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RNA-Seq analysis of inguinal white adipose tissue (iWAT) from control and high fat diet mice treated with THCA and THCA+T007

ABSTRACT: Medicinal cannabis has garnered worldwide attention in recent years but has been hampered by the psychotropic activity of Δ9-tetrahydro-cannabinol (Δ9-THC). However, the biological activity of its precursor Δ9-THC acid (Δ9-THCA) remain largely unexplored; yet, it is known that Δ9-THCA is not psychotropic and displays PPARg agonistic activity. We report here that Δ9-THCA is a partial and selective PPARg, albeit with lower adipogenic activity than the full PPARg agonist, rosiglitazone (RGZ). In addition, Δ9-THCA enhanced osteoblastogenesis in human mesenchymal stem cells. Docking and in vitro functional assays indicated that Δ9-THCA binds and activated PPARg by acting at both the canonical and the alternative binding sites in the PPARg ligand-binding pocket. Indeed, transcriptomic signature at inguinal white adipose tissue (iWAT) from mice treated with Δ9-THCA confirmed its mode of action at PPARg. Administration of Δ9-THCA for 3-weeks in a mouse model of high fat diet (HFD)-induced obesity significantly reduced fat mass and body weight gain, and markedly ameliorated glucose intolerance and insulin resistance, while largely preventing liver steatosis, adipogenesis and macrophage infiltration in fat tissues. In addition, immunohistochemistry, transcriptomic and plasmatic biomarkers analyses showed that treatment with Δ9-THCA caused browning of iWAT and displayed potent anti-inflammatory actions in HFD mice. Altogether, our studies collectively document the potent biological activity of Δ9-THCA as a PPARggonist with capacity to substantially improve metabolic syndrome and inflammation associated to obesity. Our findings also imply that non-decarboxylated, Cannabis sativa extracts could be added to the arsenal of cannabis preparations already available in countries where medicinal cannabis is authorized.

ORGANISM(S): Mus musculus

PROVIDER: GSE129573 | GEO | 2019/12/20

REPOSITORIES: GEO

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Project description:Background: The regular use of cannabis by young men has been associated with an increased incidence of testicular germ cell tumors (TGCT). TGCT, the most common cancer in young adults, is believed to arise from an alteration of testicular fetal germ cells differentiation during development, with a possible subsequent environmental trigger (eg drugs or other chemicals) during puberty or adulthood leading to cancer. Cannabis consumption by pregnant women is currently increasing worldwide, and legalization for its recreational and therapeutic purposes is debated in numerous countries. In this context, we aimed to determine whether cannabis exposure can affect development of the fetal testis. Methods: Since phytocannabinoids act on an endogenous system called the endocannabinoid system (ECS), we first investigated these signaling pathways in the human fetal testis, from 6 to 17 developmental weeks. We next investigated the effects of the two main components of cannabis, (−)-Δ9-trans-tetrahydrocannabinol (THC) and cannabidiol (CBD), on the human fetal testis ex vivo. Results: We show the presence of two key endocannabinoids, 2-arachidonylglycerol (2-AG) and anandamide (AEA), albeit with lower levels. The human fetal testis also expressed several enzymes and receptors of this signaling pathway. Human fetal testicular explants collected from first trimester were exposed to CBD, THC or CBD/THC [ratio 1:1] at concentrations ranging from 10-7 to 10-5M during 72h to 14 days. Phytocannabinoids treatments affected fetal testicular cell proliferation and viability, as well as testosterone secretion by Leydig cells and AMH secretion by Sertoli cells. Transcriptomic analysis performed by BRB-seq on exposed versus unexposed fetal testis explants showed 187 differentially expressed genes (DEGs), some of which involved in toxic substances response and steroid synthesis. Conclusions: Our study provides the first evidence of the presence of ECS in human fetal testis and support a potential adverse effect of cannabis consumption in pregnant women on the male reproductive function development.

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RNA-Seq analysis of inguinal white adipose tissue (iWAT) from control and high fat diet mice treated with THCA and THCA+T007

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