Type 2 diabetes (T2DM) is a life-threatening disease characterized by hepatic and peripheral insulin resistance, which dysregulate inter-tissue metabolic flux and communication to promote hyperglycemia and dyslipidemia. Insulin signaling throughout the body is mediated by the insulin receptor substrate proteins IRS1 and IRS2. Within the liver, insulin regulates gene expression and metabolism largely via the IRS-dependent inhibition of transcription factor FoxO1. This renewal is founded on the striking observation that hepatic insulin resistance in ‘LDKO’ mice—which lack Irs1 and Irs2 in liver—propagates insulin resistance to the skeletal muscle and white and brown adipose tissues (WAT and BAT). Excessive hepatic glucose production (HGP) during diabetes owes, at least in part, to hepatic insulin resistance and activation of gluconeogenic genes by FoxO1. However, HGP is normalized in LDKO-mice upon inactivation/deletion of hepatic FoxO1 (i.e., ‘LTKO’ mice), suggesting that unknown, FoxO1-dependent factors secreted by the liver (‘hepatokines’) act to promote insulin resistance in peripheral tissues. This competitive renewal focuses upon the dysregulated hepatokines in LDKO liver to reveal how peripheral metabolic disease depends upon FoxO1—rather than hepatic insulin signaling per se. This is an innovative departure from the study of a single tissue or pathway that can, moreover, reveal the mechanisms by which hepatic resistance alone gives rise to many of the features of T2DM in mice. Robust preliminary data allow us to focus upon functionally important hepatokines that are elevated or decreased in LDKO liver, but normalized in LTKO liver. In addition to increased cardiovascular disease risk, T2DM is associated with non-alcoholic fatty liver disease (NAFLD) that can progress to non-alcoholic steatohepatitis (NASH) and eventual hepatocellular carcinoma (HCC); we have further established that this progression is attenuated in LTKO mice. Using deletion of floxed hepatokine alleles—or hepatotropic AAV (adeno-associated virus) to knock-down or over-express hepatokine genes—we employ both LDKO and LTKO mice to reveal (and corroborate) the effects of dysregulated FoxO1-dependent hepatokines upon systemic nutrient homeostasis and the progression of liver disease.