The presence of brown adipose tissue (BAT) in human adults opens attractive perspectives to treat metabolic disorders. Indeed, BAT dissipates energy as heat via uncoupling protein (UCP)1. Brown adipocytes are located in specific deposits or can emerge among white fat through the so-called browning process. Although numerous inducers have been shown to drive this process, no study has investigated whether it could be controlled by specific metabolites. Here, we show that lactate, an important metabolic intermediate, induces browning of murine white adipose cells with expression of functional UCP1. Lactate-induced browning also occurs in human cells and in vivo. Lactate controls Ucp1 expression independently of hypoxia-inducible factor-1a and PPARa pathways but requires active PPARg signaling. We demonstrate that the lactate effect on Ucp1 is mediated by intracellular redox modifications as a result of lactate transport through monocarboxylate transporters. Further, the ketone body b-hydroxybutyrate, another metabolite that impacts redox state, is also a strong browning inducer. Because this redox-dependent increase in Ucp1 expression promotes an oxidative phenotype with mitochondria, browning appears as an adaptive mechanism to alleviate redox pressure. Our findings open new perspectives for the control of adipose tissue browning and its physiological relevance.

The product of the recently cloned mouse obese (ob) gene is likely to play an important role in a loop regulating the size of the adipose tissue mass. The hormonal regulation of the ob gene could affect adiposity. To investigate this point, the effect of insulin on ob gene expression was examined in cells of the 3T3-F442A preadipocyte clonal line. ob mRNA is absent from exponentially growing, undifferentiated cells as well as from confluent preadipose cells. Terminal differentiation of preadipose to adipose cells leads to the expression of ob mRNA detected by a sensitive and quantitative ribonuclease protection assay. In adipose cells, the level of ob mRNA is sensitive to insulin in the nanomolar range of concentrations with an increase from an average of 1 copy to 5-10 copies/cell. The effect of insulin was fully reversible and takes place primarily at a transcriptional level. The ob mRNA shows a rapid turnover, with a halflife of approximately 2 h in the absence or presence of insulin. The level of secreted Ob protein is also regulated by insulin. These results indicate that the ob gene is expressed in mature fat cells only and support the possibility that insulin is an important regulator of ob gene expression.The "lipostat" or "adipostat" theory postulates that the size of body fat stores is regulated by a feedback loop (1). This hypothesis is based upon the recovery of initial body weight following lipectomy (2) and parabiosis experiments between genetically obese and wild-type mice suggesting the existence of putative factor(s) regulating food intake (3). The recently cloned ob gene from mouse, rat, and human encodes a circulating factor of 16 kDa that is secreted from adipocytes from various adipose depots (4 -8). The OB protein, named leptin, appears to act at a distant site since injections of the leptin decrease food intake and body weight in ob/ob mice and their lean counterparts (9 -12). This phenomenon implicates directly or indirectly the hypothalamus since mice with chemical lesions of the ventromedial nucleus of the hypothalamus (VMH), 1 after becoming rapidly hyperinsulinemic, express a dramatic increase in the levels of ob mRNA (5, 13). A substantial fall in ob mRNA in the epididymal fat of lean mice has been observed after fasting; this phenomenon is rapidly reversed on refeeding (13-16). The correlation between insulin level and the levels of ob mRNA and plasma leptin suggests that insulin may have direct effects on ob gene expression (15)(16)(17)(18). In this paper, we present data using cultured adipocytes that support this hypothesis. EXPERIMENTAL PROCEDURESCell Culture-Culture conditions of cells of the 3T3-F442A clonal line have been described (19). Cells were plated at 10 3 cells/cm 2 in 60-or 100-mm dishes and maintained in Dulbecco's modified Eagle's medium (DMEM) supplemented with 10% fetal bovine serum. This medium was defined as standard medium. At confluence, standard medium was supplemented with 2 nM triiodothyronine (T 3 ) and 3 nM insulin, termed differentiation medium, for 10 ...