Cardiac natriuretic peptides act via p38 MAPK to induce the brown fat thermogenic program in mouse and human adipocytes.
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.
Metabolic Signaling and Disease Program, Diabetes and Obesity Research Center, Sanford-Burnham Medical Research Institute, Orlando, Florida 32827, USA.
Marica
M
Bordicchia
Dianxin
D
Liu
Ez-Zoubir
EZ
Amri
Gerard
G
Ailhaud
Paolo
P
Dessì-Fulgheri
Chaoying
C
Zhang
Nobuyuki
N
Takahashi
Riccardo
R
Sarzani
Sheila
S
Collins
D017667:Adipocytes / Q000166:cytology; D000273:Adipose Tissue / Q000378:metabolism; D002001:Adipose Tissue, Brown / Q000378:metabolism*; D000818:Animals; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008928:Mitochondria / Q000378:metabolism; D008957:Models, Genetic; D009206:Myocardium / Q000378:metabolism*; D045265:Natriuretic Peptides / Q000378:metabolism*; D010641:Phenotype; D011943:Receptors, Adrenergic, beta / Q000378:metabolism; D015398:Signal Transduction; D022722:Thermogenesis; D014157:Transcription Factors / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
D045265:Natriuretic Peptides; D011943:Receptors, Adrenergic, beta; D014157:Transcription Factors; D048051:p38 Mitogen-Activated Protein Kinases