MiR-494-3pはPGC1-αを介して脂肪細胞のベージュ化におけるミトコンドリアバイオジェネシスと体温調節を制御する

Scientific Reports. 2018 Oct 10;8(1):15096.滋賀医科大学平成30年

MicroRNA-494-3p inhibits formation of fast oxidative muscle fibres by targeting E1A-binding protein p300 in human-induced pluripotent stem cells.

MYOD-induced microRNA-494-3p expression inhibits fast oxidative myotube formation by downregulating myosin heavy chain 2 (MYH2) in human induced pluripotent stem cells (hiPSCs) during skeletal myogenesis. However, the molecular mechanisms regulating MYH2 expression via miR-494-3p remain unknown. Here, using bioinformatic analyses, we show that miR-494-3p potentially targets the transcript of the E1A-binding protein p300 at its 3\u27-untranslated region (UTR). Myogenesis in hiPSCs with the Tet/ON-myogenic differentiation 1 (MYOD1) gene (MyoD-hiPSCs) was induced by culturing them in doxycycline-supplemented differentiation medium for 7 days. p300 protein expression decreased after transient induction of miR-494-3p during myogenesis. miR-494-3p mimics decreased the levels of p300 and its downstream targets MYOD and MYH2 and myotube formation efficiency. p300 knockdown decreased myotube formation efficiency, MYH2 expression, and basal oxygen consumption rate. The binding of miR-494-3p to the wild type p300 3\u27-UTR, but not the mutated site, was confirmed using luciferase assay. Overexpression of p300 rescued the miR-494-3p mimic-induced phenotype in MyoD-hiPSCs. Moreover, miR-494-3p mimic reduced the levels of p300, MYOD, and MYH2 in skeletal muscles in mice. Thus, miR-494-3p might modulate MYH2 expression and fast oxidative myotube formation by directly regulating p300 levels during skeletal myogenesis in MyoD-hiPSCs and murine skeletal muscle tissues

Amla Enhances Mitochondrial Spare Respiratory Capacity by Increasing Mitochondrial Biogenesis and Antioxidant Systems in a Murine Skeletal Muscle Cell Line

Amla is one of the most important plants in Indian traditional medicine and has been shown to improve various age-related disorders while decreasing oxidative stress. Mitochondrial dysfunction is a proposed cause of aging through elevated oxidative stress. In this study, we investigated the effects of Amla on mitochondrial function in C2C12 myotubes, a murine skeletal muscle cell model with abundant mitochondria. Based on cell flux analysis, treatment with an extract of Amla fruit enhanced mitochondrial spare respiratory capacity, which enables cells to overcome various stresses. To further explore the mechanisms underlying these effects on mitochondrial function, we analyzed mitochondrial biogenesis and antioxidant systems, both proposed regulators of mitochondrial spare respiratory capacity. We found that Amla treatment stimulated both systems accompanied by AMPK and Nrf2 activation. Furthermore, we found that Amla treatment exhibited cytoprotective effects and lowered reactive oxygen species (ROS) levels in cells subjected to t-BHP-induced oxidative stress. These effects were accompanied by increased oxygen consumption, suggesting that Amla protected cells against oxidative stress by using enhanced spare respiratory capacity to produce more energy. Thus we identified protective effects of Amla, involving activation of mitochondrial function, which potentially explain its various effects on age-related disorders

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

<div><p>Background</p><p>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.</p><p>Aim</p><p>To evaluate the effects of teff on body weight and glucose metabolism compared with an isocaloric diet containing wheat.</p><p>Results</p><p>Mice fed teff weighed approximately 13% less than mice fed wheat (<i>p</i> < 0.05). The teff-based 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 <i>TNFα</i>, <i>Mcp1</i>, and <i>CD11c</i>, 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 <i>Ucp-1</i> (~7-fold) and <i>Cidea</i> (~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.</p><p>Conclusions</p><p>Teff improved glucose tolerance likely by promoting beige adipocyte formation and improved adipose inflammation.</p></div

A proposed model of the effects of teff diet on glucose metabolism.

<p>Illustrated is a model of how teff improves glucose tolerance by increasing beige adipocyte formation and inhibiting adipose inflammation through increasing SCFAs concentrations.</p

The possible role of beige adipocyte formation in CD-teff treated mice.

<p>A: mRNA levels of thermogenic and beige adipocyte marker genes in the inguinal adipose tissue from mice fed for 14 weeks with CD-what or CD-teff. All mRNA expression data were normalized to <i>36B4</i>. B: Core body temperatures were measured at 10:00 AM under <i>ad lib</i> feeding conditions. C: Hematoxylin and eosin staining and Ucp-1 immunostaining in iWAT from CD-wheat and CD-teff mice (left and right columns, respectively). D: Immunofluorescence staining of perilipin (green) in iWAT. E: The size and distribution of adipocytes from iWAT pad of CD-wheat and CD-teff mice quantified by ImageJ. F: Number of adipocyte. n = 3. *<i>p</i> < 0.05, ** <i>p</i> < 0.01. n.s. = not significant.</p

Comparison of body weight and glucose metabolism between mice fed a chow diet with wheat (CD-wheat: Blue) or teff (CD-teff: Red).

<p>A: Study design. B: Body weight. C: Energy intake. D: Intraperitoneal glucose tolerance test (IPGTT) at week 6 (2.0 g/kg). E: Blood glucose levels after oral mixed meal administration of each assigned diet (2.2g/kg body weight, 33% solution in dH₂O) after 16 h of fasting at week 6. F: Plasma insulin levels during OMTT. G: Oral glucose tolerance test (OGTT) at week 9 (2 g/kg). H: Insulin concentration during OGTT. I: Intraperitoneal insulin tolerance test (IPITT) at week 9 (0.5 U/kg). * <i>p</i> < 0.05, n.s. = not significant. n = 5–9 in each groups.</p

Comparison of body weight and glucose metabolism between mice fed a high-fat diet with wheat (HFD-wheat: Blue) or teff (HFD-teff: Red).

<p>A: Study design. B: Body weight. C: Energy intake. D: Intraperitoneal glucose tolerance test (IPGTT) at week 6 (2 g/kg). E: Blood glucose levels after oral mixed meal administration of each assigned diet (2.2g/kg body weight, 33% solution in dH₂O) after 16 h of fasting at week 6. F: Plasma insulin levels during OMTT. G: Oral glucose tolerance test (OGTT) at week 9 (2 g/kg). H: Insulin concentration during OGTT. I: Intraperitoneal insulin tolerance test (IPITT) at week 9 (0.5 U/kg). * <i>p</i> < 0.05, n.s. = not significant. n = 5–9 in each groups.</p