The Role of Phosphatidylinositol-3-Kinase and AMP-Activated Kinase in the Rapid Estrogenic Attenuation of Cannabinoid-Induced Changes in Energy HomeostasisReport as inadecuate




The Role of Phosphatidylinositol-3-Kinase and AMP-Activated Kinase in the Rapid Estrogenic Attenuation of Cannabinoid-Induced Changes in Energy Homeostasis - Download this document for free, or read online. Document in PDF available to download.

Department of Basic Medical Sciences, Western University of Health Sciences, Pomona, CA 91766, USA





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Abstract We sought to determine the involvement of phosphatidyl inositol 3-kinase PI3K and AMP-activated protein kinase AMPK in the estrogenic antagonism of the cannabinoid regulation of energy homeostasis. Food intake and body weight were evaluated in ovariectomized female guinea pigs treated s.c. with estradiol benzoate EB or its sesame oil vehicle, or the CB1 receptor antagonist AM251 or its cremephor-ethanol-0.9% saline vehicle. AMPK catalytic subunit, PI3K p85α regulatory subunit and proopiomelanocortin POMC gene expression was assessed via quantitative RT-PCR in microdissected hypothalamic tissue. Whole-cell patch clamp recordings were performed in hypothalamic slices. Both EB and AM251 decreased food intake and weight gain, and increased AMPKα1, AMPKα2 and PI3K p85α gene expression in the mediobasal hypothalamus. 17β-Estradiol rapidly and markedly attenuated the decreases in glutamatergic miniature excitatory postsynaptic current mEPSC frequency caused by the cannabinoid receptor agonist WIN 55,212-2 in POMC neurons. This rapid estrogenic diminution of cannabinoid-induced decreases in mEPSC frequency was blocked by the estrogen receptor ER antagonist ICI 182,780 and the PI3K inhibitor PI 828, the latter of which also prevented the AM251-induced increase in mEPSC frequency. In addition, the AMPK activator metformin reversed the EB-induced decreases in food intake and weight gain and restored the ability of WIN 55,212-2 to reduce mEPSC frequency. These data reveal that estrogens physiologically antagonize cannabinoid-induced changes in appetite and POMC neuronal activity by activating PI3K and inhibiting AMPK. As such, they provide insight into the neuroanatomical substrates and signal transduction mechanisms upon which these counter-regulatory factors converge in the control of energy homeostasis. View Full-Text

Keywords: estrogen; POMC; appetite; cannabinoids; PI3K; AMPK estrogen; POMC; appetite; cannabinoids; PI3K; AMPK





Author: Garrett S. Jeffery, Kelly C. Peng and Edward J. Wagner *

Source: http://mdpi.com/



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