Adipocyte-hepatocyte crosstalk and the pathogenesis of nonalcoholic fatty liver disease


  • Briohny Smith,

    1. University of Western Australia, Nedlands, Western Australia, Australia
    2. Storr Liver Unit, Westmead Millennium Institute, University of Sydney and Westmead Hospital, Westmead, New South Wales, Australia
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  • Jacob George

    1. Storr Liver Unit, Westmead Millennium Institute, University of Sydney and Westmead Hospital, Westmead, New South Wales, Australia
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  • Potential conflict of interest: Nothing to report.

Sabio G, Das M, Mora A, Zhang Z, Jun JY, Ko HJ, et al. A stress signaling pathway in adipose tissue regulates hepatic insulin resistance. Science 2008;322:1539-1543. (Reprinted with permission.)


A high-fat diet causes activation of the regulatory protein c-Jun NH2-terminal kinase 1 (JNK1) and triggers development of insulin resistance. JNK1 is therefore a potential target for therapeutic treatment of metabolic syndrome. We explored the mechanism of JNK1 signaling by engineering mice in which the Jnk1 gene was ablated selectively in adipose tissue. JNK1 deficiency in adipose tissue suppressed high-fat diet–induced insulin resistance in the liver. JNK1-dependent secretion of the inflammatory cytokine interleukin-6 by adipose tissue caused increased expression of liver SOCS3, a protein that induces hepatic insulin resistance. Thus, JNK1 activation in adipose tissue can cause insulin resistance in the liver.


The bulk of chronic liver disease is secondary to viral hepatitis or to alcoholic and nonalcoholic forms of fatty liver disease [alcoholic liver disease and nonalcoholic fatty liver disease (NAFLD)]. Direct liver injury or intrahepatic immune responses are the usual culprits that initiate and perpetuate liver damage from viruses and alcohol. In contrast, a unique feature of the pathogenesis of NAFLD is the crosstalk between the liver and peripheral tissues such as the adipose compartment, skeletal muscle, and pancreas. In particular, hepatic steatosis in NAFLD develops as a result of insulin resistance, a reduction in the sensitivity of the body to insulin. In insulin-resistant individuals who fail to maintain pancreatic insulin secretion to levels that control blood glucose, type 2 diabetes (T2DM) ensues. Although obesity and altered body fat topography predispose to the development of insulin resistance and T2DM, the precise molecular mechanisms have not been fully elucidated. Alterations in multiple intracellular signaling pathways mediated by changes in the intracellular content of lipid mediators such as fatty acyl coenzyme A, diacylglycerol, and ceramides in part explain the development of tissue insulin resistance. Some of the relevant pathways include protein kinase C isoforms, c-jun NH2 terminal kinase, and IK β-kinase. As with hepatic steatosis, the development of steatohepatitis [nonalcoholic steatohepatitis (NASH)] in NAFLD is intricately associated with the development of insulin resistance,1–3 both peripheral and hepatic.3, 4 Indeed, increased severity of insulin resistance and metabolic syndrome are associated with more advanced liver disease in NAFLD.5

The factors that convert a proportion of fatty livers into ones with steatohepatitis are incompletely understood. Visceral obesity is a key determinant, increasing the likelihood of hepatic inflammation and fibrosis.6 In obesity, adipose tissue becomes infiltrated with macrophages, and improved vascular supply occurs by neoangiogenesis.7 In addition, peripheral and central adipocytes increase in volume.7, 8 Recent evidence suggests that the interaction between adipose tissue and the innate immune system (macrophages) that occurs in obesity may be responsible for producing the low-grade inflammatory state that is an accompaniment of metabolic syndrome.9 This state is characterized by elevated levels of circulating inflammatory markers and cytokines and adipokine secretion dysregulation.10 The inflammatory proteins, including tumor necrosis factor α (TNFα), interleukin 6 (IL-6), adiponectin, leptin, and resistin, may act locally in an autocrine or paracrine manner or exert their effects on distant organs such as the liver and pancreas and the cardiovascular system.

c-Jun NH2-terminal kinase 1 (JNK1) is activated by serum-free fatty acids, cytokines such as TNFα, and endoplasmic reticulum stress10, 11 and can be induced by a high-fat diet. In turn, activated JNK1 may directly [via phosphorylation of insulin receptor substrate 1 (IRS1) at an inhibitory site] and indirectly (via the induction of pro-inflammatory cytokines in target cells such as macrophages) result in insulin resistance.12-14 Mice fed a high-fat diet have elevated levels of activated JNK1 in the liver, adipose tissue, and skeletal muscle, along with insulin resistance.10, 15 Conversely, JNK1 knockout mice fed a high-fat diet have normalization of insulin sensitivity with improved insulin receptor signaling and decreased adiposity, and they lack steatohepatitis.14, 16, 17 This suggests that the JNK1 signaling pathway plays a major role in the pathogenesis of insulin resistance.

