diet, similar to wild-type mice. These findings suggest that enhancing natriuretic peptide signaling in adipose tissue could be a way to counteract obesity.


In addition to controlling blood pressure, cardiac natriuretic peptides (NPs) can stimulate lipolysis in adipocytes and promote the “browning” of white adipose tissue. NPs may also increase the oxidative capacity of skeletal muscle. To unravel the contribution of NP-stimulated metabolism in adipose tissue compared to that in muscle in vivo, we generated mice with tissue-specific deletion of the NP clearance receptor, NPRC, in adipose tissue (NprcAKO) or in skeletal muscle (NprcMKO). We showed that, similar to Nprc null mice, NprcAKO mice, but not NprcMKO mice, were resistant to obesity induced by a high-fat diet. NprcAKO mice exhibited increased energy expenditure, improved insulin sensitivity, and increased glucose uptake into brown fat. These mice were also protected from diet-induced hepatic steatosis and visceral fat inflammation. These findings support the conclusion that NPRC in adipose tissue is a critical regulator of energy metabolism and suggest that inhibiting this receptor may be an important avenue to explore for combating metabolic disease.

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