Considerable data support the idea that Foxo1 drives the liver transcriptional program during fasting and is inhibited by Akt after feeding. Mice with hepatic deletion of Akt1 and Akt2 were glucose intolerant, insulin resistant, and defective in the transcriptional response to feeding in liver. These defects were normalized upon concomitant liver–specific deletion of Foxo1. Surprisingly, in the absence of both Akt and Foxo1, mice adapted appropriately to both the fasted and fed state, and insulin suppressed hepatic glucose production normally. Gene expression analysis revealed that deletion of Akt in liver led to constitutive activation of Foxo1–dependent gene expression, but once again concomitant ablation of Foxo1 restored postprandial regulation, preventing its inhibition of the metabolic response to nutrient intake. These results are inconsistent with the canonical model of hepatic metabolism in which Akt is an obligate intermediate for insulin’s actions. Rather they demonstrate that a major role of hepatic Akt is to restrain Foxo1 activity, and in the absence of Foxo1, Akt is largely dispensable for hepatic metabolic regulation in vivo.

Summary Insulin drives the global anabolic response to nutrient ingestion, regulating both carbohydrate and lipid metabolism. Previous studies have demonstrated that Akt2/protein kinase B is critical to insulin’s control of glucose metabolism, but its role in lipid metabolism has remained controversial. Here we show that Akt2 is required for hepatic lipid accumulation in obese, insulin-resistant states induced by either leptin-deficiency or high fat diet feeding. Lepob/ob mice lacking hepatic Akt2 failed to amass triglycerides in their livers, associated with and most likely due to a decrease in lipogenic gene expression and de novo lipogenesis. However, Akt2 is also required for steatotic pathways unrelated to fatty acid synthesis, as mice fed high fat diet had reduced liver triglycerides in the absence of hepatic Akt2 but did not exhibit changes in lipogenesis. These data demonstrate that Akt2 is a requisite component of the insulin-dependent regulation of lipid metabolism during insulin resistance.

The increasing prevalence of overnutrition and reduced activity has led to a worldwide epidemic of obesity. In many cases, this is associated with insulin resistance, an inability of the hormone to direct its physiological actions appropriately. A number of disease states accompany insulin resistance such as type 2 diabetes mellitus, the metabolic syndrome, and non-alcoholic fatty liver disease. Though the pathways by which insulin controls hepatic glucose output have been of intense study in recent years, considerably less attention has been devoted to how lipid metabolism is regulated. Thus, both the proximal signaling pathways as well as the more distal targets of insulin remain uncertain. In this review, we consider the signaling pathways by which insulin controls the synthesis and accumulation of lipids in the mammalian liver and, in particular, how this might lead to abnormal triglyceride deposition in liver during insulin-resistant states.

Under conditions of obesity and insulin resistance, the serine/threonine protein kinase Akt/PKB is required for lipid accumulation in liver. Two forkhead transcription factors, FoxA2 and FoxO1 have been suggested to function downstream of and to be negatively regulated by Akt and proposed as key determinants of hepatic triglyceride content. In this study, we utilize genetic loss of function experiments to show that constitutive activation of neither FoxA2 nor FoxO1 can account for the protection from steatosis afforded by deletion of Akt2 in liver. Rather, another downstream target positively regulated by Akt, the mTORC1 complex, is required in vivo for de novo lipogenesis and Srebp1c expression. Nonetheless, activation of mTORC1 and SREBP1c are not sufficient to drive postprandial lipogenesis in the absence of Akt2. These data show that insulin signaling through Akt2 promotes anabolic lipid metabolism independent of Foxa2 or FoxO1 and through pathways additional to the mTORC1-dependent activation of SREBP1c.

Summary Insulin rapidly suppresses hepatic glucose production and slowly decreases expression of genes encoding gluconeogenic proteins. In this study, we show that an immediate effect of insulin is to redirect newly synthesized glucose-6-phosphate to glycogen without changing the rate of gluconeogenesis. This process requires hepatic Akt2, as revealed by blunted insulin-mediated suppression of glycogenolysis in the perfused mouse liver, elevated hepatic glucose production during a euglycemic-hyperinsulinemic clamp, or as diminished glycogen accumulation during clamp or re-feeding in mice without hepatic Akt2. Surprisingly, the absence of Akt2 disrupted glycogen metabolism independent of GSK3α/β phosphorylation, which is thought to be an essential step in the pathway by which insulin is regulates glycogen synthesis through Akt. These data show that 1) the immediate action of insulin to suppress hepatic glucose production functions via an Akt2-dependent redirection of glucose-6-phosphate to glycogen and 2) insulin increases glucose phosphorylation and conversion to glycogen independent of GSK3.