In order to examine whether JNK1 activation in particular tissues is responsible for metabolic stress–induced insulin resistance, Sabio et al.15 generated mice with JNK1-depleted myeloid cells. After a high-fat diet, however, these mice had no alterations in their response to glucose and insulin challenge in comparison with wild-type animals. The authors then investigated the role of adipocyte-specific JNK1 deletion. After 16 weeks of a high-fat diet, wild-type (FWT) mice and adipocyte JNK1–deficient (FKO) mice gained similar body masses, became glucose-intolerant with reduced glucose-induced insulin secretion, developed mild fasting hyperglycemia, and had similar serum lipid profiles. However, high-fat diet–fed FKO mice surprisingly demonstrated improved insulin sensitivity and reduced hyperinsulinemia in comparison with FWT mice. A hyperinsulinemic-euglycemic clamp study confirmed that high-fat diet–fed FWTmice developed hepatic insulin resistance, whereas FKO mice were protected. As expected, high-fat diet–fed FWT mice had reduced downstream insulin-stimulated Akt phosphorylation in the adipose tissue, liver, and skeletal muscle, whereas FKO mice had reduced Akt phosphorylation only in the skeletal muscle and not in the liver or adipose tissue.

In looking for the mediators of these adipocyte-specific JNK1 knockdown–mediated changes in hepatic insulin resistance, the authors measured circulating and adipose tissue messenger RNA for a variety of adipokines. High-fat diet–fed FWT and FKO mice had similar levels of circulating TNFα, leptin, and resistin, but FKO mice had significantly decreased levels of circulating IL-6 and adipose tissue messenger RNA for IL-6 and decreased levels of circulating high-molecular-weight adiponectin. IL-6 has previously been shown to induce hepatic insulin resistance18, 19 by increasing the expression of suppressor of cytokine signaling 3 (SOCS3),20 which inhibits the insulin receptor and potentiates IRS proteosomal degradation.21 In their experiments, a high-fat diet increased SOCS3 expression and decreased IRS1 in the livers of FWT mice but not FKO mice. Finally, to assess whether adipose-secreted IL-6 is responsible for insulin resistance, FKO mice were treated with exogenous IL-6. Exogenous IL-6 administration reverted the FKO mice to a phenotype similar to that of the FWT mice. These mice developed increased insulin resistance with increased hepatic SOCS3 expression and reduced insulin-induced Akt activation.

Sabio et al.15 have importantly demonstrated that JNK1 in adipocytes contributes to hepatic insulin resistance and that this regulates IL-6 secretion following a high-fat diet. The precise cellular source of this IL-6, adipocytes or adipose-infiltrating macrophages, has not been clarified, however. Although this study demonstrated no role for myeloid-derived JNK1 in the pathogenesis of insulin resistance, this finding is the opposite of the findings of Solinas et al.14 In that study of bone marrow chimeric mice, high-fat diet–induced insulin resistance was prevented in mice lacking JNK1 in myeloid cells. The reasons for the discrepancy are unclear.

What then are the implications of the study by Sabio et al.15 for the pathogenesis of NASH and NAFLD? Most significantly, the data point to the critical role of the crosstalk between the periphery, particularly adipocytes and adipose-infiltrating macrophages, and the liver to the pathogenesis of NAFLD (Fig. 1). In conjunction with other published data, this communication is important both for the development of hepatic steatosis via the development of peripheral and hepatic insulin resistance and for the progression to steatohepatitis.6, 22 Furthermore, adipose tissue–derived circulating IL-6 may be a key mediator, mediating both insulin resistance and hepatic inflammation,6, 19 although the effects of IL-6 per se on systemic insulin resistance are complex. Likewise, Sabio et al. noted that a high-fat diet decreased circulating levels of high-molecular-weight adiponectin in FWT mice, whereas FKO mice had levels similar to those of their chow-fed counterparts. A mechanism linking JNK1 in adipocytes and circulating adiponectin isoforms was not determined, but the role of this hormone in the pathogenesis of NAFLD,23 steatohepatitis,24 and hepatic fibrosis25 has been previously emphasized. Looking into the future, this study opens avenues both for the treatment or prevention of T2DM and for the modulation of NAFLD/NASH by agents that either target the JNK1 pathway or inhibit the actions of IL-6.

Figure 1.

Adipocyte-hepatocyte crosstalk in nonalcoholic fatty liver disease. JNK1 activation in adipocytes leads to elevated circulating levels of IL-6. In the liver, IL-6 inhibits insulin signaling leading to hepatic insulin resistance. Macrophage activation and the release of inflammatory cytokines amplify this process. JNK1 activation in extrahepatic tissues may also contribute to the development of hepatic inflammation. Abbreviations: IRS1, insulin receptor substrate 1; JNK1, c-Jun NH2-terminal kinase 1; IL-6, interleukin 6; SOCS3, suppressor of cytokine signaling 3; TNFα, tumor necrosis factor α.