Sex differences in the effects of maternal voluntary oral Cannabis consumption on the metabolic outcomes of high-fat diet in adult offspring

Background and PurposeGiven the recent rise in Cannabis legalisation, accessibility to Cannabis and consumption have increased during pregnancy. Therefore, there could be unintended developmental consequences. The endocannabinoid system plays a key role in fetal development and later-life energy homeostasis. We explored the long-term effects of maternal voluntary Cannabis consumption on the metabolic outcomes of a high-fat diet (HFD) in adult offspring.Experimental ApproachPregnant mice voluntarily consumed Cannabis extract equivalent to 5 mg kg-1 day-1 Delta 9-tetrahydrocannabinol (THC) from gestational day 1.5 until postnatal day (PD) 10. Pregnancy and pup outcomes and active maternal behaviour were recorded. Male and female offspring (PD49) were placed on a 12-week HFD or control diet; their weight gain, adiposity, glucose tolerance, insulin sensitivity, circulating hormones and pancreatic structure were measured.Key ResultsPerinatal Cannabis exposure (PCE) pup weight was initially reduced but restored by PD16. PCE did not influence weight gain or metabolic characteristics of male mice on a HFD. PCE female but not male offspring on a HFD had reduced accumulation of adipose tissue and lower insulin, leptin and resistin independent of body weight. PCE females on control diet also showed altered basal insulin sensitivity likely because of increased glucagon levels in parallel with reduced islets of Langerhans size and enhanced gene expression of cannabinoid 2 receptors in white adipose tissue.Conclusion and ImplicationsPCE adversely affected glycaemic control in female offspring on control diet while it mitigated HFD-induced metabolic dysfunction. This raises concerns about the long-term effects of PCE on the metabolic health of offspring.