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

Publisher: American Society for Clinical Investigation Country of Publication: United States NLM ID: 7802877 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1558-8238 (Electronic) Linking ISSN: 00219738 NLM ISO Abbreviation: J Clin Invest Subsets: MEDLINE

Publication: 1999- : Ann Arbor, MI : American Society for Clinical Investigation
Original Publication: New Haven [etc.] American Society for Clinical Investigation.

Adipose Tissue, Brown/*metabolism ; Myocardium/*metabolism ; Natriuretic Peptides/*metabolism ; p38 Mitogen-Activated Protein Kinases/*metabolism; Adipocytes/cytology ; Adipose Tissue/metabolism ; Animals ; Humans ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Mitochondria/metabolism ; Models, Genetic ; Phenotype ; Receptors, Adrenergic, beta/metabolism ; Signal Transduction ; Thermogenesis ; Transcription Factors/metabolism

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.

Erratum in: J Clin Invest. 2012 Apr 2;122(4):1584.
Comment in: J Clin Invest. 2012 Mar;122(3):804-7. (PMID: 22307322)

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R01 DK053092 United States DK NIDDK NIH HHS; R01DK53092 United States DK NIDDK NIH HHS

0 (Natriuretic Peptides)
0 (Receptors, Adrenergic, beta)
0 (Transcription Factors)
EC 2.7.11.24 (p38 Mitogen-Activated Protein Kinases)

Date Created: 20120207 Date Completed: 20120430 Latest Revision: 20211021

20240829

PMC3287224

10.1172/JCI59701

22307324