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Oxidative Stress Inhibits Healthy Adipose Expansion Through Suppression Of

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Oxidative Stress Inhibits Healthy Adipose Expansion Through Suppression Of Page 1 of 52 Diabetes Oxidative stress inhibits healthy adipose expansion through suppression of SREBF1-mediated lipogenic pathway Short title: ROS inhibits healthy adipose expansion Authors Yosuke Okuno1, Atsunori Fukuhara1,2, Erika Hashimoto1, Hironori Kobayashi1, Sachiko Kobayashi1,3, Michio Otsuki1, Iichiro Shimomura1 Affiliations 1Department of Metabolic Medicine, Osaka University Graduate School of Medicine, 2-2, Yamadaoka, Suita, Osaka, Japan 2Department of Adipose Management, Osaka University Graduate School of Medicine, 2-2, Yamadaoka, Suita, Osaka, Japan 3Department of Metabolism and Atherosclerosis, Osaka University Graduate School of Medicine, 2-2, Yamadaoka, Suita, Osaka, Japan Corresponding author Atsunori Fukuhara; Department of Metabolic Medicine, Osaka University Graduate School of Medicine, 2-2, Yamadaoka, Suita, Osaka 565-0871, Japan. Phone: +81-6-6879-3732; Email: [email protected] Word count: 4453 Number of tables and figures: 8 Diabetes Publish Ahead of Print, published online April 4, 2018 Diabetes Page 2 of 52 Abstract Recent studies have emphasized the association of adipose oxidative stress (Fat ROS) with the pathogenesis of metabolic disorders in obesity. However, the causal roles of Fat ROS in metabolic disturbances in vivo remain unclear because no mouse model has been available in which oxidative stress is manipulated targeting adipocytes. In this research, we generated two models of Fat ROS-manipulated mice and evaluated the metabolic features in diet-induced obesity. Fat ROS-eliminated mice in which Cat and Sod1 were overexpressed in adipocytes exhibited adipose expansion with decreased ectopic lipid accumulation and improved insulin sensitivity. Conversely, Fat ROS-augmented mice, in which glutathione was depleted specifically in adipocytes, exhibited restricted adipose expansion associated with increased ectopic lipid accumulation and deteriorated insulin sensitivity. In the white adipose tissues of these mice, macrophage polarization, tissue fibrosis and de novo lipogenesis were significantly changed. In vitro approaches identified KDM1A-mediated attenuation of SREBF1 transcriptional activities as the underlying mechanism for the suppression of de novo lipogenesis by oxidative stress. Thus, our study uncovered the novel roles of Fat ROS in healthy adipose expansion, ectopic lipid accumulation and insulin resistance, providing the possibility for the adipocyte-targeting antioxidant therapy. Page 3 of 52 Diabetes The prevalence of obesity and type 2 diabetes (T2DM) is increasing worldwide. T2DM is characterized by peripheral insulin resistance and insufficient insulin release from pancreatic beta cells. Among the drugs used for the treatment of T2DM, two agents, metformin and PPARγ agonists, can clinically improve peripheral insulin resistance. For better treatment of T2DM, it is important to elucidate the mechanisms of insulin resistance in obesity and to develop insulin-sensitizing drugs. Under excess calorie intake or insufficient energy expenditure, the white adipose tissue (WAT) stores lipids and becomes hypertrophic. Hypertrophic adipocytes impair insulin signaling not only in these cells but also in other insulin-sensitive organs through dysregulated secretion of adipocytokines, such as ADIPOQ (1), TNF (2), IL6 (3) and RETN (4). Recent works have demonstrated that such changes are preceded by various changes in WAT, such as infiltration of inflammatory cells (5), endoplasmic reticulum stress (6), hypoxia (7) and oxidative stress (8). We reported that the presence of high levels of prooxidants, such as NADPH oxidases, and low levels of antioxidant enzymes, such as Cat and Sod, in obese WAT resulted in high oxidative stress, conceptualized as adipose oxidative stress (Fat reactive oxygen species (ROS)), in mice (8) and humans (9-11). Many studies have suggested that Fat ROS is involved in various pathways in metabolic syndrome, including adipocyte insulin signaling (12), adipose inflammation (8), endoplasmic reticulum stress (13), mitochondrial function (14), cellular senescence (15), gut microbiota (16), adiponectin (Adipoq) (8), adiponectin receptor (AdipoR) (17) and angiotensin II signaling (18). Systemic or skeletal muscle-specific manipulation of oxidative stress in vivo, including administration of apocynin (8) or MnTBAP (19), overexpression of Sod (19; 20) or Cat (21; 22) and glutathione depletion (23-25) showed various effects on insulin sensitivity. However, the causal role of Fat ROS in Diabetes Page 4 of 52 obesity in vivo still remains unclear because no mouse model has been available in which oxidative stress is manipulated targeting adipocytes. We describe