The role of AMP-activated protein kinase in the androgenic potentiation of cannabinoid-induced changes in energy homeostasis

Orexigenic mediators can impact the hypothalamic feeding circuitry via the activation of AMP-dependent protein kinase (AMPK). Given that testosterone is an orexigenic hormone, we hypothesized that androgenic changes in energy balance are due to enhanced cannabinoid-induced inhibition of anorexigenic...

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Published in:American journal of physiology: endocrinology and metabolism 2015-03, Vol.308 (6), p.E482-E495
Main Authors: Borgquist, Amanda, Meza, Cecilia, Wagner, Edward J
Format: Article
Language:English
Subjects:
AMP-Activated Protein Kinases - physiology
Androgens - pharmacology
Animals
Arcuate Nucleus of Hypothalamus - drug effects
Arcuate Nucleus of Hypothalamus - metabolism
Cannabinoids - pharmacology
Cells
Eating - drug effects
Energy Metabolism - drug effects
Guinea Pigs
Homeostasis - drug effects
Male
Neurons
Neurons - drug effects
Neurons - metabolism
Piperidines - pharmacology
Proteins
Pyrazoles - pharmacology
Receptor, Cannabinoid, CB1 - antagonists & inhibitors
Receptor, Cannabinoid, CB1 - metabolism
Rodents
Testosterone
Testosterone Propionate - pharmacology
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Summary:Orexigenic mediators can impact the hypothalamic feeding circuitry via the activation of AMP-dependent protein kinase (AMPK). Given that testosterone is an orexigenic hormone, we hypothesized that androgenic changes in energy balance are due to enhanced cannabinoid-induced inhibition of anorexigenic proopiomelanocortin (POMC) neurons via activation of AMPK. To this end, whole animal experiments were carried out in gonadectomized male guinea pigs treated subcutaneously with either testosterone propionate (TP; 400 μg) or its sesame oil vehicle (0.1 ml). TP-treated animals displayed increases in energy intake associated with increases in meal size. TP also increased several indices of energy expenditure as well as the p-AMPK/AMPK ratio in the arcuate nucleus (ARC) measured 2 and 24 h posttreatment. Subcutaneous administration of the CB1 receptor antagonist AM251 (3 mg/kg) rapidly blocked the hyperphagic effect of TP. This was mimicked largely upon third ventricular administration of AM251 (10 μg). 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. TP also increased the basal frequency of miniature inhibitory postsynaptic currents. In addition, depolarization-induced suppression (DSE) is potentiated in cells from TP-treated animals and blocked by AM251. The AMPK inhibitor compound C attenuated DSE from TP-treated animals, whereas the AMPK activator metformin enhanced DSE from vehicle-treated animals. These effects occurred in a sizable number of identified POMC neurons. Collectively, these results indicate that the androgen-induced increases in energy intake are mediated via an AMPK-dependent augmentation in endocannabinoid tone onto POMC neurons.
ISSN:0193-1849
1522-1555
DOI:10.1152/ajpendo.00421.2014