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Science Signaling Podcast for 25 July 2017: Natriuretic peptide signaling in metabolism

2017-07-25T10:53:13-07:00

Abstract

This Podcast features a conversation with Shelia Collins, senior author of a Research Article that appears in the 25 July 2017 issue of Science Signaling, about how cardiac natriuretic peptides (NPs) exert their beneficial effects on whole-body metabolism. NPs control blood pressure by acting on the kidneys, but they also affect metabolism by stimulating adipose tissue and skeletal muscle to become more metabolically active. Obese individuals have less of these peptides circulating in their blood, suggesting a connection between NP signaling and obesity. NPs stimulate intracellular signaling by binding to and activating the receptors NPRA and NPRB. A third receptor, the NP clearance receptor (NPRC), antagonizes signaling through NPRA and NPRB by binding to and stimulating the internalization and degradation of NPs. To determine whether the beneficial metabolic effects of NPs were due to the action of these peptides in adipose tissue or in skeletal muscle, Wu et al. knocked out NPRC specifically in these tissues in mice. Although mice lacking NPRC in skeletal muscle responded similarly to a high-fat diet as wild-type mice, mice lacking NPRC in adipose tissue were resistant to many of the detrimental metabolic effects of a high-fat diet. These findings suggest that stimulating NP signaling or inhibiting NPRC in adipose tissue may be a potential strategy for treating metabolic disease.

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Papers of note in Science Translational Medicine 9 (399)

2017-07-25T10:53:13-07:00

This week’s articles describe how CAR T cells might be used to treat recurrent glioblastoma and how microvascular cells induce inflammation in the autoimmune disease giant cell arteritis.




Paper of note in Science 357 (6348)

2017-07-25T10:53:13-07:00

This week’s article is a review that highlights how epigenetic factors may make cells more or less susceptible to oncogenic transformation.




Papers of note in Nature 547 (7663)

2017-07-25T10:53:13-07:00

This week’s articles identify a surprising role for dopamine outside the nervous system and a cryptic binding pocket that promotes leak currents through a potassium channel.




Olfactory control of metabolism

2017-07-25T10:53:13-07:00

Activation of olfactory sensory neurons promotes adiposity and insulin resistance in mice.




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

2017-07-25T10:53:13-07:00

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.




The glucocorticoid-Angptl4-ceramide axis induces insulin resistance through PP2A and PKC{zeta}

2017-07-25T10:53:13-07:00

Chronic glucocorticoid exposure is associated with the development of insulin resistance. We showed that glucocorticoid-induced insulin resistance was attenuated upon ablation of Angptl4, a glucocorticoid target gene encoding the secreted protein angiopoietin-like 4, which mediates glucocorticoid-induced lipolysis in white adipose tissue. Through metabolomic profiling, we revealed that glucocorticoid treatment increased hepatic ceramide concentrations by inducing enzymes in the ceramide synthetic pathway in an Angptl4-dependent manner. Angptl4 was also required for glucocorticoids to stimulate the activities of the downstream effectors of ceramide, protein phosphatase 2A (PP2A) and protein kinase C (PKC). We further showed that knockdown of PP2A or inhibition of PKC or ceramide synthesis prevented glucocorticoid-induced glucose intolerance in wild-type mice. Moreover, the inhibition of PKC or ceramide synthesis did not further improve glucose tolerance in Angptl4–/– mice, suggesting that these molecules were major downstream effectors of Angptl4. Overall, our study demonstrates the key role of Angptl4 in glucocorticoid-augmented hepatic ceramide production that induces whole-body insulin resistance.