Glycogen synthase 2 is a novel target gene of peroxisome proliferator-activated receptors

Glycogen synthase 2 (Gys-2) is the ratelimiting enzyme in the storage of glycogen in liver and adipose tissue, yet little is known about regulation of Gys-2 transcription. The peroxisome proliferator-activated receptors (PPARs) are transcription factors involved in the regulation of lipid and glucose metabolism and might be hypothesized to govern glycogen synthesis as well. Here, we show that Gys-2 is a direct target gene of PPAR alpha, PPAR beta/delta and PPAR gamma. Expression of Gys-2 is significantly reduced in adipose tissue of PPAR alpha-/-, PPAR beta/delta-/- and PPAR gamma+/- mice. Furthermore, synthetic PPAR beta/delta, and gamma agonists markedly up-regulate Gys-2 mRNA and protein expression in mouse 3T3-L1 adipocytes. In liver, PPAR alpha deletion leads to decreased glycogen levels in the refed state, which is paralleled by decreased expression of Gys-2 in fasted and refed state. Two putative PPAR response elements (PPREs) were identified in the mouse Gys-2 gene: one in the upstream promoter (DR-1prom) and one in intron 1 (DR-1int). It is shown that DR-1int is the response element for PPARs, while DR-1prom is the response element for Hepatic Nuclear Factor 4 alpha (HNF4 alpha). In adipose tissue, which does not express HNF4 alpha, DR-1prom is occupied by PPAR beta/delta and PPAR gamma, yet binding does not translate into transcriptional activation of Gys-2. Overall, we conclude that mouse Gys-2 is a novel PPAR target gene and that transactivation by PPARs and HNF4 alpha is mediated by two distinct response elements.