Sex Differences in the Cannabinoid Modulation of Appetite, Body Temperature and Neurotransmission at POMC Synapses

Abstract

We sought to determine whether sex differences exist for the cannabinoid modulation of appetite, body temperature and neurotransmission at pro-opiomelanocortin (POMC) synapses. Gonadectomized male and female guinea pigs were outfitted to monitor core body temperature and injected with either the CB1 receptor agonist WIN 55,212-2 (1 mg/kg s.c.), antagonist AM251 (3 mg/kg s.c.) or vehicle (1 ml/kg s.c.) and evaluated for changes in six indices of feeding behavior under ad libitum conditions for 7 days. WIN 55,212-2 elicited an overt, sexually differentiated hyperphagia in which males displayed larger increases in hourly and daily intake, consumption/gram body weight, meal size and meal duration. The agonist also produced a more robust acute hypothermia in males than in females. In addition, males were more sensitive to the hypophagic effect of AM251, manifested by comparatively sizeable decreases in hourly intake, consumption/gram body weight, meal frequency and hyperthermia. To gain additional insight into the cellular mechanism underlying cannabinoid regulation of energy homeostasis, we performed whole-cell patch clamp recordings in hypothalamic slices prepared from gonadectomized male and female guinea pigs, and monitored miniature excitatory and inhibitory postsynaptic currents (mEPSCs and mIPSCs) in arcuate (ARC) neurons. ARC neurons from females exhibited a higher basal mEPSC frequency. WIN 55,212-2 dose-dependently reduced mEPSC and mIPSC frequency; however, cells from males were far less sensitive to the CB1 receptor-mediated decrease in mIPSC frequency. These effects were observed in neurons subsequently identified as POMC neurons. These data reveal pronounced sex differences in how cannabinoids influence the hypothalamic control of homeostasis.

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

“…This was corroborated several years later using our guinea pig animal model, when we showed the cannabinoid receptor agonist WIN 55,212-2 stimulated cumulative energy intake to a greater extent in orchidectomized males than it did in ovariectomized females (Diaz et al, 2009). This was associated with sexually disparate changes in meal pattern; with males exhibiting cannabinoid-induced increases in meal size, meal frequency and meal duration, and females exhibiting an increase in meal frequency only (Diaz et al, 2009). In addition, males are more sensitive to the hypothermic effects of cannabinoid receptor agonists; exhibiting an ~0.5 °C greater reduction in core body temperature in response to WIN 55,212-2 than did females (Diaz et al, 2009).…”

“…This was associated with sexually disparate changes in meal pattern; with males exhibiting cannabinoid-induced increases in meal size, meal frequency and meal duration, and females exhibiting an increase in meal frequency only (Diaz et al, 2009). In addition, males are more sensitive to the hypothermic effects of cannabinoid receptor agonists; exhibiting an ~0.5 °C greater reduction in core body temperature in response to WIN 55,212-2 than did females (Diaz et al, 2009). We have resolved these sex differences in the cannabinoid regulation of energy homeostasis down to the level of the hypothalamic feeding circuitry, where the pleiotropic actions of cannabinoids inhibit the excitability of anorexigenic POMC neurons in a sexually discrepant manner.…”

Behavioral, Metabolic, and Immune Consequences of Chronic Alcohol or Cannabinoids on HIV/AIDs: Studies in the Non-Human Primate SIV Model

“…Changes in body composition due to HIV wasting have been shown to be sex-specific and women lose more body fat while men lose more lean body mass (Grinspoon et al 1997; Kotler et al 1985). This could be partially explained by the increased sensitivity of males to cannabinoid receptor 1 (CB1R) agonist/antagonist effects on food intake and body weight (Diaz et al 2009) together with the effects of estrogen on food consumption (Czaja 1975). …”

Effects of Alterations in Cannabinoid Signaling, Alone and in Combination with Morphine, on Pain-Elicited and Pain-Suppressed Behavior in Mice

“…Agonists at cannabinoid type 1 (CB1) receptors produce behavioral effects that include disruption of locomotor activity (Pascual et al, 2005;Smith et al, 2009), dysregulation of food consumption (Jä rbe and DiPatrizio, 2005;Li et al, 2006), interference with thermoregulation (Wang et al, 2008;Diaz et al, 2009), and reinforcing effects (Justinova et al, 2008;Negus and Rice, 2009). Research also implicates the endogenous cannabinoid system in the mediation of pain responses.…”