Abstract B36: Pyruvate kinase M2 regulates adipocyte differentiation and the expression of enzymes involved in glucose metabolism

The number of overweight and obese individuals continues to increase in both the U.S. and worldwide. This increase has led to a significant increase in obesity-related medical problems including diabetes mellitus, cardiovascular disease and cancer. In obesity, the differentiation of adipocytes is suppressed. Although adipocyte differentiation is associated with changes in glucose metabolism, little is known about the potential of enzymes involved in glucose metabolism to modulate this process. Pyruvate kinase (PK) mediates the rate-limiting step of glycolysis. The M2 isoform of PK (PKM2) is expressed in adipocytes but its role in adipogenesis is unknown. Here we demonstrate that PKM2 regulates the differentiation of both human and mouse adipocytes. Silencing of PKM2 in preadipocytes led to increased lipid accumulation, enhanced expression of markers (FABP4, PPARgamma, C/EBPBeta) of adipocyte differentiation and caused a shift in the pattern of enzymes involved in glucose metabolism favoring the TCA cycle. Overexpression of PKM2 suppressed adipocyte differentiation. In obesity, increased numbers of macrophages are found in adipose tissue and are believed to contribute to insulin resistance. Interestingly, we found that activated macrophages produce factors that inhibit adipocyte differentiation leading to increased levels of enzymes involved in aerobic glycolysis including PKM2. Given its importance in regulating adipocyte differentiation, we investigated the mechanism by which PKM2 expression was regulated. The HIF-1alpha - c-Myc - HnRNPA1 pathway induced PKM2 in preadipocytes. The redox sensor CtBP1 was found to be a negative regulator of this pathway. Taken together, these results provide evidence that PKM2 is not only expressed in adipose tissue but is also a determinant of adipocyte differentiation. Whether pharmacologically targeting PKM2 will impact on obesity or its consequences warrants further investigation. Citation Format: Tetsuo Kimura, Priya Bhardwaj, Domenick J. Falcone, Andrew J. Dannenberg, Kotha Subbaramaiah. Pyruvate kinase M2 regulates adipocyte differentiation and the expression of enzymes involved in glucose metabolism. [abstract]. In: Proceedings of the Thirteenth Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2014 Sep 27-Oct 1; New Orleans, LA. Philadelphia (PA): AACR; Can Prev Res 2015;8(10 Suppl): Abstract nr B36.