Modulatory influences of estradiol and other anorexigenic hormones on metabotropic, Gi/o-coupled receptor function in the hypothalamic control of energy homeostasis. Issue 160 (June 2016)

• Record Type: Journal Article
• Authors: Mela, Virginia; Vargas, Amanda; Meza, Cecilia; Kachani, Malika; Wagner, Edward J.
• Is Part Of: Journal of steroid biochemistry and molecular biology. Issue 160(2016)
• Page Start: 15
• Page End: 26
• Publication Date: 2016-06
• Subjects: 2-AG 2-arachidonoylglycerol -- AgRP agouti-related peptide -- AMPK AMP-activated protein kinase -- ARC hypothalamic arcuate nucleus -- CRH corticotropin-releasing hormone -- DSI depolarization-induced suppression of inhibition -- ERK extracellular signal-regulated protein kinase -- GIRK G protein-gated, inwardly-rectifying K+ -- JAK Janus kinase -- LHA lateral hypothalamic area -- MCH melanin-concentrating hormone -- mEPSC miniature excitatory postsynaptic current -- nNOS neuronal nitric oxide synthase -- NPY neuropeptide Y -- OFQ/N orphanin FQ/nociceptin -- ORL opioid receptor-like -- PI3K phosphatidylinositol-3-kinase -- PLC phospholipase C -- PKC protein kinase C -- POMC proopiomelanocortin -- PVN hypothalamic paraventricular nucleus -- SF steroidogenic factor -- STAT signal transducer and activator of transcription -- THC tetrahydrocannabinol -- TRPC transient receptor potential C -- VMN hypothalamic ventromedial nucleus; Cachexia -- Cannabinoid -- Sex difference -- Estradiol -- Nociceptin -- Leptin -- Phosphatidylinositol-3-kinase; Steroid hormones -- Periodicals; Biochemistry -- Periodicals; Hormones -- Periodicals; Molecular Biology -- Periodicals; Hormones stéroïdes -- Périodiques; Steroid hormones; Periodicals; 572.579
• DOI: 10.1016/j.jsbmb.2015.07.014
• Languages: English
• ISSNs: 0960-0760

Abstract

Highlights: CB1 and ORL1 receptors are orexigenic, Gi/o -coupled receptors. Estradiol and leptin physiologically antagonize the function of these receptors. This may be a fundamental mechanism by which anorexigenic hormones suppress appetite. Abstract: The appetite suppressant actions of estradiol are due to its ability to attenuate orexigenic signals and potentiate anorexigenic signals. The work from my laboratory has shown that male guinea pigs are more sensitive to the hyperphagic and hypothermic effects of cannabinoids than their female counterparts. Cannabinoid sensitivity is further dampened by the activational effects of estradiol. This occurs via the hypothalamic feeding circuitry, where estradiol rapidly attenuates the cannabinoid CB1 receptor-mediated presynaptic inhibition of glutamatergic input onto anorexigenic proopiomelanocortin (POMC) neurons in the arcuate nucleus. This disruption is blocked by the estrogen receptor antagonist ICI 182, 780, and associated with increased expression of phosphatidylinositol-3-kinase (PI3K). Moreover, the ability of estradiol to reduce both the cannabinoid-induced hyperphagia and glutamate release onto POMC neurons is abrogated by the PI3K inhibitor PI 828. The peptide orphanin FQ/nociceptin (OFQ/N) activates opioid receptor-like (ORL)1 receptors to hyperpolarize and inhibit POMC neurons via the activation of postsynaptic G protein-gated, inwardly-rectifying (GIRK) channels. We have demonstrated that the fasting-induced hyperphagia observed in ORL1-null mice is blunted compared to wild type controls. In addition, the ORL1 receptor-mediated activation of GIRK channels in POMC neurons from ovariectomized female rats is markedly impaired by estradiol. The estrogenic attenuation of presynaptic CB1 and postsynaptic ORL1 receptor function may be part of a more generalized mechanism through which anorexigenic hormones suppress orexigenic signaling. Indeed, we have found that leptin robustly suppresses the OFQ/N-induced activation of GIRK channels in POMC neurons. Furthermore, its ability to augment excitatory input onto POMC neurons is blocked by PI 828. Thus, estradiol and other hormones like leptin reduce energy intake at least partly by activating PI3K to disrupt the pleiotropic functions of Gi/o -coupled receptors that inhibit anorexigenic POMC neurons.