Increased Energy Expenditure, White Adipose Tissue Browning, And Resistance to Central Obesity And Type 2 Diabetes in Mice Lacking Alpha2‐Adrenoceptors
Authors: Ruohonen Suvi T. , Savontaus Eriika , Norlund Wendy , Ailanen Liisa , Röyttä Matias , Baur Nadja , Joos Thomas , Scheinin Mika 
Published: November 2023

The three subtypes of α2‐adrenoceptors (ARs) (α2A, α2B and α2C) are Gi‐coupled receptors of which the α2A and α2C subtypes function as autoreceptors to inhibit the release of norepinephrine (NE) and epinephrine (Epi). α2A‐ARs also have important postjunctional functions in regulation of insulin secretion and lipolysis. We have earlier shown that mice lacking α2A‐ARs, and mice lacking receptor subtypes A and C (α2A−/− and α2AC−/− mice, respectively) display sympathetic hyperactivity, hyperinsulinemia and improved glucose tolerance. The purpose of this study was to (1) reveal the roles and mechanisms of sympathoneural vs. adrenomedullary activity on susceptibility to obesity in a longitudinal study setting in mice, and (2) study the efficacy of α2‐AR blockade as a possible target for drug discovery in obesity and type 2 diabetes (T2D). α2A−/−, α2AC−/− and wildtype (WT) C57BL/6J male mice were exposed to 45% high fat diet (HFD) for 9 weeks to study the development of obesity and T2D. In further cohorts of mice, HFD was fed for 3 weeks in order to study the mechanisms just before the weights began to differ. As results, we found that WT and α2A−/− mice gained weight at a similar rate, whereas α2AC−/− mice were more resistant to obesity. However, α2A−/− mice accumulated less visceral fat than WT mice. Food intake did not differ between the groups. WT mice developed T2D, but both knock‐outs remained glucose tolerant. α2A−/−And α2AC−/− mice were physically less active, yet showed higher basal metabolic rate. HFD increased energy expenditure in all groups, but more profoundly in the knock‐outs. Baseline NE and Epi levels were significantly higher in α2A−/− and α2AC−/− mice. However, HFD had strong effects on urine NE and Epi levels in all mice, suggesting that increased weight gain associates with high NE and low Epi, and resistance to obesity with high NE and high Epi. Consequently, adrenalectomy abolished the diet‐resistant phenotype of the α2AC−/− mouse. Furthermore, the knock‐out mice displayed enhanced lipolytic response to β‐AR agonists, and increased amounts of lipids in their feces suggesting altered fat mobilization and absorption. Expression levels of UCP‐1 were higher in knock‐out inguinal white fat (iWAT), whereas HFD suppressed BAT UCP‐1 in all study groups. Leptin‐hypothalamus axis showed normal function, but NE‐induced suppression of hypothalamic neuropeptide Y was not evident in α2A−/− and α2AC−/− mice suggesting it may be under α2A‐AR regulation. In conclusion, obesity is linked with chronic activation of the sympathoneural and suppression of adrenomedullary tones in obesity‐prone C57BL/6J WT mice providing evidence that inducing only NE release may not be a sufficient mechanism for weight loss. We have also shown that depletion of α2A‐AR signalling was effective in preventing obesity‐induced diabetes, and reducing central adiposity by increasing energy expenditure, visceral lipolytic activity and stimulating iWAT browning without affecting food intake; a phenotype resembling the use of direct β‐AR agonists.Support or Funding InformationThis study was supported by the Academy of Finland (grant 252441), Finnish Cultural Foundation and Turku University Foundation.