No abstract

The alpha2A-adrenoceptors (α_2A-ARs) are Gi-coupled receptors, which prejunctionally inhibit the release of norepinephrine (NE) and epinephrine (Epi), and postjunctionally inhibit insulin secretion and lipolysis. We have earlier shown that α_2A^–/– mice display sympathetic hyperactivity, hyperinsulinemia and improved glucose tolerance. Here we employed α_2A^–/– mice and placed the mice on a high-fat diet (HFD) to test the hypothesis that lack of α_2A-ARs protects from diet-induced obesity and type 2 diabetes (T2D). In addition, a high-caloric diet was combined with running wheel exercise to test the interaction of diet and exercise. HFD was obesogenic in both genotypes, but α_2A^–/– mice accumulated less visceral fat than the wild-type controls, were protected from T2D, and their insulin secretion was unaltered by the diet. Lack of α_2A-ARs is associated with an increased sympatho-adrenal tone, which resulted in increased energy expenditure and fat oxidation rate potentiated by HFD. Fittingly, α_2A^–/– mice displayed enhanced lipolytic responses to Epi, and increased faecal lipids suggesting altered fat mobilization and absorption. Subcutaneous white fat appeared to be thermogenically more active (measured as Ucp1 mRNA expression) in α_2A^–/– mice, and brown fat showed an increased response to NE. Exercise was effective in reducing total body adiposity and increasing lean mass in both genotypes, but there was a significant diet-genotype interaction, as even modestly increased physical activity combined with lack of α_2A-AR signalling promoted weight loss more efficiently than exercise with normal α_2A-AR function. These results suggest that blockade of α_2A-ARs may be exploited to reduce visceral fat and to improve insulin secretion.

Objectives α2-Adrenoceptors (α2-AR) mediate both constriction and dilatation of blood vessels. There is substantial inter-individual variability in dorsal hand vein (DHV) constriction responses to α2-AR agonist activation. Genetic factors appear to contribute significantly to this variation. The present study was designed to identify genetic factors contributing to the inter-individual variability in α2-AR-mediated vascular constriction induced by the selective α2-AR agonist dexmedetomidine. Methods DHV constriction responses to local infusion of dexmedetomidine were assessed by measuring changes in vein diameter with a linear variable differential transformer. The outcome variable was log-transformed dexmedetomidine ED50 for constriction. A genome-wide association study (GWAS) of 433,378 single nucleotide polymorphisms (SNPs) was performed for the sensitivity of DHV responses in 64 healthy Finnish subjects. 20 SNPs were selected based on the GWAS results and their associations with the ED50 of dexmedetomidine were tested in an independent North American study population of 68 healthy individuals. Results In both study populations (GWAS and replication samples), the SNP rs9922316 in the gene for protein kinase C type β was consistently associated with dexmedetomidine ED50 for dorsal hand vein constriction (unadjusted p = 0.00016 for the combined population). Conclusions Genetic variation in protein kinase C type β may contribute to the inter-individual variation in dorsal hand vein constriction responses to α2-AR activation by the agonist dexmedetomidine.