Endocrine Abstracts

Background: Therapeutic 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).

Methods: Thirty 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 per day) or exercise training (1 h/d, 5 d/week). Metabolic assessment was undertaken in CLAMS during the last 48 h 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).

Results: No interventions reduced body weight or fat mass. There was no difference in 24 h 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. Only FASN, SCD1 and ACACA were upregulated in Cold whilst IL18R1, TLR4 and EMR1 were downregulated. Similarly, β3 increased FASN whilst downregulating IL18R1, IL6 and STAT3. Finally, Exercise upregulated FASN, SCD1, HK, ACACA, ACACB and PDK2 whilst downregulating NLRP3, IL1β and PYCARD.

Conclusion: Whilst there is an intervention specific effect on immune genes in BAT we show there is no consistent upregulation of thermogenic genes in response to common stimuli when animals are raised at thermoneutrality. Effects of interventions to activate 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.