Phosphorylation of RXRα mediates the effect of JNK to suppress hepatic FGF21 expression and promote metabolic syndrome.

The cJun NH-terminal kinase (JNK) signaling pathway in the liver promotes systemic changes in metabolism by regulating peroxisome proliferator-activated receptor α (PPARα)-dependent expression of the hepatokine fibroblast growth factor 21 (FGF21). Hepatocyte-specific gene ablation studies demonstrated that the gene (encoding JNK2) plays a key mechanistic role. Mutually exclusive inclusion of exons 7a and 7b yields expression of the isoforms JNK2α and JNK2β.

Aberrant Ca signaling by IPRs in adipocytes links inflammation to metabolic dysregulation in obesity.

Chronic metabolic inflammation is a key feature of obesity, insulin resistance, and diabetes. Here, we showed that altered regulation of the Ca channel inositol trisphosphate receptor (IPR) was an adipocyte-intrinsic event involved in the emergence and propagation of inflammatory signaling and the resulting insulin resistance. Inflammation induced by cytokine exposure in vitro or by obesity in vivo led to increases in the abundance and activity of IPRs and in the phosphorylation of the Ca-dependent kinase CaMKII in adipocytes in a manner dependent on the kinase JNK.

A feed-forward regulatory loop in adipose tissue promotes signaling by the hepatokine FGF21.

The cJun NH-terminal kinase (JNK) signaling pathway is activated by metabolic stress and promotes the development of metabolic syndrome, including hyperglycemia, hyperlipidemia, and insulin resistance. This integrated physiological response involves cross-talk between different organs. Here we demonstrate that JNK signaling in adipocytes causes an increased circulating concentration of the hepatokine fibroblast growth factor 21 (FGF21) that regulates systemic metabolism.

Regulation of adipose tissue inflammation by interleukin 6.

Obesity is associated with a chronic state of low-grade inflammation and progressive tissue infiltration by immune cells and increased expression of inflammatory cytokines. It is established that interleukin 6 (IL6) regulates multiple aspects of metabolism, including glucose disposal, lipolysis, oxidative metabolism, and energy expenditure. IL6 is secreted by many tissues, but the role of individual cell types is unclear.

JNK regulates muscle remodeling via myostatin/SMAD inhibition.

Skeletal muscle has a remarkable plasticity to adapt and remodel in response to environmental cues, such as physical exercise. Endurance exercise stimulates improvements in muscle oxidative capacity, while resistance exercise induces muscle growth. Here we show that the c-Jun N-terminal kinase (JNK) is a molecular switch that when active, stimulates muscle fibers to grow, resulting in increased muscle mass.

Endoplasmic reticulum chaperone GRP78 regulates macrophage function and insulin resistance in diet-induced obesity.

Obesity-mediated inflammation is a major cause of insulin resistance, and macrophages play an important role in this process. The 78-kDa glucose-regulated protein (GRP78) is a major endoplasmic reticulum chaperone that modulates unfolded protein response (UPR), and mice with GRP78 heterozygosity were resistant to diet-induced obesity. Here, we show that mice with macrophage-selective ablation of GRP78 (Lyz- GRP78) are protected from skeletal muscle insulin resistance without changes in obesity compared with wild-type mice after 9 wk of high-fat diet.

An alternative splicing program promotes adipose tissue thermogenesis.

Alternative pre-mRNA splicing expands the complexity of the transcriptome and controls isoform-specific gene expression. Whether alternative splicing contributes to metabolic regulation is largely unknown. Here we investigated the contribution of alternative splicing to the development of diet-induced obesity.

Inflammation Mediated by JNK in Myeloid Cells Promotes the Development of Hepatitis and Hepatocellular Carcinoma.

The cJun NH2-terminal kinase (JNK) signaling pathway is required for the development of hepatitis and hepatocellular carcinoma. A role for JNK in liver parenchymal cells has been proposed, but more recent studies have implicated non-parenchymal liver cells as the relevant site of JNK signaling. Here, we tested the hypothesis that myeloid cells mediate this function of JNK.

Hepatic acetyl CoA links adipose tissue inflammation to hepatic insulin resistance and type 2 diabetes.

Impaired insulin-mediated suppression of hepatic glucose production (HGP) plays a major role in the pathogenesis of type 2 diabetes (T2D), yet the molecular mechanism by which this occurs remains unknown. Using a novel in vivo metabolomics approach, we show that the major mechanism by which insulin suppresses HGP is through reductions in hepatic acetyl CoA by suppression of lipolysis in white adipose tissue (WAT) leading to reductions in pyruvate carboxylase flux. This mechanism was confirmed in mice and rats with genetic ablation of insulin signaling and mice lacking adipose triglyceride lipase.

Analysis of in vitro insulin-resistance models and their physiological relevance to in vivo diet-induced adipose insulin resistance.

Diet-induced obesity (DIO) predisposes individuals to insulin resistance, and adipose tissue has a major role in the disease. Insulin resistance can be induced in cultured adipocytes by a variety of treatments, but what aspects of the in vivo responses are captured by these models remains unknown. We use global RNA sequencing to investigate changes induced by TNF-α, hypoxia, dexamethasone, high insulin, and a combination of TNF-α and hypoxia, comparing the results to the changes in white adipose tissue from DIO mice.

Acyl-CoA synthetase 1 is induced by Gram-negative bacteria and lipopolysaccharide and is required for phospholipid turnover in stimulated macrophages.

