3a, testosterone (100 nM) increased AMPK phosphorylation, peaking at 3 h to 6 h, and returning to basal levels after 12 h of hormone stimulation. Levels of mRNA for Hk2 were evaluated in cells treated with testosterone 100 nM for 10 h in the presence or absence of bicalutamide (2 µM). A ECAR kinetics in cells treated with bicalutamide (2 µM) and testosterone 100 nM for 24 h. Additionally, we determined the Hk2 mRNA levels after 10 h of testosterone incubation and bicalutamide abolished testosterone-induced increases in mRNA levels of Hk2 (Fig. 3d). Increased glucose uptake through GLUT4 is required to induce cardiomyocyte hypertrophy by testosterone. A Extracellular acidification rate (ECAR) in cells treated with 100 nM testosterone for 24 h. The role of GLUT4-mediated glucose uptake in regulating cardiomyocyte growth induced by testosterone was next assessed by using indinavir.
Two well-known endogenous ligands for cannabinoid receptors are anandamide (13) and 2-arachidonoylglycerol (2-AG) (49), which are produced and released from neurons in a Ca2+-dependent manner (59). TP also increased the basal frequency of miniature inhibitory postsynaptic currents. Electrophysiological studies revealed that TP potentiated the ability of the cannabinoid receptor agonist WIN 55,212-2 to decrease the frequency of miniature excitatory postsynaptic currents in ARC neurons.
Moreover, we observed that AMPK phosphorylation was significantly increased in twofold after 48 h of testosterone stimulation as compared to control non stimulated cells (Fig. 4a). AR is required for glucose metabolic changes in testosterone-induced cardiomyocyte hypertrophy. These results suggest that AR activation signaling is required for increasing glucose uptake and glucose metabolism triggered by testosterone. The increase in hypertrophic markers such as cellular area and β-mhc mRNA levels were prevented by treating cells with 2 µM indinavir prior testosterone stimulation for 24 h (Fig. 2b, c). To investigate whether the increased intracellular glucose resulting from the augmented uptake rate is metabolized via glycolysis, we analyzed, by RT-qPCR the gene expression of Hk2 a key enzyme regulating glycolysis . To determine changes in glucose metabolism upon long-term (24 h) testosterone exposure in cardiomyocytes, we examined glucose uptake and glycolysis. Sato et al. (2008) showed in skeletal muscle, that testosterone activates glucose metabolism, increasing the levels of GLUT4 protein and its translocation to the plasma membrane .
Our finding for long-term testosterone exposure showed phosphorylation peaks at 3, 6 and 48 h. In fact, it has been suggested that AMPK plays dual roles in the development of cardiac hypertrophy 71, 72. AMPK upregulates GLUT4 expression via histone deacetylase (HDAC)5, and MEF2 appears to be the essential regulator of GLUT4 expression .
The AMPK inhibitor compound C attenuated DSE from TP-treated animals, whereas the AMPK activator metformin enhanced DSE from vehicle-treated animals. Subcutaneous administration of the CB1 receptor antagonist AM251 (3 mg/kg) rapidly blocked the hyperphagic effect of TP. Hematoxylin and Eosin staining confirmed the improvement in liver morphology, and further analyses demonstrated that T's effects were mediated via the modulation of AMPK and related lipid metabolism pathways. In the HF diet mouse model, T treatment significantly alleviated hepatic steatosis, lowered body weight, improved glucose tolerance, and normalized lipid profiles, reflecting the results observed in vitro. This activation reduces de novo lipogenesis, suppresses lipid droplet growth, and enhances fatty acid oxidation.
B Glycolysis and maximal glycolytic capacity parameters induced by testosterone (100 nM) after 24 h of stimulation. Insulin (100 nM for 30 min) served as positive control of glucose uptake (Fig. 1c). A total of 12 male 8-week-old Sprague–Dawley rats were used, and orchiectomy (ORX) was performed in 8 rats to reduce circulating levels of testosterone. SiRNA-AMPKα2 (sc , Sta. Cruz Biotechnology) was used to decrease AMPK protein levels. Cells were cultured on gelatin-coated coverslips for 24 h, and then treated for 24 h with testosterone (100 nM), bicalutamide (2 µM) or CC (2 µM).
Similar results have been reported in prostate cancer cells, in which androgen treatment promoted cell growth, depending on AMPK . Here, we determined that AMPK inhibition blocked testosterone-mediated glycolysis and hypertrophy. We and others previously showed that testosterone activates MEF2 in cardiomyocytes 41, 65.
HH was defined as subnormal free testosterone concentration (2). AMPKα is important in mediating the action of exercise and in enhancing glucose transport. This mechanism, although independent of insulin action, can amplify insulin signal transduction, since insulin action also involves AKT kinase and GLUT4. These effects may contribute to the improved insulin sensitivity following testosterone therapy. Testosterone modulates the expression of AMPKα and phosphorylated AMPKα.

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