Cold Exposure Drives Weight Gain and Adiposity following Chronic Suppression of Brown Adipose Tissue

Abstract

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.

Effects of ambient temperatures between 5 and 35 °C on energy balance, body mass and body composition in mice

“…Our data contrast the observations in rats kept until 12 weeks old at 28 °C and then transferred for 4 weeks to 20 °C [ 88 ]. In that study there was a suggested increase in adiposity, the opposite of our observation of decreased adiposity coincident with declining temperatures.…”

“…However, the sample size in that study was small (two temperature exposure groups with n = 6 per group) and there were no discernible impacts of the temperature manipulation on either food intake or energy expenditure, indicating the exposure did not take the rats outside their thermoneutral zone when ‘cold exposed’. Moreover, while increased adiposity was mentioned in the title and abstract of the paper, the increase in total adipose tissue in the cold was not significant ( Figure 2 C in ref [ 88 ], p = 0.0532).…”