Abstract
Activation of energy-dissipating brown/beige adipocytes represents an attractive therapeutic strategy against metabolic disorders. While lactate is known to induce beiging through the regulation of Ucp1 gene expression, the role of lactate transporters on beige adipocytes' ongoing metabolic activity remains poorly understood. To explore the function of the lactate-transporting monocarboxylate transporters (MCTs), we used a combination of primary cell culture studies, 13C isotopic tracing, laser microdissection experiments, and in situ immunofluorescence of murine adipose fat pads. Dissecting white adipose tissue heterogeneity revealed that the MCT1 is expressed in inducible beige adipocytes as the emergence of uncoupling protein 1 after cold exposure was restricted to a subpopulation of MCT1-expressing adipocytes suggesting MCT1 as a marker of inducible beige adipocytes. We also observed that MCT1 mediates bidirectional and simultaneous inward and outward lactate fluxes, which were required for efficient utilization of glucose by beige adipocytes activated by the canonical β3-adrenergic signaling pathway. Finally, we demonstrated that significant lactate import through MCT1 occurs even when glucose is not limiting, which feeds the oxidative metabolism of beige adipocytes. These data highlight the key role of lactate fluxes in finely tuning the metabolic activity of beige adipocytes according to extracellular metabolic conditions and reinforce the emerging role of lactate metabolism in the control of energy homeostasis.
Highlights
Thermogenic brown and beige adipose tissues increase systemic energy expenditure and represent putative targets to cure obesity and related metabolic diseases including type II diabetes (1,2)
We demonstrate that MCT1 is expressed by inducible beige adipocytes scattered in white adipose tissues and mediates bidirectional lactate transport, a process that finely tunes their metabolic activation by the β3 adrenergic system upon cold exposure (Fig. 7)
We provide strong evidence that MCT1 expression is tightly correlated to the sub-population of adipocytes susceptible to cold-induced beiging remodeling
Summary
Thermogenic brown and beige adipose tissues increase systemic energy expenditure and represent putative targets to cure obesity and related metabolic diseases including type II diabetes (1,2). We found that approximatively 80% of lactate was derived from exogenous glucose, whatever CL or AZD treatments (Fig. 5G) Together, these experiments indicate that inhibiting lactate transport did not change the fraction of glucose contributing to lactate production, but significantly impaired the glycolytic flux and reveal the importance of MCT1-dependent lactate fluxes for efficient utilization of glucose by beige adipocytes activated by the canonical β3adrenergic signaling pathway. We found that UK5099 abrogated lactate import, in both glucose (Fig. 6I, 6J) and lactate (Fig. 6K, 6L) containing media, demonstrating that lactate consumption is directly dependent of the mitochondrial pyruvate utilization Together, these data highlight that MCT1 drives both the export and import of lactate, and that the imported lactate feeds the oxidative metabolism of beige adipocytes
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