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 4

NPs induce UCP1, PGC-1α, and cytochrome c levels in human adipocytes through PKG.

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NPs induce UCP1, PGC-1α, and cytochrome c levels in human adipocytes thr...
(A) hMADS cells were treated or not with ANP, Iso, or the β3-AR agonist L755 (100 nM each), and protein levels were measured by Western blot with GAPDH as the internal standard, as described in Methods. CYTO C, cytochrome c; C, control. (B) As in A after treatment or not with 100 nM BNP. (C) hMADS cells were pretreated or not for 30 minutes with 500 μM PKGi followed by ANP (100 nM, 6 hours), and mRNA levels for indicated genes were measured. Typical cycle threshold values in untreated cells are as follows: UCP1, 27; PGC-1α, 23; CYCS, 20. (D) Human subcutaneous adipocytes were treated as in A and C, and samples were analyzed for protein levels by Western blotting or (E) mRNA levels of indicated genes. Typical cycle threshold values in untreated cells are as follows: UCP1, 29; PGC-1, 24; and cytochrome c, 23. Results are mean ± SD of 3 to 5 independent experiments. **P < 0.01, ***P < 0.001 ANP versus untreated controls; ††P < 0.01 PKGi versus untreated controls.