Publications

Methylsulfonylmethane (MSM), an organosulfur compound, has been used as a dietary supplement that can improve various metabolic diseases. However, the effect of MSM on obesity-linked metabolic disorders remains unclear. The goal of the current study is to determine whether MSM has beneficial effects on glucose and lipid homeostasis in obesity-associated pathophysiologic states. High-fat diet-induced obese (DIO) and genetically obese diabetic db/db mice treated with MSM (1%-5% v/v, by drinking water) were studied. Metabolic parameters involved in glucose and lipid metabolism were determined. Treatment of DIO mice with MSM leads to a significant decrease in blood glucose levels. DIO mice treated with MSM are hypersensitive to insulin, as evidenced by decreased serum insulin and an increase in the area above the curve during an ITT. Concurrently, MSM reduces hepatic triglyceride and cholesterol contents in DIO mice. These effects are accompanied by reductions in gene expression of key molecules involved in lipogenesis and inflammation. FACS analysis reveals that MSM markedly increases the frequency of B cells and decreases the frequency of myeloid cells in peripheral blood and in bone marrow. Moreover, overnutrition-induced changes of femur microarchitecture are restored by MSM. In db/db mice, a marked impairment in glucose and lipid metabolic profiles is notably ameliorated when MSM is supplemented. These data suggest that MSM has beneficial effects on multiple metabolic dysfunctions, including hyperglycemia, hyperinsulinemia, insulin resistance, and inflammation. Thus, MSM could be the therapeutic option for the treatment of obesity-related metabolic disorders such as type 2 diabetes and fatty liver diseases.

Polyethylene (PE) separators have been the most popular option for commercial Li-ion batteries because of their uniform pore size, high tensile strength, low cost, and electrochemical stability. Unfortunately, PE separators generally suffer from significant dimensional changes at high temperatures, which frequently results in serious safety problems. In this regard, the integration of inorganic nanoparticles with PE separators has been considered to be a promising approach. Here, inorganic nanoparticles with a hierarchical pore structure were coated on a conventional polymer separator. The resultant composite separator exhibited superior Li ion transportation compared with separators coated with mesopore-only nanoparticles or conventional nonporous nanoparticles. The mesopores and macropores act synergistically to improve the electrolyte uptake and ionic conductivity of the inorganic nanoparticles, while other positive aspects such as their thermal and mechanical properties are still maintained.

Age is a major risk factor in age-related macular degeneration (AMD), but the underlying cause is unknown. We find increased Rho-associated kinase (ROCK) signaling and M2 characteristics in eyes of aged mice, revealing immune changes in aging. ROCK isoforms determine macrophage polarization into M1 and M2 subtypes. M2-like macrophages accumulated in AMD, but not in normal eyes, suggesting that these macrophages may be linked to macular degeneration. M2 macrophages injected into the mouse eye exacerbated choroidal neovascular lesions, while M1 macrophages ameliorated them, supporting a causal role for macrophage subtypes in AMD. Selective ROCK2 inhibition with a small molecule decreased M2-like macrophages and choroidal neovascularization. ROCK2 inhibition upregulated M1 markers without affecting macrophage recruitment, underlining the plasticity of these macrophages. These results reveal age-induced innate immune imbalance as underlying AMD pathogenesis. Targeting macrophage plasticity opens up new possibilities for more effective AMD treatment.

Selective inhibition of glycogen synthase kinase-3 (GSK3) has been targeted as a novel therapeutic strategy for diabetes mellitus. We investigated the anti-diabetic efficacy and molecular mechanisms of KICG1338 (2-(4-fluoro-phenyl)-3H-imidazo[4,5-b]pyridine-7-carboxylic acid(4-methyl-pyridin-3-yl)-amide), a GSK3β inhibitor, in three animal models: Otsuka Long-Evans Tokushima Fatty (OLETF) rats, leptin receptors-deficient db/db mice, and diet-induced obese (DIO) mice. Biochemical parameters including glucose tolerance tests and gene expressions associated with glucose metabolism were investigated. Glucose excursion decreased significantly by KICG1338-treated OLETF rats, accompanied by increase in insulin receptor substrate-1 and glucose transporter (GLUT)-4 expressions in muscle and decreased GLUT-2 expression in liver. Glucose-lowering effects were similarly observed in KICG1338-treated db/db and DIO mice. KICG1338 treatment increased adiponectin levels and decreased TNF-α levels. KICG1338 therapy also led to greater β-cell preservation and less hepatic fat infiltration with decreased expressions of genes involved in inflammation and endoplasmic reticulum stress. These data demonstrate anti-diabetic efficacy of KICG1338, a novel GSK3β inhibitor.

