Regulation of glycolysis in brown adipocytes by HIF-1α

Abstract

Brown adipose tissue takes up large amounts of glucose during cold exposure in mice and humans. Here we report an induction of glucose transporter 1 expression and increased expression of several glycolytic enzymes in brown adipose tissue from cold-exposed mice. Accordingly, these genes were also induced after β-adrenergic activation of cultured brown adipocytes, concomitant with accumulation of hypoxia inducible factor-1α (HIF-1α) protein levels. HIF-1α accumulation was dependent on uncoupling protein 1 and generation of mitochondrial reactive oxygen species. Expression of key glycolytic enzymes was reduced after knockdown of HIF-1α in mature brown adipocytes. Glucose consumption, lactate export and glycolytic capacity were reduced in brown adipocytes depleted of Hif-1α. Finally, we observed a decreased β-adrenergically induced oxygen consumption in Hif-1α knockdown adipocytes cultured in medium with glucose as the only exogenously added fuel. These data suggest that HIF-1α-dependent regulation of glycolysis is necessary for maximum glucose metabolism in brown adipocytes.

Restricting glycolysis impairs brown adipocyte glucose and oxygen consumption

“…Underlining the importance of glucose metabolism in activated BAT, many genes involved in glucose uptake and catabolism are upregulated after cold exposure (50). Consistent with this, we have reported increased expression of many glycolytic enzymes in BAT from cold-exposed mice (5,16). However, the contribution and importance of glucose and glycolysis for BAT thermogenesis are not yet fully understood.…”

Pyruvate kinase M2 represses thermogenic gene expression in brown adipocytes

“…We have previously shown that the expression of PKs is induced in BAT by cold exposure and by β‐adrenergic stimulation in primary brown adipocytes and in the brown adipocyte cell line WT‐1 . To gain insight into the expression levels and differences in expression between the different isoenzymes of PK, we profiled the mRNA levels of Pklr, Pkm1, and Pkm2 in different mouse tissues.…”

“…PKM2 is known for its role in cancer cell biology . The increased expression of PK in BAT induced by cold suggests a function of PKM2 also in adipose tissue. Here, we report that PKM2 is expressed at higher levels in BAT compared with white adipose tissue (WAT) (Fig.…”

“…We have previously reported an extensive regulation of genes encoding enzymes involved in glucose metabolism, including glycolysis, in BAT from cold‐exposed mice . In the present study, we have specifically investigated pyruvate kinase (PK), the enzyme catalyzing the final step of glycolysis, and the formation of pyruvate and ATP from phosphoenolpyruvate and ADP.…”

“…PKM1 and PKM2 possess both overlapping and nonoverlapping functions. Expression of both PKM isoforms is increased by thermogenic activation in BAT . Here, we have investigated the significance of the two isoforms by specifically depleting PKM1 or PKM2 in mature brown adipocytes.…”