Cardiac natriuretic peptides act via p38 MAPK to induce the brown fat thermogenic program in mouse and human adipocytes
Marica Bordicchia, … , Riccardo Sarzani, Sheila Collins
Marica Bordicchia, … , Riccardo Sarzani, Sheila Collins
Published February 6, 2012
Citation Information: J Clin Invest. 2012;122(3):1022-1036. https://doi.org/10.1172/JCI59701.
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Research Article

Cardiac natriuretic peptides act via p38 MAPK to induce the brown fat thermogenic program in mouse and human adipocytes

Abstract

The ability of mammals to resist body fat accumulation is linked to their ability to expand the number and activity of “brown adipocytes” within white fat depots. Activation of β-adrenergic receptors (β-ARs) can induce a functional “brown-like” adipocyte phenotype. As cardiac natriuretic peptides (NPs) and β-AR agonists are similarly potent at stimulating lipolysis in human adipocytes, we investigated whether NPs could induce human and mouse adipocytes to acquire brown adipocyte features, including a capacity for thermogenic energy expenditure mediated by uncoupling protein 1 (UCP1). In human adipocytes, atrial NP (ANP) and ventricular NP (BNP) activated PPARγ coactivator-1α (PGC-1α) and UCP1 expression, induced mitochondriogenesis, and increased uncoupled and total respiration. At low concentrations, ANP and β-AR agonists additively enhanced expression of brown fat and mitochondrial markers in a p38 MAPK–dependent manner. Mice exposed to cold temperatures had increased levels of circulating NPs as well as higher expression of NP signaling receptor and lower expression of the NP clearance receptor (Nprc) in brown adipose tissue (BAT) and white adipose tissue (WAT). NPR-C–/– mice had markedly smaller WAT and BAT depots but higher expression of thermogenic genes such as Ucp1. Infusion of BNP into mice robustly increased Ucp1 and Pgc-1α expression in WAT and BAT, with corresponding elevation of respiration and energy expenditure. These results suggest that NPs promote “browning” of white adipocytes to increase energy expenditure, defining the heart as a central regulator of adipose tissue biology.

Authors

Marica Bordicchia, Dianxin Liu, Ez-Zoubir Amri, Gerard Ailhaud, Paolo Dessì-Fulgheri, Chaoying Zhang, Nobuyuki Takahashi, Riccardo Sarzani, Sheila Collins

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Figure 12

Model for parallel β-AR and NPRA activation of p38 MAPK to trigger expression of the brown fat thermogenic gene program.

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Model for parallel β-AR and NPRA activation of p38 MAPK to trigger expre...
Catecholamines bind the heptahelical β-ARs on adipocytes to activate the G protein Gs and increase cAMP (pink ovals). cAMP binds the regulatory (R) subunits of PKA. The released catalytic (C) subunits (purple ovals) can then phosphorylate targets, including HSL and perilipin (Peri A), to allow lipolysis of stored triglycerides. Lipolysis can also be activated by NPs. ANP and BNP bind to guanylyl cyclase (GC) receptor NPRA to increase cGMP (yellow circles). Adipocytes also express NPRC that mainly removes NPs from circulation. The cGMP produced by NPRA activates PKG (α and β subunits are represented as thin green and yellow ovals, respectively), whose substrate specificity for phosphorylation closely overlaps that of PKA. Thus, PKG can phosphorylate the same targets as PKA to elicit lipolysis. β-ARs and PKA can also activate a protein kinase cascade, culminating in the activation of p38α MAPK (p38 MK). Now, we can add NPs and PKG as parallel activators of p38α MAPK. Thus, in response to β-agonist or NPs, p38α MAPK phosphorylates (light blue ovals) the transcriptional regulators ATF2 and PGC-1α. PGC-1α interacts with PPARγ and RXRα. These phosphorylated and activated factors are recruited to specific motifs within the UCP1 enhancer (PPRE, CRE2) to increase its gene expression (blue arrow). ATF2 also binds the CRE in the PGC-1α promoter to increase transcription (blue arrow) and increase the amount of PGC-1α.