Modulatory influences of estradiol and other anorexigenic hormones on metabotropic, Gi/o-coupled receptor function in the hypothalamic control of energy homeostasis

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.

Rapid steroid hormone actions via membrane receptors

“…The modulation of these hypothalamic homeostatic functions by E 2 is due in large part to the attenuation of the coupling of metabotropic G i/o coupled receptors and their effector systems [102,103]. One example of this is in E 2 's regulation of STE20/ SPS1-related proline alanine rich kinase (SPAK) and oxidative stress response kinase (OSR1), which affects Na + -K + -2Cl − (NKCCl) activation and subsequent GABA depolarization, which is essential for normal gonadotropin secretion and hypothalamic homeostasis in developing brains [104].…”

Sex differences in cannabinoid-regulated biology: A focus on energy homeostasis

“…Activation of these receptors by estradiol elicits a signal transduction cascade involving phosphatidylinositol-3-kinase (PI3K), protein kinase C (PKC), protein kinase A (PKA) and neuronal nitric oxide synthase (nNOS) to unravel the coupling of the presynaptic CB1 receptors to their effector systems (Borgquist et al, 2015a; Mela et al, 2015; Washburn et al, 2013) (Figure 1). PI3K is a signaling molecule that is activated upon both ERα and ERβ stimulation (Gingerich and Krukoff, 2008; Smith et al, 2013), as well as by other anorexigenic hormones such as leptin and insulin (Hill et al, 2008; Mela et al, 2015; Qiu et al, 2014), within various elements of the hypothalamic feeding circuitry. PI3K signaling in murine POMC neurons plays an important role in the ERα-mediated regulation of appetite and insulin sensitivity (Zhu et al, 2015).…”

“…The same is likely to hold true for the cannabinoid regulation of energy balance. Estradiol negatively modulates metabotropic, G i/o -coupled receptor function in guinea pigs, rats and mice (Mela et al, 2015; Qiu et al, 2006). However, there is striking variability in how (or if) cannabinoids influence POMC neuronal excitability to affect changes in energy intake in mice.…”

“…Alternatively, the nitric oxide produced may act retrogradely to uncouple the CB1 receptor from its effector system(s) in the glutamatergic nerve terminal. Modified from (Mela et al, 2015). …”

Extra-gonadal sites of estrogen biosynthesis and function

“…Food intake is significantly decreased during the preovulatory period when estradiol levels are increasing (114). These actions are attributed to estradiol inhibiting appetite indirectly through cannabinoid receptors (115). Further, blocking estrogen receptors with ICI182,270 ablates any action of estradiol on appetite (115).…”