Leptin prevents the metabolic effects of adiponectin in L6 myotubes

Abstract

Aims/hypothesis Adiponectin and leptin are negatively and positively correlated with human obesity respectively, and have both been shown to regulate energy metabolism in skeletal muscle. However, little is known about their signalling and functional crosstalk. Here we investigated the effects of leptin on metabolic actions of (1) globular adiponectin (gAd) and (2) full-length adiponectin (fAd) in L6 cells. Methods Glucose uptake was measured upon gAd and fAd treatment after incubation with different doses (0.3, 0.6, 3, 6, 60 nmol/l) of leptin for 6, 12 and 24 h. We also measured adiponectin receptor (ADIPOR) expression and stimulation of downstream signalling by gAd and fAd using coimmunoprecipitation and western blotting following leptin pretreatment, as well as analysis of fatty acid uptake and oxidation using radiolabelled tracers. Results Leptin attenuated the stimulation of glucose uptake by gAd and fAd in a dose-and time-dependent manner, a finding correlated with decreased levels of ADIPOR1 and ADIPOR2. gAd and fAd increased palmitate uptake via activation of AMP protein kinase (T172), enhanced expression of the fatty acid transporter CD36, phosphorylated acetyl-CoA carboxylase (S79) and enhanced palmitate oxidation, all of which were attenuated by leptin pretreatment. Adiponectin can also enhance insulin sensitivity via direct signalling crosstalk; here we show that enhanced insulin-stimulated IRS-1 (Y612) and Akt (T308) phosphorylation in response to fAd was attenuated by leptin. APPL1 was recently identified as a critical mediator of adiponectin action in skeletal muscle. We demonstrated that leptin attenuated binding of APPL1 to LKB1, a downstream target leading to AMPK phosphorylation. Conclusions/interpretation The direct metabolic and insulin-sensitising effects of adiponectin were attenuated in the presence of leptin.

Mitochondrial Biogenesis and Peroxisome Proliferator–Activated Receptor-γ Coactivator-1α (PGC-1α) Deacetylation by Physical Activity

“…Although chronic leptin treatment in rodents was shown to increase AMPK expression and activation (47), others did not detect significant changes in the expression of mitochondrial genes in response to leptin treatment compared with pair-fed mice (48). Furthermore, whereas leptin-mediated activation of AMPK was demonstrated in H9C2 cardiomyoblasts (49), others have reported that leptin attenuates AMPK activation induced by globular or full-length adiponectin in L6 myotubes (50). Thus, whereas adiponectin has consistently been shown to activate AMPK, the effects of leptin are more obscure and may depend on additional not-yet-identified coactivators.…”

Adipokines promote lipotoxicity in human skeletal muscle cells

“…selective up-regulation of CD36 protein abundance by CM as well as PA. Heat-inactivation of CM prevented this effect thus indicating that possible causative agents are protein factors. Several factors were already described to up-regulate CD36 in different cell types such as interleukin-4 in monocytes (Yesner et al, 1996), and adiponectin in L6 myotubes (Fang et al, 2009). Another factor potentially involved in up-regulating CD36 is thrombospondin-1 (TSP1).…”

Adiponectin Action: A Combination of Endocrine and Autocrine/Paracrine Effects

“…Cell based in vitro studies show adiponectin can increase both basal and insulin-stimulated glucose uptake by promoting GLUT4 translocation to the cell membrane (Ceddia et al, 2005; Fang et al, 2005, 2009; Mao et al, 2006a) and increase fatty acid uptake and oxidation (Tomas et al, 2002; Yoon et al, 2006) through the activation of AMPK, p38-MAPK, and PPARα pathways (Yamauchi et al, 2002, 2003b; Yoon et al, 2006). Animal model studies in vivo correlate well with these observations as systemic infusion, adenoviral-based delivery or genetic overexpression of adiponectin can successfully correct high-fat diet-induced insulin resistance in skeletal muscle and decrease serum TG and FFA levels (Yamauchi et al, 2001, 2003c; Maeda et al, 2002; Combs et al, 2004).…”