Liver and systemic insulin resistance
Authors: Ling Yang, Ekihiro Seki
Journal: Hepatology (2014)

We appreciate the comments by Drs. Lanthier and Leclercq on our recent study that examined hepatocyte-specific function of transforming growth factor beta (TGF-β) signaling in the development of diet-induced fatty liver disease. Nutrition overload is one of the major environmental factors known to affect the interorgan networks.1 The liver is actively in the synthesis and oxidation of various lipids and is also exposed to lipids, such as free fatty acids, cholesterol, and triglycerides, by the portal vein from diet and the release from visceral adipose tissues. Both the liver and adipose tissue participate in glucose and lipid metabolism through secretion of various humoral factors and/or neural networks.1 Fatty liver disease is considered as a manifestation of metabolic syndrome and may influence the development of obesity and insulin resistance (IR). In fact, disruption of insulin receptor or Janus kinase 2 in hepatocytes results in hepatic steatosis and systemic IR, compared to WT mice.2, 3 In contrast, mice with liver-specific inactivation of p70S6K or protein tyrosine phosphatase 1B exhibited suppressed hepatic steatosis and IR.4, 5 These observations clearly indicate that the alteration of hepatic glucose and/or lipid metabolism affect systemic insulin sensitivity. However, there are several other factors that contribute to hepatic pathology, but not to systemic IR. Mice with liver-specific ablation of nuclear factor kappa B essential modulator or liver-specific overexpression of diacylglycerol acyltransferase 2 display increased hepatic steatosis, but no changes in systemic IR were observed.6, 7 In addition, depletion of Kupffer cells (KCs), the liver-resident macrophages, improved hepatic insulin sensitivity, but not peripheral insulin sensitivity.8 These factors appear to play a role specifically in the liver. Nutrition overload causes adipose tissue dysfunction and inflammation that release adipokines known to function as pro- or anti-inflammatory mediators. These cytokines associated with peripheral IR also travel to the liver and may enhance liver inflammation and hepatocyte dysfunction. On the contrary, inflammatory cytokines released from KCs and hepatocytes in fatty liver disease may reach peripheral adipose tissues, which affect peripheral insulin sensitivity. In addition, as pointed out by Drs. Lanthier and Leclercq, altered hepatic IR can directly modulate systemic IR. Our previous study demonstrated that choline-deficient L-amino-acid (CDAA) diet-fed animals show mild IR, as assessed by the homeostasis model assessment of IR, similar to that of CSAA diet-fed animals.9 It is possible that similar induction of peripheral IR is associated with similar degrees of body-weight gain and adiposity in choline-supplemented L-amino-acid (CSAA) and CDAA diet-fed animals, whereas liver inflammation and fibrosis are not essential for altering systemic insulin sensitivity. Our recent article has demonstrated that the TGF-β signaling in hepatocytes modulates hepatocyte lipid metabolism and systemic IR, as assessed by glucose and insulin tolerance tests.10 Insulin-induced protein kinase B (Akt) phosphorylation was slightly and dramatically suppressed in hepatocytes isolated from CSAA and CDAA diet-fed mice, respectively (Fig. 1). Restoration of insulin-induced Akt phosphorylation was observed in hepatocytes from Tgfbr2Δhep mice (Fig. 1), indicating amelioration of hepatic insulin signaling by inhibition of TGF-β signaling. This suggests that the development of systemic IR is partly the result of the hepatic IR related to TGF-β signaling. We fully agree with the suggestion from Drs. Lanthier and Leclercq for the interpretation of liver versus peripheral IR. Additional analysis of the insulin signaling in adipose tissue, skeletal muscle, and liver, as well as the hyperinsulinemic-euglycemic clamp study, will help to evaluate liver versus peripheral IR more in detail. Ling Yang, M.D., Ph.D.1,2 Ekihiro Seki, M.D., Ph.D.1 1Division of Gastroenterology Department of Medicine University of California, San Diego School of Medicine La Jolla, CA 2Division of Gastroenterology Department of Internal Medicine Union Hospital Tongji Medical College Huazhong University of Science and Technology Wuhan, China