New Role for Growth/Differentiation Factor 15 in the Survival of Transplanted Brown Adipose Tissues in Cooperation with Interleukin-6
Masako Oka,
Norihiko Kobayashi,
Kazunori Matsumura,
Miwako Nishio,
Kenta Nakano,
Tadashi Okamura,
Hitoshi Okochi,
Tamiko Minamisawa,
Kiyotaka Shiba,
Kumiko Saeki
Affiliations
Masako Oka
Department of Disease Control, Research Institute, National Center for Global Health and Medicine, Tokyo 162-8655, Japan
Norihiko Kobayashi
Department of Disease Control, Research Institute, National Center for Global Health and Medicine, Tokyo 162-8655, Japan
Kazunori Matsumura
Department of Disease Control, Research Institute, National Center for Global Health and Medicine, Tokyo 162-8655, Japan
Miwako Nishio
Department of Laboratory Molecular Genetics of Hematology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo 113-8510, Japan
Kenta Nakano
Department of Laboratory Animal Medicine, Research Institute, National Center for Global Health and Medicine, Tokyo 162-8655, Japan
Tadashi Okamura
Department of Laboratory Animal Medicine, Research Institute, National Center for Global Health and Medicine, Tokyo 162-8655, Japan
Hitoshi Okochi
Department of Regenerative Medicine, Research Institute, National Center for Global Health and Medicine, Tokyo 162-8655, Japan
Tamiko Minamisawa
Division of Protein Engineering, Cancer Institute, Japanese Foundation for Cancer Research, Tokyo 135-8550, Japan
Kiyotaka Shiba
Division of Protein Engineering, Cancer Institute, Japanese Foundation for Cancer Research, Tokyo 135-8550, Japan
Kumiko Saeki
Department of Disease Control, Research Institute, National Center for Global Health and Medicine, Tokyo 162-8655, Japan
To identify factors involved in the earliest phase of the differentiation of human embryonic stem cells (hESCs) into brown adipocytes (BAs), we performed multi-time point microarray analyses. We found that growth/differentiation factor 15 (GDF15) expressions were specifically upregulated within three days of differentiation, when expressions of immature hESC markers were sustained. Although GDF15 expressions continued to increase in the subsequent differentiation phases, GDF15-deficient hESCs differentiated into mature BAs (Day 10) without apparent abnormalities. In addition, GDF15-deficient mice had normal brown adipose tissue (BAT) and were metabolically healthy. Unexpectedly, we found that interleukin-6 (IL6) expression was significantly lowered in the BAT of GDF15-/- mice. In addition, GDF15-/- hESCs showed abortive IL6 expressions in the later phase (>Day 6) of the differentiation. Interestingly, GDF15 expression was markedly repressed throughout the whole course of the differentiation of IL6-/- hESCs into BAs, indicating IL6 is essential for the induction of GDF15 in the differentiation of hESCs. Finally, intraperitoneally transplanted BAT grafts of GDF15-/- donor mice, but not those of wild-type (WT) mice, failed in the long-term survival (12 weeks) in GDF15-/- recipient mice. Collectively, GDF15 is required for long-term survival of BAT grafts by creating a mutual gene induction loop with IL6.
