Adolescent exposure to low-dose THC disrupts energy balance and adipose organ homeostasis in adulthood

Lin, Lin; Jung, Kwang-Mook; Lee, Hye-Lim; Le, Johnny; Colleluori, Georgia; Wood, Courtney; Palese, Francesca; Squire, Erica; Ramirez, Jade; Su, Shiqi; Torrens, Alexa; Fotio, Yannick; Tang, Lingyi; Yu, Clinton; Yang, Qin; Huang, Lan; DiPatrizio, Nicholas V.; Jang, Cholsoon; Cinti, Saverio; Piomelli, Daniele

doi:10.1016/j.cmet.2023.05.002

Cited by 8 publications

(15 citation statements)

References 64 publications

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“…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.…”

Section: Eating Habitscontrasting

confidence: 89%

“…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.…”

Section: Adipositymentioning

confidence: 98%

Section: Adipositymentioning

confidence: 99%

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

Hume,

Baglot,

Javorcikova

et al. 2023

Preprint

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Abstract4-20% of people report using cannabis during pregnancy, thereby it is essential to assess the associated risks. There is some evidence that prenatal cannabis exposure (PCE) may be associated with increased risk for development of obesity and diabetes later in life, however this has not been well explored under controlled conditions. The aim of this study was to use a translational THC vapor model in rodents to characterize the effects of PCE on adiposity, glucose metabolism, and feeding patterns in adulthood, with focus on potential sex differences. Pregnant Sprague Dawley rats were exposed to vaporized THC (100mg/ml) or control (polyethylene glycol vehicle) across the entire gestational period. Adult offspring from PCE or control litters were subjected to measures of adiposity, glucose metabolism and feeding behavior. Rats were then placed onto special diets (60% high-fat diet [HFD] or control 10% low fat diet [LFD]) for 4-months, then re-subjected to adiposity, glucose metabolism and feeding behavior measurements. PCE did not influence maternal weight or food consumption but was associated with transient decreased pup weight. PCE did not initially influence bodyweight or adiposity, but PCE did significantly reduce the rate of bodyweight gain when animals were maintained on special diets (HFD/LFD), regardless of which diet. Further, PCE had complex effects on glucose metabolism and feeding behavior that were both sex and diet dependent. No effects of PCE were found on plasma leptin or insulin, or white adipose tissue mass. Overall, this data enhances current understanding of the potential impacts of PCE.

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Section: Eating Habitscontrasting

confidence: 89%

Section: Adipositymentioning

confidence: 98%

Section: Adipositymentioning

confidence: 99%

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

Hume,

Baglot,

Javorcikova

et al. 2023

Preprint

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show abstract

“…For example, adolescent pubertal administration of the potent CBR agonist WIN 55,212 alters OFC-dependent reversal learning in the attentional set-shifting task (Gomes et al, 2015), though adolescent vaporized cannabis or cannabis smoke did not impact this same type of reversal learning (Hernandez et al, 2021;Freels et al, 2024). Again, discrepancies between studies may reflect differences in effects of cannabinoid drugs, doses, exposure timing, and washout period; further underscoring the need for a consistent, rationally-designed AdoTHC exposure model in the field-we argue that the model used here is the best-characterized to date in the field (Torrens et al, 2020;Ruiz et al, 2021b;Lee et al, 2022;Torrens et al, 2022;Halbout et al, 2023;Lin et al, 2023;Lee et al, 2024). This said, the possibility that OFC is even more sensitive to disruption by AdoTHC than mPFC should be directly tested in future studies.…”

Section: Adolescent Thc Exposure Enhances Initial Discrimination Lear...mentioning

confidence: 71%

Adolescent THC impacts on mPFC dopamine-mediated cognitive processes in male and female rats

