Adolescent Exposure to Low-Dose THC Disrupts Energy Balance and Adipose Organ Homeostasis in Adulthood

Abstract

One of cannabis′ most iconic effects is the stimulation of hedonic high-calorie eating - the ′munchies′ - yet habitual cannabis users are on average leaner than non-users. We asked whether this unexpected phenotype might result from lasting changes in energy balance established during adolescence, when habitual use of the drug often begins. We found that daily low-dose administration of cannabis′ intoxicating constituent, delta-9-tetrahydrocannabinol (THC), to adolescent mice causes an adult metabolic phenotype characterized by reduced fat mass, increased lean mass and utilization of fat as fuel, partial resistance to diet-induced obesity and dyslipidemia, and enhanced thermogenesis. Multi-omics analyses revealed that this phenotype is associated with multiple molecular anomalies in the adipose organ, which include ectopic overexpression of muscle-associated proteins and heightened anabolic processing. Thus, adolescent exposure to THC may promote an enduring ′pseudo-lean′ state that superficially resembles healthy leanness but might in fact be rooted in adipose organ dysfunction.

Prenatal exposure to THC vapor influences feeding, bodyweight and glucose metabolism under both basal conditions and following high fat diet

“…Interestingly, THC reducing bodyweight gain has been observed in other rodent models of cannabis exposure and HFD access during adolescence/adulthood (52, 53). Lin et al 2023 showed that adolescence THC exposure is associated with reduced bodyweight gain, decreased fat mass, increased lean mass and increased energy expenditure with HFD access in adulthood (53).…”

“…Interestingly, THC reducing bodyweight gain has been observed in other rodent models of cannabis exposure and HFD access during adolescence/adulthood (52, 53). Lin et al 2023 showed that adolescence THC exposure is associated with reduced bodyweight gain, decreased fat mass, increased lean mass and increased energy expenditure with HFD access in adulthood (53). It is not known if the PCE-induced decrease in bodyweight gain observed in the present study is due to changes in lean body mass or energy expenditure as we did not take these measures.…”

“…However, we did not measure locomotion, thermogenesis, respiration, or other measures of energy expenditure in this study. It is not known if PCE alters energy expenditure in adulthood, but there is evidence that cannabis exposure during adolescence is associated with increased thermogenesis in adulthood (53). Differences in findings between the present study and previously published studies could be due to route of administration, dose, or testing age.…”

Prior acute exercise restores postprandial fat oxidation in active cannabis users

“…Finally, a rodent study may shed some light on the discrepancies in the literature. In that study, adolescent mice exposed to THC presented as apparently healthy adults, with lower levels of body fat, increased fat oxidation, resistance to diet‐induced obesity and dyslipidemia, and an improved lipid panel compared to non‐THC‐treated mice (Lin et al., 2023). However, these mice also exhibited altered thermoregulation, decreased cold and β‐receptor stimulated lipolysis, and an increased expression of skeletal muscle proteins and other abnormalities in adipose tissue (Lin et al., 2023).…”

“…In that study, adolescent mice exposed to THC presented as apparently healthy adults, with lower levels of body fat, increased fat oxidation, resistance to diet‐induced obesity and dyslipidemia, and an improved lipid panel compared to non‐THC‐treated mice (Lin et al., 2023). However, these mice also exhibited altered thermoregulation, decreased cold and β‐receptor stimulated lipolysis, and an increased expression of skeletal muscle proteins and other abnormalities in adipose tissue (Lin et al., 2023). Future work should consider conducting skeletal muscle and adipose tissue biopsies during meal challenges to explore whether similar findings would be observed in humans.…”