The transcription factor Foxp1 regulates aerobic glycolysis in adipocytes and myocytes

In recent years, lactate has been recognized as an important circulating energy substrate rather than only a dead-end metabolic waste product generated during glucose oxidation at low levels of oxygen. The term aerobic glycolysis has been coined to denote increased glucose uptake and lactate pro-duction despite normal oxygen levels and functional mito-chondria. Hence, in aerobic glycolysis, lactate production is a metabolic choice, whereas in anaerobic glycolysis, it is a metabolic necessity based on inadequate levels of oxygen. Interestingly, lactate can be taken up by cells and oxidized to pyruvate and thus constitutes a source of pyruvate that is in-dependent of insulin. Here, we show that the transcription factor Foxp1 regulates glucose uptake and lactate production in adipocytes and myocytes. Overexpression of Foxp1 leads to increased glucose uptake and lactate production. In addition, protein levels of several enzymes in the glycolytic pathway are upregulated, such as hexokinase 2, phosphofructokinase, aldolase, and lactate dehydrogenase. Using chromatin immu-noprecipitation and real-time quantitative PCR assays, we demonstrate that Foxp1 directly interacts with promoter consensus cis-elements that regulate expression of several of these target genes. Conversely, knockdown of Foxp1 suppresses these enzyme levels and lowers glucose uptake and lactate production. Moreover, mice with a targeted deletion of Foxp1 in muscle display systemic glucose intolerance with decreased muscle glucose uptake. In primary human adipocytes with induced expression of Foxp1, we find increased glycolysis and glycolytic capacity. Our results indicate Foxp1 may play an important role as a regulator of aerobic glycolysis in adipose tissue and muscle.

Automated summary

In recent years, lactate has been recognized as an important circulating energy substrate and aerobic glycolysis has been identified as a metabolic choice involving increased glucose uptake and lactate production despite normal oxygen levels. This study demonstrates that the transcription factor Foxp1 regulates glucose uptake and lactate production in adipocytes and myocytes. Foxp1 directly interacts with the promoter consensus cis-elements that regulate expression of several enzymes in the glycolytic pathway. Knockdown of Foxp1 suppresses these enzyme levels and impairs glucose uptake and lactate production. This suggests that Foxp1 plays a crucial role in regulating aerobic glycolysis in adipose tissue and muscle.