Sex differences in the cannabinoid regulation of energy homeostasis

Abstract

Summary This review highlights the progress made thus far in characterizing the behavioral and cellular mechanisms through which cannabinoids regulate energy homeostasis. We performed microstructural analysis of feeding behavior in gonadectomized guinea pigs and gonadally intact, transgenic CB1 receptor knockout mice to determine how cannabinoids affect circadian rhythms in food intake and meal pattern. We also implanted data loggers into the abdominal cavity to correlate the appetite-modulating properties of cannabinoids with changes in core body temperature. We then coupled the effects on feeding behavior and temperature regulation with synaptic changes in the hypothalamic feeding circuitry via whole-cell patch clamp electrophysiological recording from neurons in the arcuate nucleus (ARC), in order to gain a more global perspective on the cannabinoid modulation of energy homeostasis. We observed marked sex differences in cannabinoid effects on food intake and core body temperature — with male guinea pigs exhibiting a comparatively greater sensitivity to the hyperphagia and hypophagia, as well as the hypothermia and hyperthermia, produced by CB1 receptor agonists and antagonists, respectively. In addition, male but not female CB1 receptor knockout mice show a diminished nocturnal food intake and average daily body weight relative to their wildtype littermate controls. The disparity in the CB1 receptor-mediated hyperphagia is paralleled by sex differences in the cellular effects of cannabinoids at anorexigenic, guinea pig proopiomelanocortin (POMC) synapses. Postsynaptically, cannabinoids potentiate an A-type K+ current (IA) in POMC neurons from female guinea pigs, whereas in males the activation of an inwardly rectifying K+ current is observed. Presynaptically, while cannabinoids inhibit glutamatergic input onto POMC neurons in males and females to similar degrees, males are more refractory to the cannabinoid-induced inhibition of convergent GABAergic input than females. These data reveal pervasive sex differences in the cannabinoid regulation of energy homeostasis that are consistent with changes in the excitability of POMC neurons.

Cigarette smoking may modify the association between cannabis use and adiposity in males

“…We found that cigarette smoking in males modifies the association between cannabis use and change in adiposity. Sex differences at the level of the pro-opiomelanocortin (POMC) neuron synapse, which are involved in stress response, feeding behavior and weight gain, may partly explain the interaction (Farhang et al, 2009). CB 1 activation of these synapses results in increased excitation in females and in inhibition in male animals (Farhang et al, 2009).…”

“…Sex differences at the level of the pro-opiomelanocortin (POMC) neuron synapse, which are involved in stress response, feeding behavior and weight gain, may partly explain the interaction (Farhang et al, 2009). CB 1 activation of these synapses results in increased excitation in females and in inhibition in male animals (Farhang et al, 2009). POMC synapses are also influenced by nicotine through a nicotine receptor located on its membrane (Mineur et al, 2011).…”

“…THC is the active component of cannabis, which is the most widely used illicit drug, with an estimated 125 to 203 million users world-wide (United Nations Office on Drugs and Crime, 2011). Its actions differ by sex at cellular and endocrine levels such that its homeostatic effects are more extreme in men, while its effects on anxiety and depression are more extreme in women (Farhang et al, 2009;Fattore and Fratta, 2010;Viveros et al, 2012).…”

Cannabinoid Receptor 1 (<i>CNR1</i>) <i>4895 C/T</i> Genetic Polymorphism was Associated with Obesity in Japanese Men

“…An experimental study also demonstrated that male but not female CNR1 knockout mice had diminished nocturnal food intake and average daily body weight as compared to their wild type littermates. In addition, gonadectomized guinea pigs showed considerably more robust stimulation of intake in males than in females 18) . In this study, while CNR1 4895 C/T polymorphism showed a significant association with WC, no significant association was found with central obesity based on WC.…”

Orphanin FQ-ORL-1 Regulation of Reproduction and Reproductive Behavior in the Female

“…ORL-1 can act at the presynaptic terminal to inhibit neurotransmitter release to the β-END neuron through reducing the activity of voltage-gated calcium channels (Farhang, Diaz, Tang, & Wagner, 2009). For example, OFQ/N presynaptically inhibits excitatory glutamatergic input to ARH neurons (Emmerson & Miller, 1999;Wagner et al, 1998).…”