Adipokines reportedly affect hepatic gluconeogenesis, and the
adipokine visfatin is known to be related to
insulin resistance and
type 2 diabetes. However, whether
visfatin contributes to hepatic gluconeogenesis remains unclear.
Visfatin, also known as
nicotinamide phosphoribosyltransferase (NAMPT), modulates sirtuin1 (
SIRT1) through the regulation of
nicotinamide adenine dinucleotide (
NAD). Therefore, we investigated the effect of extracellular
visfatin on
glucose production in HepG2 cells, and evaluated whether extracellular
visfatin affects hepatic gluconeogenesis via an
NAD+-
SIRT1-dependent pathway. Treatment with
visfatin significantly increased
glucose production and the
mRNA expression and
protein levels of
phosphoenolpyruvate carboxykinase (PEPCK) and
glucose-6-phosphatase (G6Pase) in HepG2 cells in a time- and concentration-dependent manner. Knockdown of
SIRT1 had no remarkable effect on the induction of gluconeogenesis by
visfatin. Subsequently, we evaluated if extracellular
visfatin stimulates the production of gluconeogenic
enzymes through the classical
protein kinase A (PKA)/
cyclic AMP-responsive
element (CRE)-
binding protein (CREB)-dependent process. The phosphorylation of CREB and PKA increased significantly in HepG2 cells treated with
visfatin. Additionally, knockdown of CREB and PKA inhibited
visfatin-induced gluconeogenesis in HepG2 cells. In summary, extracellular
visfatin modulates
glucose production in HepG2 cells through the PKA/CREB pathway, rather than via
SIRT1 signaling.