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Hiroyoshi Taketani,1,* Taichiro Nishikawa,1,* Hisakazu Nakajima,2 Kazuki Kodo,2 Satoru Sugimoto,2 Wataru Aoi,3 Shin-ichi Horike,4 Makiko Meguro-Horike,4 Hiroshi Ishiba,1 Yuya Seko,1 Atsushi Umemura,1 Kanji Yamaguchi,1 Michihisa Moriguchi,1 Kohichiroh Yasui,1 Yoshito Itoh11Department of Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kyoto, Japan; 2Department of Pediatrics, Kyoto Prefectural University of Medicine, Kyoto, Japan; 3Division of Applied Life Sciences, Graduate School of Life and Environmental Sciences, Kyoto Prefectural University, Kyoto, Japan; 4Advanced Science Research Center, Kanazawa University, Kanazawa, Japan*These authors contributed equally to this workCorrespondence: Taichiro NishikawaKyoto Prefectural University of Medicine, 465 Kajii-cho, Kawaramachidouri Hirokouji Agaru, Kamigyo-ku, Kyoto 602-8566, JapanTel +81 75 251 5519Fax +81 75 251 1017Email taichi@koto.kpu-m.ac.jpBackground and aims: Nonalcoholic fatty liver disease (NAFLD) is a hepatic manifestation of metabolic syndrome, and its progression is associated with aging-associated impairment in metabolic homeostasis. Recently, energy metabolism in adipose tissue has been the subject of renewed interest, because significant energy expenditure can be induced in cells derived from white adipose tissue progenitors, in addition to brown adipose tissue (BAT). Here we evaluated whether aging-associated change in various adipose tissue depots affects the progression of NAFLD.Methods: Six-week-old male C57BL/6NCrSlc mice were fed control chow (C) or high-fat diet (60% fat; HF) for 12 or 24 weeks (12w/C, 12w/HF, 24w/C and 24w/HF groups, respectively) or switched from C to HF diet at 18 weeks of age (24w/C/HF group) and fed for a further 24 weeks. Some 24w/HF mice received a subcutaneous transplantation of adipose progenitors (106, cells/mouse) from young donor mice. Basal energy expenditure, glucose tolerance, and liver and adipose tissue histology were then evaluated. In addition, features of senescence and the capacity of adipose progenitors to “brown” were compared in mice of various ages.Results: 12w/HF mice demonstrated compensation in the forms of hypertrophy of interscapular classical BAT and the appearance of subcutaneous beige adipocytes, consistent with improved metabolic homeostasis. In contrast, 24w/HF and 24w/C/HF mice developed obesity, glucose intolerance, and severe NAFLD, with accelerated senescence and loss of adipose progenitors in subcutaneous fat tissues. Recruitment of adipose progenitors ameliorated these findings in 24w/HF mice.Conclusion: Impaired metabolic compensation in adipose tissue resulted in the progression of NAFLD, which was associated with aging-related deterioration in adipose progenitors. A new approach targeting adipose tissue progenitors might represent a potential strategy for the prevention of NAFLD.Keywords: nonalcoholic fatty liver disease, obesity, scenescence, brown adipocyte, mesenchymal stem cells, cell transplantation

Yuya Seko,1 Taichiro Nishikawa,1 Atsushi Umemura,1 Kanji Yamaguchi,1 Michihisa Moriguchi,1 Kohichiroh Yasui,1 Mayumi Kimura,2 Hiroaki Iijima,3 Toshio Hashimoto,3 Yoshio Sumida,4 Takeshi Okanoue,5 Yoshito Itoh1 1Department of Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kyoto, Japan; 2Ikuyaku. Integrated Value Development Division, Mitsubishi Tanabe Pharma Corporation, Osaka, Japan; 3Ikuyaku. Integrated Value Development Division, Mitsubishi Tanabe Pharma Corporation, Tokyo, Japan; 4Division of Hepatology and Pancreatology, Department of Internal Medicine, Aichi Medical University, Aichi, Japan; 5Department of Gastroenterology and Hepatology, Saiseikai Suita Hospital, Osaka, Japan Aim: Nonalcoholic fatty liver disease (NAFLD), including nonalcoholic steatohepatitis (NASH), is known to be associated with type 2 diabetes mellitus (T2DM) in high rate. The improvement in hepatic function due to sodium-glucose co-transporter 2 (SGLT2) inhibitors has been reported in T2DM patients with and without NAFLD. However, only a few studies have attempted to evaluate the role of SGLT2 inhibitors in T2DM patients with biopsy-proven NASH, and no detailed prospective studies including the individual hepatic fibrosis stage have been reported. Therefore, we investigated the effect of canagliflozin on hepatic function in T2DM patients with biopsy-confirmed NASH. Methods: T2DM patients with NASH (hepatic fibrosis stage 1–3 confirmed via liver biopsy, n=10) were enrolled and received canagliflozin (100 mg) once a day for 12 weeks. The primary end point was change in serum alanine aminotransferase (ALT) levels from baseline to week 12. Secondary end points were liver function/fibrosis markers, metabolic parameters, and safety. Results: The change in ALT from baseline to week 12 was -23.9 U/L (95% CI –48.1 to 0.3, P=0.0526). Significant improvements in several hepatic function/fibrosis markers, such as aspartate aminotransferase, fibrosis-4 index, and FM-fibro index, and metabolic parameters including hemoglobin A1c and body weight were found. No serious or liver-related adverse events were reported. Regarding individual patients, different trends in ALT-lowering effects between stage 1 and stage 2/3 subjects were observed; the degree of ALT-lowering effect tended to be greater in the stage 1 group than in the stage 2/3 group. Conclusion: Our results suggest that canagliflozin is effective and well-tolerated in patients with T2DM and NASH. Canagliflozin may be useful for the treatment of T2DM patients with NASH, especially those in early stages of NASH. Keywords: canagliflozin, Japanese, NASH, fibrosis stages, SGLT2 inhibitor, type 2 diabetes mellitus

Incorporation of wave functions of electrons and holes in each layer of the superlattice barriers improves the theoretical results of the optical transition energies in GaInP quantum wells having GaInP/AlInP superlattice barriers. Theoretical results agree with experimental results. These observations prove the validity of effective-mass approximation.