Physiological Regulation of Brown Adipose Tissue with Obesity by Mild‐Cold Exposure, a β3‐Agonist and Exercise Training at Thermoneutrality
Authors: Aldiss Peter , Lewis Jo , Ebling Fran , Budge Helen , Symonds Michael 
Published: June 2021

Background and aimTherapeutic activation of thermogenic brown adipose tissue (BAT) is a potential strategy to prevent obesity and metabolic disease in humans. However, it is now recognised that rodent studies examining BAT physiology are carried out at sub‐thermoneutral temperatures (e.g. ~20°C), and are not translationally relevant to humans as BAT is ‘hyperactive’. Therefore, the aim of this study was to determine the effect of common regulators of BAT metabolism when animals were raised at thermoneutrality (28°C).Material and methodsThirty weanling Sprague‐Dawley rats were housed at thermoneutrality (28°C) and randomised to either chow (C, n=6) or a high‐fat diet (HFD, n=24) from 3‐weeks of age. At 12 weeks, subgroups (n=6) of HFD were randomised to either mild‐cold exposure (20°C), Mirabegron, a selective β3‐agonist (0.75 mk/kg/d) or exercise training (1h/d, 5 d/week). Metabolic assessment was undertaken in CLAMS during the last 48h to assess energy intake (EI), expenditure (EE) and physical activity (PA) in addition to the acute response to administration of Mirabegron. Key thermogenic and metabolic genes were analysed in interscapular BAT by qPCR in addition to targeted insulin resistance PCR Arrays (86 key genes, n=3).ResultsNo interventions reduced body weight or fat mass. Intriguingly however, mild‐cold exposure significantly increased weight‐gain during the 4‐week period (78.6 vs. 119.8g). This was accompanied by a significant increase in inguinal AT (7.14 vs 16.14g) in cold‐exposed animals whilst BAT mass was significantly increased with exercise‐training (0.74 vs. 1.2g). There was no difference in 24h EE, EI or PA between groups. Key thermogenic genes in BAT were unchanged by the interventions. CITED1 expression was upregulated by HFD and reduced by all interventions whilst PRDM16 expression was reduced by HFD and increased by exercise. Similarly, expression of PPARA, mTOR and the ‘beige’ marker TBX1 were upregulated by exercise only. Targeted PCR arrays demonstrated an upregulation of inflammatory markers e.g. TLR4, EMR1, CASP1 and IL18R1 and a downregulation of metabolic genes e.g. SCD1, FASN, ACACB, HK2 with HFD. β3 increased FASN, whilst IL18R1, IL6 and STAT3 were downregulated along with IRS2, LEP, ADIPOR1, INSR and PIK3R1. Exercise upregulated FASN, SCD1, HK, ACACA, ACACB and PDK2 but NLRP3, IL1β, PYCARD, LPL, IRS2, INSR, FABP4 and CD36 were all downregulated.ConclusionWe show there is no consistent upregulation of BAT as determined by key thermogenic genes in response to common stimuli when examined at thermoneutrality. Effects of interventions on BAT carried out at sub‐thermoneutrality are most likely to be a consequence of chronic mild‐cold stress and are unlikely to be translated to humans.Support or Funding InformationBritish Heart FoundationThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.