Abstract
Endocannabinoids (ECs) mediate effects via cannabinoid receptors type1&2 (CB1&2) and TRPV1 channels. In high fat diet (HFD)-induced obese mice overactivity of the EC system and inhibition of CB1 increases skeletal muscle glucose uptake. We explored the role of TRPV1. Male TRPV1+/+(WT) and TRPV1-/-(KO)-mice were fed (20wks) standard (SLD) or HFD. Intraperitoneal glucose tolerance test was performed. RT-PCR was performed to measure mRNA of genes involved in glucose/lipid metabolism and the EC system in soleus (SOL) and extensor digitorum longus (EDL) muscles. Cultured L6-cells were used to measure glucose uptake in skeletal muscle. HFD-mice weighed more and had higher insulin levels than SLD-mice with no genotype differences. Basal and peak glucose was higher in HFD-mice irrespective of genotype but glucose cleared faster in HFD/WT vs HFD/KO-mice. 2-arachidonoylglycerol augmented insulin induced glucose uptake in skeletal L6-cells, an effect blocked by the TRPV1 antagonist SB366791. In EDL, fatty acid amide hydrolase (FAAH) mRNA was increased in KO vs WT-mice, irrespective of diet. Pyruvate dehydrogenase kinase isozyme4 (PDK4) and mitochondrial uncoupling protein3 (UCP3) were elevated and FA desaturase2 (FADS2) mRNA lower in HFD-mice, irrespective of genotype. CB1 and stearoyl-CoA desaturase (SCD1) were lower in HFD/WT-mice only. In SOL, PDK4, UCP3, hormone-sensitive lipase (LIPE), fatty acid translocase (CD36) and Carnitine Palmitoyl Transferase2 (CPT2) were elevated and, SCD1, FAAH, FADS2 and Troponin1 (TNNC1) mRNA lower in HFD-mice, irrespective of genotype. In conclusion, TRPV1 regulates glucose disposal in HFD-mice. We propose TRPV1 plays a role coordinating glucose metabolism in EDL under conditions of metabolic stress.
