Comprehensive quantification of fuel use in cold-induced thermogenesis in vivo

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SUMMARY Cold-induced thermogenesis (CIT) allows endotherms, including mammals, to maintain body temperature at ~37oC despite sometimes much colder ambient temperature. Pharmaceutical activation of CIT is being investigated by many groups as a potential therapeutic approach to obesity. Despite decades of investigations of CIT, however, how different fuels are burned during CIT, by which tissues, and to what extent, remains ill- defined. We propose here to carry out a comprehensive quantification of systemic metabolic fluxes during cold exposure in mice. These studies are enabled by the development by us and others of: (1) steady-state infusions with non-perturbative amounts of heavy isotope-labeled fuels in live, awake, and ambulatory mice, allowing precise quantification of whole-body fuel turnover and of relative contribution of each fuel to tissue oxidation rates; and (2) acute kinetic studies to allow quantitative estimates of rates of tricarboxylic acid cycle turnover, and thus of VO2, in individual tissues. Based on extensive preliminary data, we hypothesize that CIT is largely fueled from fat stores, but that it is nevertheless critically dependent on anaplerotic carbohydrate sources, provided by the liver, to sustain fatty acid oxidation. We will have 3 aims: Aim 1: Comprehensive quantification of whole-body fuel turnover during CIT in mice. Aim 2: Comprehensive quantification of fuel use in individual tissues during CIT in mice. Aim 3: Test the role of carbohydrate flux in BAT during CIT.