The Cannabinoid Receptor Agonist THC Attenuates Weight Loss in a Rodent Model of Activity-Based Anorexia

Abstract

Anorexia nervosa (AN) is characterized by anhedonia whereby patients experience little pleasure or reward in many aspects of their lives. Reward pathways and the endocannabionid system have been implicated in the mediation of food intake. The potential to exploit these systems to reverse weight loss is investigated in a rodent model of activity-based anorexia (ABA). The effect of subchronic (6 days) Δ(9)-tetrahydrocannabinol (THC) treatment (0.1, 0.5, or 2.0 mg/kg/day) was assessed on chow and high-fat diet (HFD) intake, body weight, running wheel activity (RWA) as well as thermogenesis in brown adipose tissue (BAT) and lipid metabolism in white adipose tissue (WAT). Limited time availability of food and continuous access to running wheels led to anorexia and significantly reduced body weight. THC treatment (0.5 and 2.0 mg/kg/day) transiently stimulated chow intake with a moderate effect on RWA. THC (2.0 mg/kg/day) significantly reduced body weight loss and shifted markers of thermogenesis in BAT and lipid metabolism in WAT in directions consistent with reduced energy expenditure and lipolysis. THC (2.0 mg/kg/day) combined with HFD, produced a transient increase in food intake, reduction in RWA, attenuation of body weight loss, and changes in markers of thermogensis in BAT and lipolysis in the WAT. These changes were significantly greater than those seen in vehicle (HFD), vehicle (chow), and THC (chow)-treated animals. These data show for the first time the effectiveness of the endocannabinoid system in attenuating the weight loss associated with the development of ABA via a mechanism involving reduced energy expenditure.

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

“…Likewise, it follows that under hypoestrogenic states brought on by primary amenorrhea (e.g., anorexia nervosa) or secondary amenorrhea (e.g., menopause), CB1 receptor-mediated signaling would proceed to the fullest extent possible. Indeed, dronabinol significantly increased weight gain in women with anorexia nervosa of at least five years duration (Andries et al, 2014), which is consistent with findings that THC diminished activity-based anorexia in female rats as assessed by THC-induced increases in energy intake, decreases in running wheel activity, reductions in weight loss, decreases in thermogenesis in brown adipose tissue and decrements in lipolysis in white adipose tissue (Verty et al, 2011). While the hypoestrogenemia that is associated with anorexia certainly appears to confer responsiveness to the appetite-stimulating properties of cannabinoid receptor agonists, different allelic forms of the CB1 receptor (CNR1) gene are reported to be preferentially transmitted in the binging/purging and restricting types of anorexia nervosa (Siegfried et al, 2004).…”

Endocannabinoids and Metabolic Disorders

“…For instance, chronic administration of rimonabant reduced feeding behavior in an animal model of binge eating disorder (Scherma et al 2013) and the same drug was able to decrease body weight and binge eating behavior in obese patients affected by binge eating disorder (Pataky et al 2013). In contrast, Verty and collaborators were able to demonstrate that Δ 9 -THC attenuated weight loss in a rodent model of activity-based anorexia through a mechanism that likely involves a decrease in energy expenditure (Verty et al 2011). However, previous clinical studies have failed to show an effect on weight loss in AN patients treated with Δ 9 -THC, while depression and perfectionism, a personality trait often found in AN patients, were ameliorated by the treatment (Gross et al 1983;Berry 2006).…”

Using the Activity-based Anorexia Rodent Model to Study the Neurobiological Basis of Anorexia Nervosa

“…The genetic basis of vulnerability has been studied using different inbred strains of mice 9 . Pharmacological manipulations can be tested in an animal model prior to human trials [20][21][22][23][24] . Genetically modified animals and transient knockdown of genes can be used to study how manipulation of particular molecular pathways can affect behavior in the ABA paradigm.…”