Small ubiquitin-like modifier (SUMO)-specific proteases (SENPs) that reverse protein modification by SUMO are involved in the control of numerous cellular processes, including transcription, cell division, and cancer development. However, the physiological function of SENPs in energy metabolism remains unclear. Here, we investigated the role of SENP2 in fatty acid metabolism in C2C12 myotubes and in vivo. In C2C12 myotubes, treatment with saturated fatty acids, like palmitate, led to nuclear factor-κB-mediated increase in the expression of SENP2. This increase promoted the recruitment of peroxisome proliferator-activated receptor (PPAR)δ and PPARγ, through desumoylation of PPARs, to the promoters of the genes involved in fatty acid oxidation (FAO), such as carnitine-palmitoyl transferase-1 (CPT1b) and long-chain acyl-CoA synthetase 1 (ACSL1). In addition, SENP2 overexpression substantially increased FAO in C2C12 myotubes. Consistent with the cell culture system, muscle-specific SENP2 overexpression led to a marked increase in the mRNA levels of CPT1b and ACSL1 and thereby in FAO in the skeletal muscle, which ultimately alleviated high-fat diet-induced obesity and insulin resistance. Collectively, these data identify SENP2 as an important regulator of fatty acid metabolism in skeletal muscle and further implicate that muscle SENP2 could be a novel therapeutic target for the treatment of obesity-linked metabolic disorders.

OBJECTIVE: The ligand-activated transcription factor peroxisome proliferator-activated receptor gamma (PPARγ) is a key factor in adipogenesis, insulin sensitivity, and cell cycle regulation. Activated PPARγ might also have anti-inflammatory and antiatherogenic properties. We tested whether lobeglitazone, a new PPARγ agonist, might protect against atherosclerosis.

METHODS: A rat model of balloon injury to the carotid artery, and high-fat, high-cholesterol diet-fed apolipoprotein E gene knockout (ApoE(-/-)) mice were studied.

RESULTS: After the balloon injury, lobeglitazone treatment (0.3 and 0.9 mg/kg) caused a significant decrease in the intima-media ratio compared with control rats (2.2 ± 0.9, 1.8 ± 0.8, vs. 3.3 ± 1.2, P < 0.01). Consistent with this, in ApoE(-/-) mice fed a high-fat diet, lobeglitazone treatment (1, 3, and 10 mg/kg) for 8 weeks reduced atherosclerotic lesion sizes in the aorta compared with the control mice in a dose-dependent manner. Treatment of vascular smooth muscle cells with lobeglitazone inhibited proliferation and migration and blocked the cell cycle G0/G1 to S phase progression dose-dependently. In response to lobeglitazone, tumor necrosis factor alpha (TNFα)-induced monocyte-endothelial cell adhesion was decreased by downregulating the levels of adhesion molecules. TNFα-induced nuclear factor kappa-B (NF-κB) p65 translocation into the nucleus was also blocked in endothelial cells. Insulin resistance was decreased by lobeglitazone treatment. Circulating levels of high sensitivity C-reactive protein and monocyte chemoattractant protein-1 were decreased while adiponectin levels were increased by lobeglitazone in the high-fat diet-fed ApoE(-/-) mice.

CONCLUSION: Lobeglitazone has antiatherosclerotic properties and has potential for treating patients with diabetes and cardiovascular risk.

