Improved glucose metabolism by Eragrostis tef potentially through beige adipocyte formation and attenuating adipose tissue inflammation

RESEARCH ARTICLE Improved glucose metabolism by Eragrostis tef potentially through beige adipocyte formation and attenuating adipose tissue inflammation Mengistu Lemecha1, Katsutaro Morino1*, Daniel Seifu2, Takeshi Imamura3, Fumiyuki Nakagawa1,4, Aki Nagata4, Takuya Okamato1, Osamu Sekine1, Satoshi Ugi1, Hiroshi Maegawa1 a1111111111 a1111111111 a1111111111 a1111111111 a1111111111 1 Division of Endocrinology and Metabolism, Department of Medicine, Shiga University of Medical Science, Otsu, Japan, 2 School of Medicine, Department of Biochemistry, Addis Ababa University, Addis Ababa, Ethiopia, 3 Division of Molecular Pharmacology, Faculty of Medicine, Tottori University, Yonago, Japan, 4 CMIC Pharma Science, Osaka, Japan * Abstract OPEN ACCESS Citation: Lemecha M, Morino K, Seifu D, Imamura T, Nakagawa F, Nagata A, et al. (2018) Improved glucose metabolism by Eragrostis tef potentially through beige adipocyte formation and attenuating adipose tissue inflammation. PLoS ONE 13(8): e0201661. https://doi.org/10.1371/journal. pone.0201661 Background Teff is a staple food in Ethiopia that is rich in dietary fiber. Although gaining popularity in Western countries because it is gluten-free, the effects of teff on glucose metabolism remain unknown. Aim Editor: Makoto Kanzaki, Tohoku University, JAPAN Received: January 17, 2018 To evaluate the effects of teff on body weight and glucose metabolism compared with an isocaloric diet containing wheat. Accepted: July 19, 2018 Published: August 2, 2018 Copyright: © 2018 Lemecha et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Data Availability Statement: All relevant data are within the paper and its Supporting Information files. Funding: The Department of Medicine at SUMS received research promotion grants [SHOGAKUKIFU] from Boehringer Ingelheim, and Astellas to HM. ML received support from the MEXT fellowship program from the Japanese government. Teff flour was provided by The Teff Company (USA). These funders had no role in the study design, data collection and analysis, decision Results Mice fed teff weighed approximately 13% less than mice fed wheat (p < 0.05). The teffbased diet improved glucose tolerance compared with the wheat group with normal chow but not with a high-fat diet. Reduced adipose inflammation characterized by lower expression of TNFα, Mcp1, and CD11c, together with higher levels of cecal short chain fatty acids such as acetate, compared with the control diet containing wheat after 14 weeks of dietary treatment. In addition, beige adipocyte formation, characterized by increased expression of Ucp-1 (~7-fold) and Cidea (~3-fold), was observed in the teff groups compared with the wheat group. Moreover, a body-weight matched experiment revealed that teff improved glucose tolerance in a manner independent of body weight reduction after 6 weeks of dietary treatment. Enhanced beige adipocyte formation without improved adipose inflammation in a body-weight matched experiment suggests that the improved glucose metabolism was a consequence of beige adipocyte formation, but not solely through adipose inflammation. However, these differences between teff- and wheat-containing diets were not observed in the high-fat diet group. PLOS ONE | https://doi.org/10.1371/journal.pone.0201661 August 2, 2018 1 / 21 Teff improved glucose metabolism via beige formation and attenuating adipose inflammation to publish, or preparation of the manuscript. CMIC Pharma Science provided support in the form of equipment and salaries for authors (FN and AN), but did not have any additional role in the study design, data collection, analysis, decision to publish or preparation of the manuscript. The specific roles of these authors are articulated in the ’author contributions’ section. Competing interests: The authors have read the journal’s policy and would like to declare the following competing interests: HM received grants from Boehringer Ingelheim, and Astellas. FN and AN are employees of CMIC Pharma Science. The authors received Teff flour from the Teff Company (USA). These do not alter the authors’ adherence to PLOS ONE policies on sharing data and materials. Conclusions Teff improved glucose tolerance likely by promoting beige adipocyte formation and improved adipose inflammation. Introduction Teff (Eragrostis tef) is an ancient, indigenous cereal crop and the main staple food in Ethiopia that is believed to have been domesticated before 1000–4000 BCE [1]. It is also grown in India, Europe, Australia and the United States of America [2], and has become popular because it is gluten-free [3]. Teff is one of the world’s smallest grains and is difficult to refine, making its flour rich in fiber from the bran and germ [4]. Its name is derived from the Amharic term “tefa”, meaning “lost”, because of its tiny size. It is estimated that 20%–40% of the carbohydrates in teff are resistant starches [5]. Recently, studies have shown that dietary fiber plays a role in lowering inflammation [6]. Dietary fiber also reduces body weight by acting on satiety mechanisms and post-prandial glycemia by inhibiting absorption [7]. In addition, diets rich in whole grains and resistant starches improve insulin responsiveness and reduce the incidence of type 2 diabetes compared with diets based on refined grains [8]. Adipose tissue inflammation is a metabolic disorder implicated in the development of insulin resistance mediated by macrophage recruitment [9]. Pro-inflammatory cytokines released from adipose tissue consequently contribute to the progression of type 2 diabetes mellitus. Adipose tissue inflammation is characterized by the increased presence of crown-like structures and upregulation of proinflammatory genes such as tumor necrosis factor α (TNFα) and monocyte chemoattractant protein 1 (Mcp1; CCL2), and the macrophage marker, F4/80 [10]. Short chain fatty acids (SCFAs), such as acetate, propionate, and butyrate, are products of the microbiota in the intestine. Resistant starches and dietary fibers are the main substrates of microbiota that produce SCFAs [11]. Notably, acetate is the most dominant product in the intestine and attenuates chronic inflammation through activation of regulatory T cells [12]. Increasing evidence shows that SCFAs are potential targets for preventing or counteracting obesity and its associated disorders, such as dysregulated glucose metabolism and insulin resistance [13]. Although teff has become a familiar health food because of its gluten-free characteristic, its effect on glucose metabolism remains completely unknown. Therefore, we evaluated the effect of teff on glucose metabolism in vivo in mice. Materials and methods Animals and dietary groups Male C57BL/6J mice were housed with a 12-h light–dark cycle at 24˚C. Animals had (...truncated)