The enzyme acyl-CoA synthetase 1 (ACSL1) is induced by peroxisome proliferator-activated receptor α (PPARα) and PPARγ in insulin target tissues, such as skeletal muscle and adipose tissue, and plays an important role in β-oxidation in these tissues. In macrophages, however, ACSL1 mediates inflammatory effects without significant effects on β-oxidation. Thus, the function of ACSL1 varies in different tissues.

JNK expression by macrophages promotes obesity-induced insulin resistance and inflammation.

The cJun NH(2)-terminal kinase (JNK) signaling pathway contributes to inflammation and plays a key role in the metabolic response to obesity, including insulin resistance. Macrophages are implicated in this process. To test the role of JNK, we established mice with selective JNK deficiency in macrophages.

Lysophosphatidylcholine as an effector of fatty acid-induced insulin resistance.

The mechanism of FFA-induced insulin resistance is not fully understood. We have searched for effector molecules(s) in FFA-induced insulin resistance. Palmitic acid (PA) but not oleic acid (OA) induced insulin resistance in L6 myotubes through C-Jun N-terminal kinase (JNK) and insulin receptor substrate 1 (IRS-1) Ser307 phosphorylation.

Imatinib mesylate reduces endoplasmic reticulum stress and induces remission of diabetes in db/db mice.

Objective: Imatinib has been reported to induce regression of type 2 diabetes in chronic leukemia patients. However, the mechanism of diabetes amelioration by imatinib is unknown, and it is uncertain whether imatinib has effects on type 2 diabetes itself without other confounding diseases like leukemia. We studied the effect of imatinib on diabetes in db/db mice and investigated possible mechanism's underlying improved glycemic control by imatinib.

Loss of autophagy diminishes pancreatic beta cell mass and function with resultant hyperglycemia.

Autophagy is a cellular degradation-recycling system for aggregated proteins and damaged organelles. Although dysregulated autophagy is implicated in various diseases including neurodegeneration, its role in pancreatic beta cells and glucose homeostasis has not been described. We produced mice with beta cell-specific deletion of Atg7 (autophagy-related 7).

Lysophosphatidylcholine as a death effector in the lipoapoptosis of hepatocytes.

The pathogenesis of nonalcoholic steatohepatitis (NASH) is unclear, despite epidemiological data implicating FFAs. We studied the pathogenesis of NASH using lipoapoptosis models. Palmitic acid (PA) induced classical apoptosis of hepatocytes.

Toll-like receptor 2 senses beta-cell death and contributes to the initiation of autoimmune diabetes.

Although it is established that defective clearance and, hence, increased accumulation of apoptotic cells can lead to autoimmunity, the mechanism by which this occurs remains elusive. Here, we observed that apoptotic cells undergoing secondary necrosis but not intact apoptotic cells provoked substantial immune responses, which were mediated through the toll-like receptor 2 (TLR2) pathway. The development of autoimmune diabetes was markedly inhibited in Tlr2(-/-) mice but not in Tlr4(-/-) mice, showing that TLR2 plays an important role in the initiation of the disease.

NF-kappa B prevents beta cell death and autoimmune diabetes in NOD mice.

Whereas NF-kappaB has potent antiapoptotic function in most cell types, it was reported that in pancreatic beta cells it serves a proapoptotic function and may contribute to the pathogenesis of autoimmune type 1 diabetes. To investigate the role of beta cell NF-kappaB in autoimmune diabetes, we produced transgenic mice expressing a nondegradable form of IkappaBalpha in pancreatic beta cells (RIP-mIkappaBalpha mice). beta cells of these mice were more susceptible to killing by TNF-alpha plus IFN-gamma but more resistant to IL-1beta plus IFN-gamma than normal beta cells.

Novel compound 2-methyl-2H-pyrazole-3-carboxylic acid (2-methyl-4-o-tolylazo-phenyl)-amide (CH-223191) prevents 2,3,7,8-TCDD-induced toxicity by antagonizing the aryl hydrocarbon receptor.

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a widespread environmental pollutant with many toxic effects, including endocrine disruption, reproductive dysfunction, immunotoxicity, liver damage, and cancer. These are mediated by TCDD binding to and activating the aryl hydrocarbon receptor (AhR), a basic helix-loop-helix transcription factor. In this regard, targeting the AhR using novel small molecule inhibitors is an attractive strategy for the development of potential preventive agents.

Luteolin inhibits the nuclear factor-kappa B transcriptional activity in Rat-1 fibroblasts.

Flavonoids are natural polyphenolic compounds that have anti-inflammatory, cytoprotective and anticarcinogenic effects. In this study, we investigated the effects of several flavonoids on nuclear factor-kappa B (NF-kappa B) activation by using luciferase reporter gene assay. Among the flavonoids examined, luteolin showed the most potent inhibition on lipopolysaccharide (LPS)-stimulated NF-kappa B transcriptional activity in Rat-1 fibroblasts.

Thiram and ziram stimulate non-selective cation channel and induce apoptosis in PC12 cells.

The neurotoxicity of dithiocarbamates has been previously reported, however, the detailed mechanism underlying the neurotoxicity is still not fully understood. Among the dithiocarbamates, we investigated thiram and ziram in a neuronal-like pheochromocytoma (PC12) cells. Thiram and ziram strongly induced cell death in both dose- and time-dependent manners with the LC(50) of 0.