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. IntroductionThe cardiac natriuretic peptides (NPs), atrial NP (ANP) and its ventricular companion (BNP), are key hormones in fluid and hemodynamic homeostasis. Their actions are mediated by binding to NP receptor A (NPRA), whose intracellular domain possesses guanylyl cyclase activity to generate the second messenger cGMP (1, 2). Another member of the NP receptor family (NPRC, which is referred to as the clearance receptor) also binds ANP and BNP to remove them from circulation (3). Almost 2 decades ago, NP receptors were unexpectedly found to be expressed in adipose tissue of both rats (4) and humans (5), and, interestingly, levels of NPRC in adipose tissue were found to be sharply decreased by fasting in rats (6). Together, these were some of the first results to suggest that perhaps cardiac NPs have a metabolic role in adipocytes, including a putative role for adipose tissue in the clearance of these peptides from the circulation (7).ANP was subsequently shown to increase lipolysis in human adipocytes, with a potency similar to that of catecholamines (8), which are the well-established physiological pathway controlling lipolysis through activation of the β-adrenergic receptors (β-ARs). Interestingly, the ability of NPs to stimulate lipolysis was reported to be primate specific and apparently absent from rodent adipose tissue (9). To understand this process mechanistically, recall that β-ARs, as the classic stimulator o...

Distinction of white, beige and brown adipocytes derived from mesenchymal stem cells

“…In addition, multiple novel nonadrenergic soluble molecules that are capable of inducing BAT activity and WAT browning have been identified [53] . Although some of these molecules act indirectly by modulating sympathetic activation and the subsequent noradrenergic pathways, several agents [e.g., fibroblast growth factor-21 (FGF21) and the cardiac peptides (ANP/BNP)] appear to have direct effects on brown adipocytes and the browning process [54][55][56] . Recently, the Spiegelman group identified irisin [57] , a novel hormonal factor that converts white fat into the more thermogenic beige fat.…”

MECHANISMS IN ENDOCRINOLOGY: White, brown and pink adipocytes: the extraordinary plasticity of the adipose organ

“…The master (107)). Among these, secreted factors such as ANP (NPPA), BMP8B, irisin and FGF21 that affect brown adipocyte activation and recruitment seem to be particularly promising for the development of new anti-obesity drugs in the near future (22,122,123,124,125).…”

Adipogenesis: new insights into brown adipose tissue differentiation

“…Whereas short-term exposure of hMADS to the peroxisome proliferator-activated receptor g (PPAR g) agonist rosiglitazone induced their differentiation to white adipocytes, chronic treatment with this compound stimulated the development of brown-adipose-like cells (Elabd et al 2009). Moreover, treatment of hMADS with T3 hormone, a well-known activator thermogenesis, or with natriuretic peptides, promotes the expression of UCP1, PPARGC1A, and other factors known to promote mitochondriogenesis and mitochondrial respiration (Bordicchia et al 2012, Lee et al 2012a. Globally considered, this suggests that hMADS could possibly represent a suitable model to study the conversion of white mature adipocyte to brown-adipose-like, although cell numbers obtained are again limited.…”