1: Adipose tissue NAD(+) biosynthesis is required for regulating adaptive thermogenesis and whole-body energy homeostasis in mice.

PNAS.

2019;116(47):23822-23828. DOI: 10.1073

Yamaguchi S, Franczyk MP, Chondronikola M, Qi N, Gunawardana SC, Stromsdorfer KL, Porter LC, Wozniak DF, Sasaki Y, Rensing N, Wong M, Piston DW, Klein S, Yoshino J.

The NAD+ biosynthesis system is known to be impaired with aging and obesity and is involved in the pathophysiology of metabolic diseases through mechanisms such as regulating the activity of sirtuins, which are related to lifespan extension and health promotion in caloric restriction. In this study, we focused on two types of fat cells—white fat, which stores energy as neutral fat, and brown fat, which consumes energy to produce heat—to examine the role of the NAD+ biosynthesis system in energy metabolism. In brown fat, impairment of the NAD+ biosynthesis system led to a decrease in mitochondrial function and the expression of UCP1, a key factor in thermogenesis. More interestingly, we discovered that for brown fat to properly produce heat in response to environmental changes, it requires free fatty acids supplied from white fat in an NAD+-sirtuin activity-dependent manner (see figure). Furthermore, a collaborative study with Professor Samuel Klein (a visiting professor at Keio University) revealed that the NAD+ biosynthesis system is also involved in the thermogenic capacity of human brown fat. These results demonstrated the importance of the regulation of fat cell function by the NAD+ biosynthesis system and the interplay between adipose tissues in the mechanism of thermogenesis regulation. Currently, the safety and efficacy of activating the NAD+ biosynthesis system in humans are being investigated, led by Professor Hiroshi Ito of the Department of Internal Medicine. Further development is expected in research examining the role of the fat cell NAD+ biosynthesis system in energy metabolism and aging-related diseases. I would like to take this opportunity to express my sincere gratitude to Professor Hiroshi Ito for his many years of guidance.

(Jun Yoshino, Class of '79, Department of Medicine, Washington University School of Medicine; Shintaro Yamaguchi, Class of '84, Division of Nephrology, Endocrinology and Metabolism)

Nature Medicine

2020 Feb;26(2):281-288. doi: 10.1038/s41591-019-0723-9. Epub 2020 Jan 20.

Tomoyuki Miyazaki, Waki Nakajima, Mai Hatano, Yusuke Shibata, Yoko Kuroki, Tetsu Arisawa, Asami Serizawa, Akane Sano, Sayaka Kogami, Tomomi Yamanoue, Kimito Kimura, Yushi Hirata, Yuuki Takada, Yoshinobu Ishiwata, Masaki Sonoda, Masaki Tokunaga, Chie Seki, Yuji Nagai, Takafumi Minamimoto, Kazunori Kawamura, Ming-Rong Zhang, Naoki Ikegaya, Masaki Iwasaki, Naoto Kunii, Yuichi Kimura, Fumio Yamashita, Masataka Taguri, Hideaki Tani, Nobuhiro Nagai, Teruki Koizumi, Shinichiro Nakajima, Masaru Mimura, Michisuke Yuzaki, Hiroki Kato, Makoto Higuchi, Hiroyuki Uchida & Takuya Takahashi

A research group led by Professor Takuya Takahashi and Associate Professor Tomoyuki Miyazaki of the Department of Physiology, Yokohama City University Graduate School of Medicine, in collaboration with the National Institutes for Quantum and Radiological Science and Technology and Keio University, has succeeded for the first time in the world in developing a tracer (compound) for positron emission tomography (PET) that visualizes AMPA receptors—the most critical molecules for brain function—in the living human brain. Using this tracer, they successfully observed a high accumulation of AMPA receptors in the focal region of medial temporal lobe epilepsy (see figure). AMPA receptors are the most important molecules supporting brain function. Visualizing these molecules in the living human brain is expected to dramatically advance the elucidation of the pathophysiology of psychiatric and neurological disorders, which has been a black box until now, and lead to the development of innovative diagnostic and therapeutic methods based on this information. Currently, using this PET tracer, a multi-center, investigator-initiated clinical trial is underway at eight institutions nationwide, with Yokohama City University Hospital as the lead institution, aiming for regulatory approval of a diagnostic agent for epilepsy. It is also being used in a clinical trial for post-stroke patients of Edonerpic Maleate (Abe et al., *Science* 2018), a drug identified by the same group in 2018 to promote the effects of post-stroke rehabilitation, to verify its effectiveness as a biomarker for functional recovery. The group is also conducting imaging of patients with psychiatric disorders in collaboration with the Department of Psychiatry at Keio University, the University of Fukui, Kyushu University, and others.

(Takuya Takahashi, Class of '00, Professor, Department of Physiology, Yokohama City University Graduate School of Medicine)

Ann Rheum Dis.

first published as 10.1136/annrheumdis-2019-215862 on 14 October 2019.

Masaru Takeshita, Katsuya Suzuki, Yukari Kaneda, Humitsugu Yamane, Kazuhiro Ikeura, Hidekazu Sato, Shin Kato, Kazuyuki Tsunoda, Hisashi Arase, Tsutomu Takeuchi

Sjögren's syndrome is an autoimmune disease that causes dryness symptoms due to chronic inflammation of exocrine glands such as the salivary glands, and autoantibodies such as anti-SSA antibodies and anti-centromere antibodies (ACA) appear in the serum. This study, a collaboration between our department and the Department of Oral and Maxillofacial Surgery, focused on antibody-producing cells infiltrating the salivary glands. We obtained the gene sequences of antibodies produced by individual cells in patient tissues, created over 250 types of antibodies, and examined their reactivity. As a result, we found that in the salivary glands of patients positive for serum autoantibodies, approximately one-third of the antibody-producing cells produce autoantibodies such as anti-SSA antibodies and ACAs, and that antigen-dependent somatic mutations strongly contribute to the improvement of their affinity. Furthermore, by examining the corresponding antigens for ACAs in serum and tissue, we showed that ACAs are a group of antibodies against various sites of a large protein complex in the centromere region, and identified a novel antigen within it, the "MIS12 complex." This study clarified the development of local humoral immunity abnormalities in the lesion, which is considered an important clue for future elucidation of the pathophysiology.

(Tsutomu Takeuchi, Class of '59; Katsuya Suzuki, Class of '75; Masaru Takeshita, Class of '86, Division of Rheumatology; Kazuyuki Tsunoda, Department of Dentistry and Oral and Maxillofacial Surgery)