Abstract
To maintain core body temperature in cold conditions, mammals activate a complex multi-organ metabolic response for heat production. White adipose tissue (WAT) primarily functions as an energy reservoir, while brown adipose tissue (BAT) is activated during cold exposure to generate heat from nutrients. Both BAT and WAT undergo specific metabolic changes during acute cold exposure. Here, we use an untargeted metabolomics approach to characterize the initial metabolic response to cold exposure in multiple adipose tissue depots in mice. Results demonstrate dramatically distinct metabolic responses during cold exposure in BAT and WAT. Amino acids, nucleotide pathways, and metabolites involved in redox regulation were greatly affected 4 hours post-exposure in BAT, while no polar metabolites were observed to significantly change in WAT depots up to 6 hours post exposure. Lipid metabolism was activated early (2 hours) in both BAT and the subcutaneous WAT depots, with the most striking change being observed in the modulation of diglyceride and monoglyceride levels in BAT. Overall, these data provide a timeline of global thermogenic metabolism in adipose depots during acute cold exposure. We have highlighted differences in visceral and subcutaneous WAT thermogenic metabolism and demonstrate the distinct metabolism of BAT during cold exposure.
Highlights
Regulation of body temperature is an essential element of mammalian life which requires activated metabolism in brown and white adipose tissues
Acute cold exposure (3 hours at 4 °C) leads to increased oxidation and depletion of reduced glutathione (GSH) in brown adipose tissue (BAT) accompanied by increased protein thiol oxidation, which has been proposed as a vital signaling mechanism required for uncoupling protein 1 (UCP1)-induced thermogenic metabolism[10]
To determine the variation in metabolic profiles of different adipose tissues and investigate the metabolic modulations induced in each of these tissues by acute cold exposure, population-based studies were performed on four groups of 6 mice each exposed to 4 °C, for 0, 2, 4 or 6 hours
Summary
Regulation of body temperature is an essential element of mammalian life which requires activated metabolism in brown and white adipose tissues. Acute cold exposure (3 hours at 4 °C) leads to increased oxidation and depletion of reduced glutathione (GSH) in BAT accompanied by increased protein thiol oxidation, which has been proposed as a vital signaling mechanism required for UCP1-induced thermogenic metabolism[10]. Systemic depletion of mitochondrial ROS prior to cold exposure is sufficient to induce hypothermia after one hour cold exposure[10] This evidence suggests there are metabolic events that occur within the initial hours of cold exposure, which are critical for thermogenesis and include mitochondrial ROS signaling, glutathione oxidation and a depletion of GSH occurring temporally in various tissues during cold exposure. The cold-induced, global metabolic response in WAT, from both subcutaneous and visceral origins, occurred later and/or slower than in BAT: no significant changes were observed in polar metabolite levels in SWAT and VWAT at any time point during the 6 hours of cold exposure. The study design and technologies applied have generated a data set of acute cold-induced metabolism in multiple tissues simultaneously that may guide further investigations of thermogenic regulation and support the development of anti-obesity therapeutics that target thermogenic mechanisms[4, 5, 18]
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