Tetrahydrocannabinolic Acid a (THCA-A) Reduces Adiposity and Prevents Metabolic Disease Caused by Diet-Induced Obesity

Abstract

25Cannabis has remarkable therapeutic potential, but its clinical use is limited by the psychotropic activity of Δ 9 -tetrahydrocannabinol (Δ 9 -THC). Surprisingly, the biological profile of the non-narcotic native precursor of Δ 9 -THC (Δ 9 -THC acid A, Δ 9 -THCA-A) is still largely unexplored. We present evidence that Δ 9 -THCA-A is a partial and selective PPARγ modulator, endowed with lower adipogenic activity than the full PPARγ agonist rosiglitazone 30 (RGZ) and with an enhanced osteoblastogenic activity in human mesenchymal stem cells.Docking and in vitro functional assays indicated that Δ 9 -THCA-A binds to and activates PPARγ by acting at both the canonical and the alternative sites of the ligand-binding domain.Transcriptomic signatures at inguinal white adipose tissue (iWAT) from mice treated with Δ 9 -THCA-A confirmed its mode of action on PPARγ. Administration of Δ 9 -THCA-A in a mouse 35 model of high fat diet (HFD)-induced obesity significantly reduced fat mass and body weight gain, markedly ameliorating glucose intolerance and insulin resistance, and largely preventing liver steatosis, adipogenesis and macrophage infiltration in fat tissues. Additionally, immunohistochemistry, transcriptomic, and plasma biomarker analyses showed that treatment with Δ 9 -THCA-A caused browning of iWAT and displayed potent anti-inflammatory actions 40 in HFD mice. Altogether, our data validate the potential of Δ 9 -THCA-A as a low adipogenic PPARγ agonist, capable of substantially improving the symptoms of obesity-associated metabolic syndrome and inflammation. These findings suggest that Δ 9 -THCA-A, and perhaps non-decarboxylated Cannabis sativa extracts, are worth considering for addition to our inventory of cannabis medicines. 45Key words: Medicinal cannabis, Δ 9 -THCA-A, PPARγ, obesity, metabolic syndrome, inflammation 50 3 SIGNIFICANCE STATEMENTThe medicinal use of Cannabis is gaining momentum, despite the adverse psychotropic effects of Δ 9 -THC, the decarboxylation product of its naturally occurring and nonpsychotropic precursor Δ 9 -THCA-A. We present evidence that Δ 9 -THCA-A is a partial ligand agonist of PPARγ with lower adipogenic activity compared to the full PPARγ agonist 55 rosiglitazone (RGZ). Moreover, chronic administration of Δ 9 -THCA-A in a mouse model of high fat diet (HFD)-induced obesity significantly reduced body weight gain and fat mass, improved glucose intolerance and insulin resistance, and prevented liver steatosis and macrophage infiltration in fat tissues, additionally inducing white adipose tissue browning.Collectively, these observations qualify Δ 9 -THCA-A, a compound devoid of psychotropic 60 effects, as an efficacious pharmacological agent to manage metabolic syndrome and obesityassociated inflammation. 65Highlights -Δ 9 -THCA-A is a partial PPARγ ligand agonist with low adipogenic activity -Δ 9 -THCA-A enhances osteoblastogenesis in bone marrow derived mesenchymal stem cells.-Δ 9 -THCA-A reduces body weight gain, fat mass, and liver steatosis in HFD-fed mice 70 -Δ 9 -THCA-A impro...

In vitro and in vivo pharmacological activity of minor cannabinoids isolated from Cannabis sativa

“…∆ 9 -THCa has previously been shown to bind murine cannabinoid receptors weakly 21 . Similar to our findings, Palomarés et al 29 recently reported ∆ 9 -THCa binding to CB1R and CB2R, with potential orthosteric and allosteric activity at CB1R. In vivo, the anti-inflammatory activity of ∆ 9 -THCa in a rodent model of arthritis was CB1R-and peroxisome proliferatoractivated receptor γ (PPARγ)-dependent 29 .…”

“…Similar to our findings, Palomarés et al 29 recently reported ∆ 9 -THCa binding to CB1R and CB2R, with potential orthosteric and allosteric activity at CB1R. In vivo, the anti-inflammatory activity of ∆ 9 -THCa in a rodent model of arthritis was CB1R-and peroxisome proliferatoractivated receptor γ (PPARγ)-dependent 29 . Similar neuroprotective and PPAR-dependent effects have been observed in rodent models of Huntington's disease 30 .…”

Δ9‐Tetrahydrocannabinolic acid alleviates collagen‐induced arthritis: Role of PPARγ and CB1 receptors

“…We have previously reported that Δ 9 ‐THCA‐A binds and activates PPARγ and exerts potent anti‐inflammatory activities in the CNS and in peripherical inflammatory conditions (Nadal et al, 2017; Palomares et al, 2019). However, the biological activity of Δ 9 ‐THCA‐A through CB 1 receptors has been poorly investigated in vivo.…”

“…Nevertheless, Δ 9 ‐THCA‐A is anti‐emetic in shrews and this activity was reversed by co‐treatment with SR141716, a selective cannabinoid CB 1 receptor antagonist (Rock, Kopstick, Limebeer, & Parker, 2013). In addition, we recently showed that Δ 9 ‐THCA‐A is a potent activator of PPARγ, endowed with remarkable biological activities (Nadal et al, 2017; Palomares et al, 2019).…”

Targeting the Endocannabinoid CB1 Receptor to Treat Body Weight Disorders: A Preclinical and Clinical Review of the Therapeutic Potential of Past and Present CB1 Drugs

“…Using ApoE-deficient mice with compromised lipid metabolism capabilities, CBDD increased body weight gain to a greater extent than vehicle-treated ApoE-deficient mice [ 87 ]. Other cannabis-related agonistic compounds such as Δ 9 -tetrahydrocannabinolic acid-A (THCA-A) have recently been studied in preclinical models and have shown promise in modulating weight; however, this is beyond the scope of this review as it is not a CB1 receptor ligand [ 173 ].…”