Increased Energy Expenditure, Lipolysis and Hyperinsulinemia Confer Resistance to Central Obesity and Type 2 Diabetes in Mice Lacking Alpha2α-Adrenoceptors

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.

Swimming training reduces glucose‐amplifying pathway and cholinergic responses in islets from lean‐ and MSG‐obese rats

“…The beneficial effects of swimming training were also observed in CON‐EXE rats for the glucose plasma levels and GSIS, while no difference was found for glucose sensitivity, indicating that the effect exercise on GSIS may be independent of changes in pancreatic islets sensitivity to glucose. Moreover, previous studies reported that physical activity also modulates the GSIS due to its effect on adrenergic pathways in pancreatic islets from lean and obese mice models, an event that could also be present in our study . The reduced GSIS in exercised groups corroborate with previous reports that also used swimming training as exercise protocol .…”

“…Moreover, previous studies reported that physical activity also modulates the GSIS due to its effect on adrenergic pathways in pancreatic islets from lean and obese mice models, an event that could also be present in our study. 36,37 The reduced GSIS in exercised groups corroborate with previous reports that also used swimming training as exercise protocol. 33,38 However, it has been also demonstrated that physical activity increases GSIS in rats submitted to intense treadmill training, while in moderate protocol no effect is observed.…”

Brown and beige adipose tissues: phenotype and metabolic potential in mice and men

“…Peripheral and central (in raphe pallidus) injections of ␣ 2 -AR agonists were recently shown to inhibit BAT thermogenesis in rats (96), indicating that ␣ 2 -AR exhibit inhibitory control over BAT thermogenesis. Emerging evidence further suggests that an interplay between the relative expression or affinities of various ARs is not only important for the thermogenic outcome in BAT, but may also influence browning of WAT depots in rodents (131). In contrast to rodents, human adipocytes predominantly express ␤ 1 -and ␤ 2 -ARs, which have also been shown to play a role in human BAT activity (115,148).…”

Phenotypic effects of dietary stress in combination with a respiratory chain bypass in mice

“…Mouse models with increased energy expenditure typically have a lean phenotype, with decreased weight gain in fat‐rich diets. Examples are knockout of the Maf1 regulator of Pol III transcription (Willis et al ), treatment with OXPHOS uncouplers (Goldgof et al ; Kalinovitch and Shabalina ; Suzuki et al, ) and genetic modifications that increase sympatho‐adrenal tone (Ruohonen et al ). Thus, our expectation was that AOX would also have this effect in mice.…”