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,
OBJECTIVEInsulin resistance is associated with elevated content of skeletal muscle lipids, including triacylglycerols (TAGs) and diacylglycerols (DAGs). DAGs are by-products of lipolysis consecutive to TAG hydrolysis by adipose triglyceride lipase (ATGL) and are subsequently hydrolyzed by hormone-sensitive lipase (HSL). We hypothesized that an imbalance of ATGL relative to HSL (expression or activity) may contribute to DAG accumulation and insulin resistance.RESEARCH DESIGN AND METHODSWe first measured lipase expression in vastus lateralis biopsies of young lean (n = 9), young obese (n = 9), and obese-matched type 2 diabetic (n = 8) subjects. We next investigated in vitro in human primary myotubes the impact of altered lipase expression/activity on lipid content and insulin signaling.RESULTSMuscle ATGL protein was negatively associated with whole-body insulin sensitivity in our population (r = −0.55, P = 0.005), whereas muscle HSL protein was reduced in obese subjects. We next showed that adenovirus-mediated ATGL overexpression in human primary myotubes induced DAG and ceramide accumulation. ATGL overexpression reduced insulin-stimulated glycogen synthesis (−30%, P < 0.05) and disrupted insulin signaling at Ser1101 of the insulin receptor substrate-1 and downstream Akt activation at Ser473. These defects were fully rescued by nonselective protein kinase C inhibition or concomitant HSL overexpression to restore a proper lipolytic balance. We show that selective HSL inhibition induces DAG accumulation and insulin resistance.CONCLUSIONSAltogether, the data indicate that altered ATGL and HSL expression in skeletal muscle could promote DAG accumulation and disrupt insulin signaling and action. Targeting skeletal muscle lipases may constitute an interesting strategy to improve insulin sensitivity in obesity and type 2 diabetes.
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