Insulin resistance is the underlying cause of type 2 diabetes; however, insulin resistance might also be a feed-back mechanism to protect cells and tissues from acute effects of over nutrition. Based upon our results with LDKO (hepatic specific Irs1L/LIrs2L/L CreAlbumin) mice, we found that hepatic insulin resistance elevated systemic oxygen consumption and energy expenditure, which was associated with a dramatic reduction of the RER (respiratory exchange ratio) and resistance to diet-induced obesity. Deletion of hepatic FoxO1 in LDKO-mice restored energy homeostasis and oxygen consumption, and increased the RER into the normal range. Contrary to the progressive peripheral insulin resistance of the LDKO-mice, Irs2 expression and insulin sensitivity increased in the PVH (paraventricular nucleus of hypothalamus). Interestingly, deletion of Irs2 in the PVH (Irs2L/L-mice intercrossed with CreSim1-mice) increased body weight and promoted obesity. To identify the molecular cross-talk between liver and brain, we used a neuronal cell line to screen for the effects of hepatokines that were dysregulated in LDKO-mice—but normalized in LTKO-mice. Among these dysregulated hepatokines, excess circulating NTF3 and GPX3 led to increased Irs2 expression and insulin sensitivity in neurons. Thus, our study suggests that hepatic FoxO1-dependent hepatokines—NTF3 or GPX3—modulate systemic energy expenditure and body weight through Irs2 expression in the PVH.
R. Tao: None. K.D. Copps: None. O. Stoehr: None. M.F. White: Advisory Panel; Self; Housey Pharmaceutical Research Laboratories.