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

Abstract

Considerable strides have been made over the past 20 years in our understanding of the ligands, receptor subtypes, signal transduction mechanisms and biological actions comprising the endocannabinoid system. From the ever-expanding number of studies that have been conducted during this time, it has become increasingly clear that sex differences are the cornerstone of cannabinoid-regulated biology. Available evidence has demonstrated that these sex differences endure in the absence of gonadal steroids, and are modulated by the acute, activational effects of these hormones. This review focuses on select aspects of sexually differentiated, cannabinoid-regulated biology, with a particular emphasis on the control of energy balance. It is anticipated that it will lend impactful insight into the pervasive and diverse disparities in how males and females respond to cannabinoids – from the organismal level down to the molecular level. Additionally, it will furnish a newfound appreciation for the need to recalibrate our thinking in terms of how cannabinoids are used as therapeutic adjuvants for a broad range of clinical disorders and associated comorbidities, including body wasting and obesity.

Long-Term Effects of Prenatal Exposure to Undernutrition on Cannabinoid Receptor-Related Behaviors: Sex and Tissue-Specific Alterations in the mRNA Expression of Cannabinoid Receptors and Lipid Metabolic Regulators

“…The results indicated that CC male rats showed an increase in body weight and abdominal fat mass that contrasted with a decrease in caloric intake and compulsive feeding during the adolescence and adulthood compared to CC female rats. As we will discuss below, these sex-differences extend to metabolic pathways under the control of the endogenous cannabinoid system, as previously suggested (Wagner, 2016). Thus, the effects of the maternal caloric restriction on the energy balance of male and female offspring should be interpreted based on their sex-dependent basal metabolism.…”

Cannabinoid receptor-1 signaling contributions to sign-tracking and conditioned reinforcement in rats

“…For both early lever-directed behavior and conditioned reinforcement, females showed stronger behavioral suppression to 1 mg/kg rimonabant. While the present study was not powered to analyze sex as a biological variable, these larger sex effect sizes in females suggest future studies should be powered to explore sex differences in sensitivity of cue-motivated behaviors to manipulations of CB1 receptor signaling (Wagner 2016). Consistent with prior PLA studies (Pitchers, Flagel et al 2015, Madayag, Stringfield et al 2017), with limited training, we did not observe notable sex effect sizes in sign- or goal-tracking behaviors.…”

µ‐opioid receptor, β‐endorphin, and cannabinoid receptor‐2 are increased in the colonic mucosa of irritable bowel syndrome patients

“…Furthermore, women with IBS showed a higher CB 2 mRNA levels compared to IBS men, whereas the difference was in the opposite direction in AC. Also, in this case, a number of studies report differential response to cannabinoid activity associated with sex differences . It is not known if there will be differences in the response to a CB 2 agonist in women and men with IBS.…”

“…Also, in this case, a number of studies report differential response to cannabinoid activity associated with sex differences. 65 It is not known if there will be differences in the response to a CB 2 agonist in women and men with IBS.…”