Statins (HMGCR/HMG-CoA reductase [3-hydroxy-3-methylglutaryl-CoA reductase] inhibitors) are widely used to lower blood cholesterol levels but have been shown to increase the risk of type 2 diabetes mellitus. However, the molecular mechanism underlying diabetogenic effects remains to be elucidated. Here we show that statins significantly increase the expression of key gluconeogenic enzymes (such as G6PC [glucose-6-phosphatase] and PCK1 (phosphoenolpyruvate carboxykinase 1 [soluble]) in vitro and in vivo and promote hepatic glucose output. Statin treatment activates autophagic flux in HepG2 cells. Acute suppression of autophagy with lysosome inhibitors in statin treated HepG2 cells reduced gluconeogenic enzymes expression and glucose output. Importantly, the ability of statins to increase gluconeogenesis was impaired when ATG7 was deficient and BECN1 was absent, suggesting that autophagy plays a critical role in the diabetogenic effects of statins. Moreover autophagic vacuoles and gluconeogenic genes expression in the liver of diet-induced obese mice were increased by statins, ultimately leading to elevated hepatic glucose production, hyperglycemia, and insulin resistance. Together, these data demonstrate that chronic statin therapy results in insulin resistance through the activation of hepatic gluconeogenesis, which is tightly coupled to hepatic autophagy. These data further contribute to a better understanding of the diabetogenic effects of stains in the context of insulin resistance.

OBJECTIVE: Fibroblast growth factor 21 (FGF21) is an emerging metabolic regulator associated with glucose and lipid metabolism. However, previous studies of FGF21 have been largely confounded by obesity, and data are limited for advanced outcomes such as coronary artery disease (CAD) and ectopic fat accumulation. We investigated the associations between serum FGF21 concentrations and glucose/lipid metabolism, CAD, and pericardial fat deposition in subjects strictly matched for obesity parameters.

DESIGN, PATIENTS AND MEASUREMENTS: We enrolled 189 patients who had undergone cardiac multidetector coronary computed tomography. We measured cardiometabolic parameters and serum FGF21 levels within body mass index (BMI)-matched groups. Correlations and linear regressions were analysed among serum FGF21 levels, pericardial fat volumes and cardiometabolic parameters. Serum FGF21 concentrations were compared in patients with and without diabetes, metabolic syndrome (MS) or CAD.

RESULTS: Serum FGF21 concentrations were significantly higher in BMI-matched patients with MS (107·2 ± 83·6 vs 82·1 ± 67·4 ng/l without MS, P < 0·05), but not among those with diabetes (84·3 ± 56·4 vs 96·3 ± 98·9 ng/l without diabetes, P = 0·300) or CAD (89·6 ± 65·8 vs 84·2 ± 83·1 ng/l without CAD, P = 0·633). Serum FGF21 concentrations correlated positively with triglycerides, low-density lipoprotein-cholesterol, insulin, HOMA-IR and pericardial fat volume. They showed an independent association with pericardial fat volume (β = 0·111 ± 0·053, P < 0·05).

CONCLUSIONS: Serum FGF21 concentrations were significantly associated with lipid profiles, insulin resistance, pericardial fat volume and MS, independently of obesity, but not with overt CAD or diabetes.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is caused by mutations in the NOTCH3 gene on chromosome 19. Previous studies showed that NOTCH3 contains mutational hotspots that can vary among individuals of different ethnic backgrounds. In this study, we investigated the spectrum of NOTCH3 mutations in Korean patients with CADASIL. We retrospectively analyzed 156 patients who underwent NOTCH3 gene testing for molecular diagnosis of CADASIL using Sanger sequencing with a tiered approach. First, we screened previously reported mutational hotspots (exons 2-6, 8, 11, 18, 19, and 22). If no mutation was detected and samples were available, we extended our analysis to additional exons (7, 9, 10, 14, 15, 20, 21, 23, and 25). In 45 of 156 patients (28.8%), 29 mutations and 16 novel variants of unknown significance (VUS) were identified. The p.R544C mutation in exon 11 of NOTCH3 was the most frequently observed mutation (n = 8), followed by p.R75P in exon 3 (n = 7), p.R332C in exon 6 (n = 3), p.R54C in exon 2 (n = 2), and p.R90C in exon 3 (n = 2). Among the VUS, p.R1175W in exon 22, p.S414C in exon 8, and p.N1207S in exon 22 were found in 5, 3, and 2 patients, respectively. Other mutations and VUS were observed in 1 patient each. Although this was not a prospective, nationwide cohort study, the results above suggested that the spectrum of NOTCH3 mutations might be different in Koreans than in individuals of Caucasian ethnicity. Therefore, further analysis of Koreans with CADASIL might be necessary to implement a Korean-specific mutation screening paradigm.