1: Colonic Pro-inflammatory Macrophages Cause Insulin Resistance in an Intestinal Ccl2/Ccr2-Dependent Manner.
Science of the Month - November 2016
CELL METABOLISM.
24 (2):295-310; 10.1016/j.cmet.2016.07.009 AUG 9 2016
Kawano Yoshinaga, Nakae Jun, Watanabe Nobuyuki, Kikuchi Tetsuhiro, Tateya Sanshiro, Tamori Yoshikazu, Kaneko Mari, Abe Takaya, Onodera Masafumi, Itoh Hiroshi
Previous studies have suggested that chronic inflammation in adipose tissue is an upstream event in the development of obesity-induced insulin resistance, and that dysbiosis, a change in the gut microbiota caused by a high-fat diet, is an important trigger. In this study, we focused on the intestinal tract, particularly gut immunity, as it is the first organ on the host side to sense changes in the gut microbiota and diet. In the colons of mice fed a high-fat diet for four weeks, the production of Ccl2 (Chemokine C-C motif ligand 2), a protein that induces macrophage accumulation, increases in the intestinal epithelium, leading to the accumulation of pro-inflammatory macrophages. Our research team generated intestinal epithelium-specific tamoxifen-inducible Ccl2-deficient mice, in which Ccl2 is deleted only in the intestinal epithelium, and analyzed their glucose tolerance under a high-fat diet. In these mice, macrophage accumulation in the colon associated with the high-fat diet was reduced, suppressing intestinal inflammation. This led to lower concentrations of inflammatory cytokines and bacterial endotoxin (LPS) in the portal vein, which in turn suppressed inflammation in adipose tissue and reduced the high-fat diet-induced increase in blood glucose levels by about 30%. These findings suggest that inflammation caused by colonic macrophages under a high-fat diet can lead to the development of diabetes. In the future, we aim to identify changes in chemokines in the colonic intestinal epithelium in human obesity and identify compounds that inhibit their activity, leading to the development of new therapeutic drugs for diabetes.
(Yoshinaga Kawano, Department of Nephrology, Endocrinology and Metabolism, Class of '86)
2：p38 alpha Activates Purine Metabolism to Initiate Hematopoietic Stem/Progenitor Cell Cycling in Response to Stress.
CELL STEM CELL.
19 (2):192-204; 10.1016/j.stem.2016.05.013 AUG 4 2016
Karigane Daiki, Kobayashi Hiroshi, Morikawa Takayuki, Ootomo Yukako, Sakai Mashito, Nagamatsu Go, Kubota Yoshiaki, Goda Nobuhito, Matsumoto Michihiro, Nishimura Emi K., Soga Tomoyoshi, Otsu Kinya, Suematsu Makoto, Okamoto Shinichiro, Suda Toshio, Takubo Keiyo
When differentiated blood cells, such as white blood cells, are depleted due to stress like chemotherapy, hematopoietic stem cells supply the lost differentiated cells. This phenomenon is called "stress hematopoiesis," but many aspects of its mechanism remain unclear. We focused on the cellular stress sensor p38α as a regulatory mechanism for stress hematopoiesis. Hematopoietic stem cells lacking p38α were vulnerable to various stresses, and their post-stress proliferation was suppressed. Through comprehensive metabolite analysis, we identified Impdh2, the rate-limiting enzyme in purine synthesis, as a downstream molecule of p38α in hematopoietic stem cells. We identified abnormal purine metabolism due to its reduced expression as the cause of defective stress hematopoiesis in p38α-deficient hematopoietic stem cells. Furthermore, we found that the transcription factor Mitf, which is essential for maintaining pigment stem cells in the skin, mediates these processes. This report demonstrates that dynamic changes in the intracellular metabolism of hematopoietic stem cells through the p38α-Mitf-Impdh2 signal are necessary for their proliferation, which may provide insights for the development of stem cell expansion technologies. Additionally, since leukemic stem cells share similar properties with normal hematopoietic stem cells, these findings are expected to contribute to understanding the pathology of leukemia and its treatment.
(Daiki Karigane, Department of Hematology, Class of '00; Keiyo Takubo, National Center for Global Health and Medicine Research Centers and Institutes, Class of '82)
Other Published Papers
1: Piwi Modulates Chromatin Accessibility by Regulating Multiple Factors Including Histone H1 to Repress Transposons.
MOLECULAR CELL.
63 (3):408-419; 10.1016/j.molcel.2016.06.008 AUG 4 2016
Iwasaki Yuka W., Murano Kensaku, Ishizu Hirotsugu, Shibuya Aoi, Iyoda Yumiko, Siomi Mikiko C., Siomi Haruhiko, Saito Kuniaki
2:Randomized Phase III Trial of Irinotecan Plus Cisplatin Compared With Paclitaxel Plus Carboplatin As First-Line Chemotherapy for Ovarian Clear Cell Carcinoma: JGOG3017/GCIG Trial.
JOURNAL OF CLINICAL ONCOLOGY.
34 (24):2881-+; 10.1200/ AUG 20 2016
Sugiyama Toru, Okamoto Aikou, Enomoto Takayuki, Hamano Tetsutaro, Aotani Eriko, Terao Yasuhisa, Suzuki Nao, Mikami Mikio, Yaegashi Nobuo, Kato Kiyoko, Yoshikawa Hiroyuki, Yokoyama Yoshihito, Tanabe Hiroshi, Nishino Koji, Nomura Hiroyuki, Kim Jae-Weon, Kim Byoung-Gie, Pignata Sandro, Alexandre Jerome, Green John, Isonishi Seiji, Terauchi Fumitoshi, Fujiwara Keiichi, Aoki Daisuke