Adaptive Thermogenesis in White Adipose Tissue: Is Lactate the New Brown(ing)?

The prevalence of obesity and type 2 diabetes has become a major economic and medical burden worldwide. Increased food intake and reduced physical activity have contributed to a shift in energy balance, resulting in excess energy storage in the white adipose tissue (WAT) depots. In contrast to WAT, brown adipose tissue (BAT) converts excess energy into heat via uncoupled respiration, which is dependent, in part, on expression by brown adipocytes of the uncoupling protein 1 (UCP1). Thus, an attractive strategy to reduce energy storage is to increase the levels of brown adipocyte activity. Although WAT does not normally express UCP1 or exhibit uncoupled respiration, WAT depots are capable of great plasticity. In response to cold exposure or genetic modifications, mouse white adipocytes can be induced to exhibit brown adipocyte–like character. These cells are known as “brite” (for brown-in-white) or “beige” adipocytes. Factors that are known to increase “browning” in mouse WAT include the transcription factors PGC1a, PRDM16, and members of the PPAR family (1). Additionally, treatment with metabolites, such as bile acids, prostaglandins, and retinoids, promotes the browning of WAT (2). Beige adipocytes express UCP1 and accumulate multilocular lipid droplets similar to genuine brown adipocytes but exhibit a gene expression signature that is distinct from classic brown adipocytes (3,4). The presence of UCP1 and increased mitochondrial activity in beige adipocytes has suggested enhanced “browning” within WAT and may be an important adjunct to classic BAT in vivo. In this issue of Diabetes, Carrière et al. (5) identified a fundamental cellular metabolite—lactate—as a new WAT browning factor. Lactate is well-known as the product of anaerobic glycolysis and is generated in high amounts in skeletal muscle during periods of intense activity. Resulting lactate may be “recycled” by the liver (which converts lactate to glucose) and also can serve as an oxidative substrate for the heart (6). This lactate transport between cells is mediated by monocarboxylate transporters (MCT) 1 to 4 (7). Within cells, high levels of lactate can be oxidized in the mitochondria by the mitochondrial lactate oxidation complex (6,8). Carrière et al. determined that mice exposed to cold for 24 h to trigger thermogenesis exhibit increased circulating lactate levels and Mct1 (lactate importer) gene expression in BAT and subcutaneous WAT. Furthermore, lactate treatment of murine and human white adipocytes substantially increased Ucp1 expression (30-fold in vitro and 2.5-fold in vivo), as well as the expression of fatty acid oxidation and mitochondrial genes. In lactate-treated mice, UCP1-positive cells within WAT depots had multilocular lipid droplets, reminiscent of brown adipocytes. The effects of lactate on Ucp1 induction required an intact PPARg signaling machinery, although lactate appears not to act as a direct PPARg activator. How do elevated lactate levels influence UCP1 levels in white adipocytes? To investigate this, Carrière et al. ruled out involvement of the lactate-responsive G-protein–coupled receptor GPR81 (9) but demonstrated that modulation of MCT lactate transporter activity altered Ucp1 expression. Pharmacological inhibition of the MCT1 lactate importer abrogated the lactate induction of Ucp1 expression, whereas reducing levels of the MCT4 lactate exporter led to a severalfold increase in Ucp1 mRNA levels. These results suggest that intracellular lactate levels influence Ucp1 expression and browning in white adipocytes. An expected consequence of the metabolism of high lactate levels within cells is the production of pyruvate and NADH (Fig. 1). By this means, lactate concentrations may influence the NADH-to-NAD ratio, and hence redox