Atrial natriuretic peptide (ANP) receptors have been described on rodent adipocytes and expression of their mRNA is found in human adipose tissue. However, no biological effects associated with the stimulation of these receptors have been reported in this tissue. A putative lipolytic effect of natriuretic peptides was investigated in human adipose tissue. On isolated fat cells, ANP and brain natriuretic peptide (BNP) stimulated lipolysis as much as isoproterenol, a nonselective beta-adrenergic receptor agonist, whereas C-type natriuretic peptide (CNP) had the lowest lipolytic effect. In situ microdialysis experiments confirmed the potent lipolytic effect of ANP in abdominal s.c. adipose tissue of healthy subjects. A high level of ANP binding sites was identified in human adipocytes. The potency order defined in lipolysis (ANP > BNP > CNP) and the ANP-induced cGMP production sustained the presence of type A natriuretic peptide receptor in human fat cells. Activation or inhibition of cGMP-inhibited phosphodiesterase (PDE-3B) (using insulin and OPC 3911, respectively) did not modify ANP-induced lipolysis whereas the isoproterenol effect was decreased or increased. Moreover, inhibition of adenylyl cyclase activity (using a mixture of alpha(2)-adrenergic and adenosine A1 agonists receptors) did not change ANP- but suppressed isoproterenol-induced lipolysis. The noninvolvement of the PDE-3B was finally confirmed by measuring its activity under ANP stimulation. Thus, we demonstrate that natriuretic peptides are a new pathway controlling human adipose tissue lipolysis operating via a cGMP-dependent pathway that does not involve PDE-3B inhibition and cAMP production.

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Cardiac natriuretic peptides (NP) are major activators of human fat cell lipolysis and have recently been shown to control brown fat thermogenesis. Here, we investigated the physiological role of NP on the oxidative metabolism of human skeletal muscle. NP receptor type A (NPRA) gene expression was positively correlated to mRNA levels of PPARγ coactivator-1α (PGC1A) and several oxidative phosphorylation (OXPHOS) genes in human skeletal muscle. Further, the expression of NPRA, PGC1A, and OXPHOS genes was coordinately upregulated in response to aerobic exercise training in human skeletal muscle. In human myotubes, NP induced PGC-1α and mitochondrial OXPHOS gene expression in a cyclic GMP-dependent manner. NP treatment increased OXPHOS protein expression, fat oxidation, and maximal respiration independent of substantial changes in mitochondrial proliferation and mass. Treatment of myotubes with NP recapitulated the effect of exercise training on muscle fat oxidative capacity in vivo. Collectively, these data show that activation of NP signaling in human skeletal muscle enhances mitochondrial oxidative metabolism and fat oxidation. We propose that NP could contribute to exercise training-induced improvement in skeletal muscle fat oxidative capacity in humans. IntroductionThe cardiac hormones, atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP), play a major role in the regulation of fluid homeostasis and cardiac physiology (1). Natriuretic peptidemediated (NP-mediated) biological responses are largely mediated through cyclic GMP (cGMP) produced by the guanylyl cyclase domain of NP receptor type A (NPRA) (2). Although classically considered as cardiovascular hormones, we have shown that NP display a potent lipolytic effect in human adipocytes (3). They promote a rapid and sustained rise of intracellular cGMP that activates a cGMP-dependent protein kinase, PRKG1, which then phosphorylates perilipin 1 and hormone-sensitive lipase, necessary steps to initiate lipolysis (4). The potent lipolytic effect of NP is restricted to primates. In contrast, murine adipocytes exhibit a predominance of the clearance receptor NP receptor type C (NPR-C) and a very low expression of the biologically active NPRA (5). Interestingly, the lipolytic effect of NP is fully rescued in adipocytes of NPR-C (also known as Npr3) knockout mice. Moreover, NP induce a "browning" of human white adipocytes (6). This finding may be physiologically relevant considering the presence of functional brown fat in humans (7). Together, these studies suggest that NP plays a potent metabolic role in human adipose tissue. Recent data suggest that mice overexpressing Nppb and Prkg1 are protected from high-fat diet-induced obesity and insulin resistance and show increased energy expenditure (8). This phenotype could be explained by significant changes in skeletal muscle fat oxidative capacity. The physiological relevance and molecular mechanisms of this finding have yet to be addressed in humans. In this study,