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Therefore, transcriptional metabolic control mediated by AMPK-AR signaling appears to be a cellular mechanism that coordinates energy requirements with the testosterone-regulated growth machinery in cardiomyocytes. In this study, we also determine whether glucose metabolism is regulated by androgens in an animal model of cardiac hypertrophy induced by testosterone. AMPK promotes glycolysis through increased glucose uptake by GLUT4 and enzyme activation (e.g., PFK2) . Here, our results showed that testosterone upregulates the transcription of the metabolic enzymes HK2 and PFK2, which are involved in glucose metabolism and glucose oxidative capacity in cardiomyocytes 24, 56, 57. Proposed mechanism for testosterone action on glucose metabolism and cell growth during cardiomyocyte hypertrophy. As depicted in the proposed model for the mechanism of testosterone action on glucose metabolism and cell growth during cardiomyocyte hypertrophy (Fig. 8). Concordant with this idea, the current study indicates that once hypertrophy is consolidated, the increase in glucose uptake persists and glycolysis is activated, which involves AMPK and AR signaling in cardiomyocytes.
In vitro studies have shown that AMPK activators, including metformin and AICAR, significantly reduce progesterone synthesis in the mature corpus luteum, suggesting that AMPK activation inhibits progesterone production, which is a crucial aspect of luteal function and involution . Thus, targeting AMPK could be a potential strategy to improve reproductive management, particularly to improve oestrus synchronisation. Furthermore, the activation of AMPK appears to be a key factor in the response of the mature corpus luteum to prostaglandin F2α (PGF2α), a process that is essential for the involution of the corpus luteum . AMPK also plays a crucial role in the regulation of progesterone production in the corpus luteum of cattle, the activation of which reduces progesterone secretion 21,22.
We have recently provided evidence in the oocyte that α1AMPK could be involved in chromatin remodeling, because we observed an increase in acetylation of H3 histone in oocytes from α1AMPK knockout oocytes (Bertoldo et al., 2015). From the reports to date, we can conclude that effects on fertility (increases or reductions in the number of egg laid depending the time and concentration of metformin treatment) remains partially understood and controversial (He and Wondisford, 2015). Elegans where metformin administration increases the lifespan and produces several diet restriction-like phenotypes such as reduction in fecundity and a decrease in fat storage in animals which are fed ad-libitum (Onken and Driscoll, 2010). Interestingly, increasing AMPK with AICAR in these oocytes during the preovulatory phase corrected the metabolic and meiotic perturbations observed. Glucose metabolism is essential for successful oocyte maturation and the recommencement of meiosis (Downs and Mastropolo, 1994). Ratchford et al. have hypothesized that abnormalities in oocyte metabolism, such as that observed in diabetes, could potentially preprogramme the oocyte for unfavorable outcomes after fertilization (Ratchford et al., 2007).
AMPK is activated in pathophysiological situations (exercise, stress), by metabolic hormones (leptin, adiponectin, ghrelin) or pharmacological agents 5-aminoimidazole-4-carboxamide-1-β-D-riboside (AICAR), metformin and thiazolidinediones (TZD) (Hardie, 2015). It can also be dephosphorylated by phosphatases Protein kinase phosphatase-1 and -2A (PP2A and PP2C) (Lu et al., 2010; Joseph et al., 2015). AMPK is sensitive to the AMP to ATP ratio and is activated by an increasing AMP concentration and by the upstream kinases including liver kinase B1 (LKB1) and calcium/calmodulin (CaM) kinase (CaMKK) (Woods et al., 2003; Hawley et al., 2005). We discuss also the role of AMPK in germ and somatic cell interactions within the cumulus-oocyte complex and in the blood testis barrier. The AMPK inhibitor compound C (Comp. C) attenuates DSE in POMC neurons from… Depolarized-induced suppression of excitation (DSE)…
To validate our model of TP replacement in orchidectomized male guinea pigs, we measured serum testosterone levels taken from gonadally intact as well as orchidectomized animals 2 and 24 h post-TP treatment (400 μg sc) and from orchidectomized animals 2 and 24 h post-vehicle treatment. We first used in vivo behavioral studies in orchidectomized male guinea pigs to examine the role of testosterone on energy intake and expenditure. In some experiments, we perfused the AM-251 (1 μM) along with SR to assess the role of the CB1 receptor in the expression of DSE occurring at ARC synapses. To evaluate whether TP modulates cannabinoid-induced presynaptic inhibition of excitatory input onto ARC neurons via an AMPK pathway, we first monitored miniature excitatory postsynaptic current (mEPSC) frequency and amplitude from a holding potential of −75 mV, using an internal solution in which Cs+ was substituted for K+. Electrophysiological recordings from ARC neurons using biocytin-filled electrodes were performed in hypothalamic slices prepared from orchidectomized guinea pigs treated 24 h prior with either TP (400 μg sc) or its sesame oil vehicle (0.1 ml sc), as described previously (16). We also measured O2 consumption, CO2 production, and the metabolic heat production as indices of energy expenditure. Therefore, we wanted to test the hypothesis that testosterone's effects on energy intake are mediated through augmented endocannabinoid and AMPK signaling.
This supports the notion that AMPK may have a critical role in oocyte developmental competence by maintaining open oocyte-somatic cell communication channels through at least gap, adherens and tight junctions. During repair of lung capillary endothelium α1AMPK promotes the development of intercellular adherens junctions by binding with N-cadherin and contributes to repair (Creighton et al., 2011). Deregulation of these proteins impacts oocyte maturation, fertilization and early embryogenesis (Ziv et al., 2002; Peluso, 2006). In an non-mammalian example, Alesutan et al., demonstrated that active AMPK decreased connexin 26 abundance in the cell membrane in xenopus oocytes (Alesutan et al., 2011), suggesting disparate regulation of gap junction communication by AMPK between species. Reductions in connexin 26 and connexin 37 expression were also described in a diabetic mouse model, where oocyte quality is poor (Ratchford et al., 2008). The connexins family, which compose gap junctions is involved in oocyte/cumulus cell communication and allows passage of ions and small organic molecules. Such that maintenance of gap junction communication and delayed meiotic resumption have been shown to increase oocyte developmental competence (Thomas et al., 2004; Gharibi et al., 2013).
AMPKα expression (A) and phosphorylation (B) in hypogonadal men pre- and post-EHC at… AMPKα expression (A) and phosphorylation (B) in hypogonadal and eugonadal men at 0… AMPKα expression (A) and phosphorylation…
3a and b, AR inhibition with bicalutamide abolished the effects testosterone on glycolysis. C Cardiomyocytes were stimulated with 100 nM testosterone for 10 h and β-mhc mRNA level was determined by RT-qPCR. Testosterone-induced 2-NBDG uptake was measured in the presence or absence of indinavir. A Glucose uptake was measured as 2-NBDG uptake (300 µM) and was normalized to the basal level after exposure to 100 nM testosterone for 24 h. The mRNA levels were normalized to 18S mRNA levels and the values shown here correspond with target-gene/18S mRNA ratios.
Slices were then perfused with the cannabinoid receptor agonist WIN 55,212-2 for 3–4 min, and an additional 3–4 min of data were collected. We perfused slices with aCSF containing TTX (500 nM) and SR (10 μM) to block GABAA receptor-mediated synaptic input. Proteins were separated by electrophoresis on a 10% sodium dodecyl sulfate polyacrylamide gel and transferred to a nitrocellulose membrane. - https://hackmd.okfn.de/s/SyypaPYj-e
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