Martinez,

Alizo Vera,

Ruiz

et al. 2024

Preprint

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Adolescent use of cannabis is linked to later-life changes in cognition, learning, and memory. Rodent models suggest this could be a causal effect of Δ9-tetrahydrocannabinol (THC) influencing the development of circuits underlying these processes, especially for the prefrontal cortex (PFC) which undergoes maturation during adolescence. Here we examined how two weeks of daily exposure to THC (5mg/kg IP) during adolescence persistently impacts cognitive processes involving mPFC dopamine. In male and female Long Evans rats treated in adolescence with THC or vehicle, we quantify acquisition of, and stable performance in two mPFC dopamine-dependent cognitive tasks—attentional set shifting and probability-based reward discounting. We also determined how acute pharmacological or chemogenetic augmentation of dopamine signaling impacts cognition in both groups and both sexes. We found that adolescent THC (AdoTHC) sex-dependently impacts acquisition of cue-guided instrumental reward seeking, but has minimal effects on set-shifting or probability discounting in either sex. When we challenged dopamine circuits by acutely potentiating monoamine signaling with amphetamine (0, 0.25, 0.5 mg/kg) during probability discounting, we confirmed prior findings that amphetamine reduced discounting of improbable reward options, and further showed that this amphetamine effect was more robust in rats with a history of adolescent THC. We next asked whether this potentiated effect of amphetamine involves AdoTHC impacts on dopamine circuits in particular, by attempting to recapitulate the amphetamine effect using more specific chemogenetic stimulation of VTA dopamine neurons. In contrast, we found that neither acute chemogenetic stimulation of VTA dopamine neurons (using a Cre-dependent DREADD in tyrosine hydroxylase:Cre rats), nor pathway-specific chemogenetic stimulation of these neurons' projection to mPFC in particular impacted probability discounting, suggesting that AdoTHC's potentiation of amphetamine effects may reflect alterations of non-VTA dopamine neurons influenced by amphetamine. Results confirm the marked specificity in the cognitive processes impacted by adolescent THC exposure, and suggest that some persistent effects of adolescent THC may alter cognitive responses to amphetamine in a manner independent of VTA dopamine projections to mPFC.

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“…The first posits that prolonged THC exposure stops energy-saving ECS signals by promoting the desensitization and downregulation of adipose CB1 receptors [ 16 ]. There are, however, two difficulties with this account: first, people who regularly use cannabis do not seem to develop tolerance to the drug’s orexigenic effects [ 15 , 22 , 51 ] and, second, in mice sub-chronically treated with THC, adipose CB1 expression is not significantly affected [ 52 ]. Another possible, non-exclusive explanation is that excessive CB1 activation during the teenage years—when regular use of cannabis typically begins [ 11 , 53 ]—produces enduring physiological changes in the still-developing adipose organ, which impact systemic energy utilization in adulthood ( Figure 2 ).…”

Section: The Ecs In the Adipose Organmentioning

confidence: 99%

Overactivation of the Endocannabinoid System in Adolescence Disrupts Adult Adipose Organ Function in Mice

Jung,

Lin,

Piomelli

2024

Cells

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Cannabis use stimulates calorie intake, but epidemiological studies show that people who regularly use it are leaner than those who don’t. Two explanations have been proposed for this paradoxical finding. One posits that Δ9-tetrahydrocannabinol (THC) in cannabis desensitizes adipose CB1 cannabinoid receptors, stopping their stimulating effects on lipogenesis and adipogenesis. Another explanation is that THC exposure in adolescence, when habitual cannabis use typically starts, produces lasting changes in the developing adipose organ, which impacts adult systemic energy use. Here, we consider these possibilities in the light of a study which showed that daily THC administration in adolescent mice produces an adult metabolic phenotype characterized by reduced fat mass, partial resistance to obesity and dyslipidemia, and impaired thermogenesis and lipolysis. The phenotype, whose development requires activation of CB1 receptors in differentiated adipocytes, is associated with overexpression of myocyte proteins in the adipose organ with unchanged CB1 expression. We propose that adolescent exposure to THC causes lasting adipocyte dysfunction and the consequent emergence of a metabolic state that only superficially resembles healthy leanness. A corollary of this hypothesis, which should be addressed in future studies, is that CB1 receptors and their endocannabinoid ligands may contribute to the maintenance of adipocyte differentiation during adolescence.

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Adolescent exposure to low-dose THC disrupts energy balance and adipose organ homeostasis in adulthood

Cited by 8 publications

References 64 publications

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

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

Adolescent THC impacts on mPFC dopamine-mediated cognitive processes in male and female rats

Overactivation of the Endocannabinoid System in Adolescence Disrupts Adult Adipose Organ Function in Mice

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