Pancreatic-derived factor (PANDER) is a pancreatic islet-specific cytokine that cosecretes with insulin and is important for b cell function. Here, we show that PANDER is constitutively expressed in hepatocytes, and its expression is significantly increased in steatotic livers of diabetic insulin-resistant db/db mice and mice fed a high-fat diet. Overexpression of PANDER in the livers of C57Bl/6 mice promoted lipogenesis, with increased Forkhead box 1 (FOXO1) expression, whereas small interfering RNA-mediated knockdown of hepatic PANDER significantly attenuated steatosis, with reduced FOXO1 expression in db/ db mice. Hepatic PANDER silencing also attenuated insulin resistance and hyperglycemia in db/db mice. In cultured hepatocytes, PANDER overexpression induced lipid deposition, increased FOXO1 expression, and suppressed insulin-stimulated Akt activation and FOXO1 inactivation. Moreover, FOXO1 overexpression increased PANDER expression in cultured hepatocytes and mouse livers. Conclusion: PANDER promotes lipogenesis and compromises insulin signaling in the liver by increasing FOXO1 activity. PANDER may represent a potential therapeutic target for the treatment of fatty liver and insulin resistance. (HEPATOLOGY 2011;53:1906-1916

ATP synthase b subunit (ATPSb) had been previously shown to play an important role in controlling ATP synthesis in pancreatic b-cells. This study aimed to investigate the role of ATPSb in regulation of hepatic ATP content and glucose metabolism in diabetic mice. ATPSb expression and ATP content were both reduced in the livers of type 1 and type 2 diabetic mice. Hepatic overexpression of ATPSb elevated cellular ATP content and ameliorated hyperglycemia of streptozocininduced diabetic mice and db/db mice. ATPSb overexpression increased phosphorylated Akt (pAkt) levels and reduced PEPCK and G6pase expression levels in the livers. Consistently, ATPSb overexpression repressed hepatic glucose production in db/db mice. In cultured hepatocytes, ATPSb overexpression increased intracellular and extracellular ATP content, elevated the cytosolic free calcium level, and activated Akt independent of insulin. The ATPSb-induced increase in cytosolic free calcium and pAkt levels was attenuated by inhibition of P2 receptors. Notably, inhibition of calmodulin (CaM) completely abolished ATPSbinduced Akt activation in liver cells. Inhibition of P2 receptors or CaM blocked ATPSb-induced nuclear exclusion of forkhead box O1 in liver cells. In conclusion, a decrease in hepatic ATPSb expression in the liver, leading to the attenuation of ATP-P2 receptor-CaM-Akt pathway, may play an important role in the progression of diabetes. In past decades, diabetes became one of the major diseases threatening our health, with an estimated global prevalence of 6.4% in 2010 (1). The liver is the key tissue that releases glucose into the circulation in fasting status, and an increase in hepatic glucose production due to insulin deficiency or insulin resistance is the central event in the development and progression of type 1 or type 2 diabetes (2). Moreover, the liver is also one of the key tissues for lipid metabolism.ATP serves as an energy molecule as well as a signal molecule in many cells (3). We previously showed that leucine upregulates the ATP synthase b (ATPSb) subunit to enhance ATP synthesis and insulin secretion in rat islets, type 2 diabetic human islets, and Rattus insulin-1 (INS-1) cells. Overexpression or knockdown of ATPSb increases or reduces cellular ATP levels in INS-1 cells (4,5). Overall, these findings suggest that ATPSb plays a crucial role in controlling ATP synthesis.