A multi-organ response drives the large increase in whole body energy expenditure during experimental cold-exposure conditions, which is same in young, healthy, and lean individuals and in older, overweight individuals, without or with T2D (5). Muscle glucose uptake and nonshivering and shivering metabolic activity is largely unavoidable in humans exposed to mild cold, and is mostly responsible for the metabolic benefits of cold exposure (1, 13). One other potential source of energy expenditure is reesterification of the increased systemic NEFA flux from white adipose tissues (WAT) by other tissues (such as the liver) that occurs with cold exposure and β-adrenergic agonist treatment alike (14, 15). While browning of WAT has been suggested to contribute to energy expenditure after chronic cold exposure, the typical increase in thermogenesis evident in BAT is not detectable in WAT in vivo using 11C-acetate (16) or ex vivo using respirometry (17), in contrast to marked WAT browning seen in rodents. This discrepancy is not due to the lack of molecular sensitivity in PET imaging, which is in the femto, or 10-15, to picomolar, or 10-12, range, as it is by far the most sensitive method to measure metabolic fluxes in vivo, and is at least as sensitive as the most sensitive in vitro and ex vivo methods. UCP1-expressing cells, like other adipocytes in WAT, could, however, contribute to the glycerolipid-NEFA (GL/NEFA) substrate cycling by providing larges fluxes of NEFA. These fluxes of NEFA could be, in part, reesterified in other adipocytes or other organs (17). BAT also likely contributes to this inter-organ GL/NEFA substrate cycling as it rapidly mobilizes up to several grams of its own TG content upon acute cold exposure (1). Recycling of this large amount of NEFA in situ and/or in other organs may contribute to energy dissipation. In support of the contribution of this GL/NEFA cycling to cold-induced thermogenesis, interrupting BAT and WAT intracellular lipolysis with nicotinic acid during cold exposure, thereby reducing this cycling, leads to increased muscle shivering while total body energy expenditure remains the same (18). Shivering and BAT- or WAT-driven GL/NEFA cycling-mediated thermogenesis thus appear to coordinate cold-induced thermogenic response (Figure 1).

Cold-induced thermogenesis is a multi-organ process. BAT thermogenesis from uncoupling protein 1–mediated mitochondrial respiration likely contributes only a small fraction (i.e., less than 3%) of whole-body, cold-induced thermogenesis in humans. Skeletal muscle shivering and nonshivering thermogenesis drive most of the whole-body thermogenic response to cold. Glycerolipid and nonesterified fatty acid (GL/NEFA) substrate cycling activated in both WAT and BAT leads to systemic NEFA mobilization, likely driving NEFA reesterification in other organs (termed inter-organ GL/NEFA cycling) and also contributing to systemic energy expenditure.