Key result
Transferring obese rats from thermoneutrality (28 °C) to mild cold (20 °C) drove weight gain and a 125% increase in subcutaneous fat mass, an effect not seen with YM-178 administration.
Why the study?
Rodents housed below thermoneutrality hyperactivate brown and beige adipose tissue, confounding studies of thermogenic activation to prevent or treat cardiometabolic disease.
In obese rats raised at thermoneutrality to mimic human physiology, mild cold exposure paradoxically promotes weight gain and adiposity, while β3-adrenoreceptor agonism fails to improve metabolic health.
Mild cold may paradoxically increase adiposity in obese models; leaves open beta-3 agonism for human translation.
Therapeutic activation of thermogenic brown adipose tissue (BAT) may be feasible to prevent, or treat, cardiometabolic disease. However, rodents are commonly housed below thermoneutrality (~20 °C) which can modulate their metabolism and physiology including the hyperactivation of brown (BAT) and beige white adipose tissue. We housed animals at thermoneutrality from weaning to chronically supress BAT, mimic human physiology and explore the efficacy of chronic, mild cold exposure (20 °C) and β3-adrenoreceptor agonism (YM-178) under these conditions. Using metabolic phenotyping and exploratory proteomics we show that transfer from 28 °C to 20 °C drives weight gain and a 125% increase in subcutaneous fat mass, an effect not seen with YM-178 administration, thus suggesting a direct effect of a cool ambient temperature in promoting weight gain and further adiposity in obese rats. Following chronic suppression of BAT, uncoupling protein 1 mRNA was undetectable in the subcutaneous inguinal white adipose tissue (IWAT) in all groups. Using exploratory adipose tissue proteomics, we reveal novel gene ontology terms associated with cold-induced weight gain in BAT and IWAT whilst Reactome pathway analysis highlights the regulation of mitotic (i.e., G2/M transition) and metabolism of amino acids and derivatives pathways. Conversely, YM-178 had minimal metabolic-related effects but modified pathways involved in proteolysis (i.e., eukaryotic translation initiation) and RNA surveillance across both tissues. Taken together these findings are indicative of a novel mechanism whereby animals increase body weight and fat mass following chronic suppression of adaptive thermogenesis from weaning. In addition, treatment with a B3-adrenoreceptor agonist did not improve metabolic health in obese animals raised at thermoneutrality.
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Aldiss et al. (2022) studied Obesity. Mild cold exposure (20 °C) and β3-adrenoreceptor agonism (YM-178) vs. Thermoneutrality (28 °C) was evaluated on Weight gain and subcutaneous fat mass. Transferring obese rats from thermoneutrality (28 °C) to mild cold (20 °C) drove weight gain and a 125% increase in subcutaneous fat mass, an effect not seen with YM-178 administration.
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