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In addition, depolarization-induced suppression (DSE) is potentiated in cells from TP-treated animals and blocked by AM251. It has recently been shown that the deletion of AMPKα in myelogenous cells leads to accelerated atherogenicity in low-density lipoprotein receptor knock-out mice (17, 18). The increase in AMPKα expression following combined insulin and testosterone administration is perhaps a reflection of their synergistic anabolic effects on muscle protein synthesis and growth (7, 12, 13). However, the expression of AMPKα increased following the infusion of insulin and glucose during EHC in both adipose and muscle tissues. We hypothesized that (1) men with HH have a lower expression and phosphorylation of AMP kinase in muscle and adipose tissue, and (2) testosterone replacement restores cellular AMPKα expression and phosphorylation to normal. Following testosterone replacement, the expression of AMPKα did not alter in the fasting state but increased markedly by 41% and 46% in adipose tissue and muscle, respectively, after the clamp. Proposed mechanism for testosterone action on glucose metabolism and cell growth during cardiomyocyte…
Testosterone induced cardiomyocyte hypertrophy that was accompanied by increased glucose uptake, glycolysis enhancement and upregulated mRNA expression of hexokinase 2. Previously, we determined that testosterone increased glucose uptake—via AMP-activated protein kinase (AMPK)—after acute treatment in cardiomyocytes. These findings suggest that, during hypertrophy, testosterone increases glucose consumption, which could be a necessary step for energy production and consequent cellular growth in cardiomyocytes. Moreover, in cardiomyocytes the preincubation with 2 µM CC abolished the increase in glucose uptake (Fig. 6a) and β-mhc mRNA levels (Fig. 6b) induced by testosterone. Moreover, treatment of cardiomyocytes with 100 nM testosterone for 10 h increased the mRNA levels of Hk2, which was inhibited by pretreating cells with 2 µM CC prior testosterone stimulation (Fig. 4a). Cultured cardiomyocytes were stimulated with 100 nM testosterone for 24 h, and hypertrophy was verified by increased cell size and mRNA levels of β-myosin heavy chain (β-mhc).
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.
In bovine COCs, metformin blocks meiotic progression at the germinal vesicle stage, activates AMPK, and inhibits MAPK3/1 phosphorylation in both the oocytes and cumulus cells during in vitro maturation. The results in porcine are supported by those in bovine where supplementation of metformin during embryo in vitro production resulted in AMPK mediated activation of TSC2 (Pikiou et al., 2015) and probably a reduction in TOR complex signaling and protein synthesis inhibition. Nuclear maturation was inhibited, however, this effect was only observed in cumulus enclosed oocytes, suggesting that cumulus cells are essential for AICAR's effect on oocyte maturation. As AMP levels rise, AMPK is triggered and activates a number of enzymes involved in energy producing pathways and inhibiting energy consuming pathways (Downs et al., 2002).
In our study, we found that despite an increase AMPKα expression following EHC in both adipose tissue and skeletal muscle, there was no change in phosphorylated AMPKα. Its synthesis and phosphorylation are dependent upon the nutritional status, such that caloric deprivation (fasting state) results in its activation/increase. It is present even in unicellular organisms performing similar energy related functions. However, the increase in phosphorylated AMPKα following testosterone happened in the absence of change in adiponectin, which we have previously shown does not change following testosterone therapy (2). The replacement of testosterone results in the restoration of insulin sensitivity and the increase in phosphorylated AMPKα.
These metabolic pathways are critical for successful oocyte maturation and resumption of meiosis (Downs and Mastropolo, 1994; Downs et al., 1996; Sutton et al., 2003a,b). The cumulus-oocyte complex (COC) also metabolizes glucose via numerous important pathways such as the pentose phosphate pathway and glycolysis. AMPK improves resumption of oocyte meiosis in mice (Chen et al., 2006; Downs and Chen, 2006; Larosa and Downs, 2007; Chen and Downs, 2008) but not in rats (Downs, 2011) and pharmacological activation of AMPK blocks nuclear oocyte maturation in pigs and cattle (Mayes et al., 2007; Tosca et al., 2007b; Santiquet et al., 2014). These effects were likely to result from a metformin-stimulated AMPK-mediated reduction in cellular proliferation (Kayampilly and Menon, 2012), indicating that the reduction in steroidogenesis occurred as a result of reduced testicular growth. Interestingly the androgen producing Leydig cell population was only reduced in the fetal period at 16 days post-coitum (Tartarin et al., 2012b). An important study for human health found that when human and mouse fetal testes were cultured in the presence of metformin, there was a reduction in testosterone secretion and mRNA of key factors which are involved in steroidogenesis (Tartarin et al., 2012b). Peutz-Jeghers syndrome is an autosomal-dominant disorder that arises as a consequence of mutations in the serine/threonine kinase 11 (STK11) gene that encodes LKB1.
Furthermore, stimulation with 100 nM testosterone for 24 h resulted in significant increases in cardiomyocyte size reaching 1,fivefold compared to control non stimulated cells (Fig. 1f). In order to confirm further the hypertrophic effects of testosterone, we evaluated well-characterized indicators of cardiomyocyte hypertrophy including cell size and mRNA levels of β-myosin heavy chain (β-mhc) . Our results showed that testosterone significantly increased mRNA levels of Hk2 (Fig. 1d). Next, we evaluate glucose uptake changes upon long-term testosterone exposure (24 h), in cardiomyocytes incubated with the fluorescent glucose analog 2-NBDG. As expected, testosterone treatment increased both glycolysis and maximal glycolytic capacity compared to control cardiomyocytes (Fig. 1a, b). Briefly, 80,000 cells/well previously treated with vehicle (0.01% ethanol), testosterone (100 nM), bicalutamide (2 μM, 30 min), or CC (2 μM, 30 min) were cultured in 96-well culture plates using the XF GlycoStress® protocol. Then, cells were treated with activators or inhibitors, prior to stimulation with testosterone.
The GABAA receptor antagonist 6-imino-3-(4-methoxyphenyl)-1(6H)-pyridazinebutanoic acid hydrobromide (SR 95531) was dissolved in ultrapure H2O to stock concentrations of 10 mM, and the stock concentrations were diluted further with aCSF to the working concentration of 10 μM. For the behavioral experiments, testosterone propionate (TP; Sigma-Aldrich, St. Louis, MO) was initially prepared as a 1 mg/ml stock solution in punctilious ethanol. We also examined whether CB1 receptor blockade could dampen the hyperphagia caused by the steroid. There is also an important interaction between ghrelin and cannabinoids, as subanorectic doses of the CB1 receptor antagonist rimonabant inhibited the orexigenic effect of ghrelin upon central administration into the PVN (73). Ghrelin is an orexigenic gut peptide that increases the overall activity of AMPK (2, 51).

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