Abstract 13356: Cardiac Natriuretic Peptides as Activators of the Adaptive Thermogenic Program in Human Adipocytes and in Mice Models
Cardiac natriuretic peptides (NP) ANP and BNP not only contribute to cardiovascular homeostasis but also interact with adipose tissue, being reduced in obesity and metabolic syndrome. To better understand the relation between NP and adipose metabolism we thoroughly investigated their effects on human adipocytes. We show that ANP and BNP, through cGMP and cGMP-dependent protein kinase (PKG) can not only stimulate lipolysis similarly to catecholamines via β-adrenergic receptors (βARs) but also drive adipocytes into a functional brown phenotype. These include robust expression of PGC-1α, uncoupling protein 1 (UCP1), cytochrome c, mitochondrial biogenesis, enhanced cellular bioenergetics and inducible respiratory uncoupling. Surprisingly, we showed that ANP share with βAR a common downstream ‘node’p38 MAPK (p38) to induce the biochemical machinery of brown fat thermogenesis. NPs regulate ATF-2 and PGC-1α itself to increase transactivation of transfected reporter genes for the UCP1 “enhancer” element, directly bound by these transcription factors. Moreover, NPs and βARs in human adipocytes can additively increase UCP1, PGC-1α, cytochrome c, sirtuin3 expression, among others. Mice with gene-disrupted NP clearance receptor are leaner and adipocytes strongly respond to NP as human adipocytes. In contrast, when the active receptor is disrupted (Npra-/-), mice shown significantly higher adipose tissue weights compared to Npra+/+ mice. In conclusion, we can define NPs as cardiometabolic hormones able to increase energy expenditure by mobilizing fatty acids through lipolysis and activating a thermogenic program. Harnessing these features of NPs may improve not only hypertension, but also reduce obesity and its related comorbid conditions.
- © 2011 by American Heart Association, Inc.