Supplementation with N-carbamoyl glutamic acid reversed these effects by increasing mTOR and phosphorylated protein kinase B (pAKT) levels and decreasing pAMPK levels; it also significantly increased the implantation rate of embryos. On the other hand, the inactivation of α1AMPK in Sertoli cells, reduces the expression of mitochondrial markers (cytochrome c and PGC1a) and the ATP content, and increases the lactate production (Bertoldo et al., 2013). Furthermore, Kayampilly and Menon observed that exposure of rat granulosa cells with a pharmacological activator of AMPK increased p27kip expression, an inhibitor of the cell cycle (Kayampilly and Menon, 2009). In conclusion, the results of the present study demonstrate that testosterone increases energy intake in male guinea pigs via activation of AMPK in the ARC and augmentation of endocannabinoid tone in anorexigenic POMC neurons. Finally, although testosterone was without effect on the rather modest, cannabinoid-induced, presynaptic inhibition of GABA release onto POMC neurons, it markedly elevated basal inhibitory input received by these cells. Testosterone enhanced the cannabinoid-induced presynaptic inhibition of glutamate release onto POMC neurons and augmented endocannabinoid-mediated DSE in these cells via activation of AMPK. Therefore, CB1 receptors are less effective in decreasing glutamatergic neurotransmission, leading to increased excitation of POMC neurons and enhanced anorexigenic tone within the hypothalamic feeding circuitry that accounts for the ability of estradiol to reduce cannabinoid-induced hyperphagia in females (39, 77). 8A, a 30-nM dose of WIN 55,212-2 modestly increased the interval between contiguous mEPSCs in recordings from orchidectomized, vehicle-treated animals. In a parallel series of experiments, we endeavored to gain a better understanding of how these TP-induced changes in energy intake are occurring on a cellular level. The cells from vehicle-treated animals had a RMP of −51.7 ± 1.4 mV and a Rin of 648.3 ± 52.5 MΩ, whereas those from TP-treated animals had a RMP of −52.9 ± 1.4 mV and a Rin of 755.6 ± 63.3 MΩ. 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 . 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.
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