Cannabis improves metabolic dysfunction and macrophage signatures in obese mice

Obesity rates continue to rise, highlighting the need for new treatments that are effective, safe, and widely accessible. Aligned with the easing of restrictions on cannabis use, interest in its therapeutic potential is evolving. As such, we examined the effects of the cannabis plant with high cannabidiol (CBD) content or high Δ⁹-tetrahydrocannabinol (THC) content on metabolic and immune dysregulation in obese mice. Briefly, female C57BL/6 mice were randomized into four groups (<i>n</i> = 15/group): <i>1</i>) lean, <i>2</i>) obese placebo, <i>3</i>) obese CBD, and <i>4</i>) obese THC. Lean mice consumed a low-fat diet for the study duration. Obese mice consumed a high-fat diet for 16 wk before a 4-wk cannabis (3 times/wk; high CBD = ∼4.2 mg/kg and high THC = ∼7.3 mg/kg) intervention. Consistent with our hypothesis, obesity increased homeostasis model assessment of insulin resistance (HOMA-IR) and metabolic dysfunction-associated steatohepatitis (MASH), both of which were significantly mitigated by either high (10.5%) CBD or high (18.16%) THC cannabis (<i>P</i> < 0.05). Interestingly, these changes appeared to occur independent of significant weight loss or measurable changes in food intake. Diet-induced obesity also increased infiltrating macrophages, pan macrophages, and M1-like proinflammatory macrophages in adipose tissue and liver. These effects were rescued by high CBD and high THC (<i>P</i> < 0.05), providing evidence consistent with causation for the improvements in HOMA-IR and MASH. Despite the legal complexities surrounding cannabis use, these data suggest that both CBD and THC can be a viable therapy to target macrophages and improve metabolic health and immune dysregulation with obesity.<b>NEW & NOTEWORTHY</b> We examined the effects of the cannabis plant with high cannabidiol (CBD) content or high Δ⁹-tetrahydrocannabinol (THC) content on metabolic and immune dysregulation in obese mice. Both CBD and THC mitigated the obesity-induced increase in Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) and metabolic dysfunction-associated steatohepatitis (MASH). Furthermore, the increase in macrophages, in particular M1-like proinflammatory macrophages, in the adipose tissue and liver was rescued by high CBD and high THC.