here the generation of mice with genetically manipulated ROS specifically in adipocytes. Elimination of Fat ROS potentiated healthy adipose expansion with decreased ectopic lipid deposition and improved insulin sensitivity. Conversely, augmented Fat ROS inhibited healthy adipose expansion with ectopic lipid accumulation and deteriorated insulin sensitivity. As a mechanism, Fat ROS accelerated adipose inflammation and adipose tissue fibrosis and inhibited de novo lipogenesis with the suppression of SREBF1 transcriptional activity through a reduction in KDM1A protein expression. Page 5 of 52 Diabetes Research Design and Methods Animal models. To generate aP2-Cat/SOD1 double transgenic mice, the rat Cat gene and human SOD1 gene were amplified by PCR and were inserted into an aP2 promoter cassette. These plasmids were microinjected into fertilized eggs from C57BL/6J mice, generating an aP2-Cat transgenic mouse and aP2-SOD1 transgenic mouse. The expression of transgenes was checked in several lines of aP2-Cat transgenic and aP2-SOD1 transgenic mice, and the line with the highest expression of each transgene in WAT was selected. In the next step, the aP2-Cat transgenic and aP2-SOD1 transgenic mice were crossed, and the resultant wild-type mice and aP2-Cat/SOD1 double transgenic mice were analyzed as littermates. Adipoq-Cre mice were kindly provided by Dr. Rosen (26). The LacZ-Neo cassette was removed from Gclc mutant mice (05085, The European Mouse Mutant Archive) by crossing them with CAG-FLPe mice (Riken). The resultant Gclc floxed mice were crossed with Adipoq-Cre mice to generate Adipoq-Gclc-knockout mice. Adipoq-Gclc-knockout mice and Gclc floxed mice were crossed, and the resultant Adipoq-Gclc-knockout mice and Gclc floxed mice were analyzed as littermates. To distinguish the floxed allele from the wild-type allele, the following primers were used: 5’-AGGAGGAGGGTGGGAAATTAC-3’ and 5’-GCATAACATCAAAGCCTGCAG. To distinguish null alleles from floxed alleles, the following primers were used: 5’-GTCAGCATCTCTGCTGTGGATC-3’ and 5’-AGGAGGAGGGTGGGAAATTAC-3’. In experiments with a high fat/high sucrose diet, the mice were fed F2HFHSD (Oriental Yeast) from 6 weeks of age. All mice were maintained under specific pathogen-free conditions and had free access to water and chow. Tissue collection. The mice were anesthetized, and blood samples were collected from the inferior vena cava. Tissues were carefully removed and snap frozen in nitrogen. Diabetes Page 6 of 52 mRNA analysis. Total RNA was isolated with Sepasol-RNA I Super G (Nacalai Tesque, Kyoto, Japan) or TRI Reagent (Sigma), according to the protocol provided by the manufacturer. First-strand cDNA was synthesized from total RNA using a Transcriptor First Strand cDNA Synthesis Kit (Roche) and was subjected to real-time RT-PCR using a Light Cycler (Roche) according to the instructions provided by the manufacturer. Values were expressed relative to the mRNA level of Rplp0. The primers used were shown in Supplementary Table. Fractionation of adipose tissue and isolation of ATMs. Adipose tissues were fractionated, and adipose tissue macrophages (ATMs) were collected by FACS Aria II (BD Biosciences) as described previously (27). M1 and M2 macrophages were analyzed by FACS Aria II as described previously (28). Measurement of enzymatic activity. Catalase and Sod activities in WAT were measured using a Catalase Assay Kit (Cayman) and a Superoxide Dismutase Assay Kit (Cayman), respectively, according to the instructions supplied by the manufacturer. Values were adjusted to the level of protein measured by a Pierce BCA Protein Assay Kit (Thermo Fisher Scientific). Measurement of hydrogen peroxide. Tissue hydrogen peroxide was measured using a Hydrogen Peroxide Assay Kit (Abcam), according to the instructions supplied by the manufacturer. Values were adjusted to the level of protein measured by a Pierce BCA Protein Assay Kit (Thermo Fisher Scientific). Page 7 of 52 Diabetes Measurement of tissue 8-isoprostane. Tissue 8-isoprostane was extracted and measured using an 8-Isoprostane EIA Kit (Cayman) according to the protocol recommended by the manufacturer. Briefly, tissue was lysed, incubated with potassium hydroxide, trapped with C18 Sep-Pak (Waters), washed with water and hexane, eluted with ethyl acetate, evaporated and reconstituted with EIA buffer. Values were adjusted to the DNA amounts measured by the CellTox Green Cytotoxicity Assay (Promega). Measurement of tissue glutathione. Tissue total glutathione was measured using a GSSG/GSH Quantification Kit (Dojindo Laboratories, Kumamoto, Japan) according to the protocol recommended by the manufacturer. Values were adjusted to the level of protein measured by Pierce BCA Protein Assay Kit (Thermo Fisher Scientific). Measurement of protein carbonylation. Tissue carbonylated protein was detected using an OxyBlot Protein Oxidation
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