Trk-fused gene plays a critical role in diet-induced adipose tissue expansion and is also involved in thyroid hormone action

Takeshi Yamamotoya; Yukino Ohata; Yasuyuki Akasaka; Shun Hasei; Masa-Ki Inoue; Yusuke Nakatsu; Machi Kanna; Hiroki Yamazaki; Akifumi Kushiyama; Midori Fujishiro; Hiraku Ono; Hideyuki Sakoda; Tetsuya Yamada; Hisamitsu Ishihara; Tomoichiro Asano

doi:10.1093/pnasnexus/pgae150

Trk-fused gene plays a critical role in diet-induced adipose tissue expansion and is also involved in thyroid hormone action

PNAS Nexus. 2024 Apr 9;3(4):pgae150. doi: 10.1093/pnasnexus/pgae150. eCollection 2024 Apr.

Authors

Affiliations

¹ Department of Biomedical Chemistry, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima City, Hiroshima 734-8553, Japan.
² Department of Internal Medicine, Teikyo University School of Medicine, 2-11-1 Kaga, Itabashi-ku, Tokyo 173-8606, Japan.
³ Department of Pharmacotherapy, Meiji Pharmaceutical University, 2-522-1 Noshio, Kiyose City, Tokyo 204-8588, Japan.
⁴ Division of Diabetes and Metabolic Diseases, Nihon University School of Medicine, 30-1 Oyaguchikamicho, Itabashi-ku, Tokyo 173-8610, Japan.
⁵ Department of Clinical Cell Biology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba City, Chiba 260-8670, Japan.
⁶ Department of Bioregulatory Sciences, Faculty of Medicine, University of Miyazaki, Miyazaki 889-1692, Japan.
⁷ Department of Molecular Endocrinology and Metabolism, Tokyo Medical and Dental University, Yushima 1-5-45, Bunkyo-ku, Tokyo 113-8510, Japan.

Abstract

Mutations in the Trk-fused gene (TFG) cause hereditary motor and sensory neuropathy with proximal dominant involvement, which reportedly has high co-incidences with diabetes and dyslipidemia, suggesting critical roles of the TFG in metabolism as well. We found that TFG expression levels in white adipose tissues (WATs) were elevated in both genetically and diet-induced obese mice and that TFG deletion in preadipocytes from the stromal vascular fraction (SVF) markedly inhibited adipogenesis. To investigate its role in vivo, we generated tamoxifen-inducible adipocyte-specific TFG knockout (AiTFG KO) mice. While a marked down-regulation of the peroxisome proliferator-activated receptor gamma target, de novo lipogenesis (DNL), and mitochondria-related gene expressions were observed in subcutaneous WAT (scWAT) from AiTFG KO mice, these effects were blunted in SVF-derived adipocytes when the TFG was deleted after differentiation into adipocytes, implying cell nonautonomous effects. Intriguingly, expressions of thyroid hormone receptors, as well as carbohydrate responsive element-binding protein β, which mediates the metabolic actions of thyroid hormone, were drastically down-regulated in scWAT from AiTFG KO mice. Reduced DNL and thermogenic gene expressions in AiTFG KO mice might be attributable to impaired thyroid hormone action in vivo. Finally, when adipocyte TFG was deleted in either the early or the late phase of high-fat diet feeding, the former brought about an impaired expansion of epididymal WAT, whereas the latter caused prominent adipocyte cell death. TFG deletion in adipocytes markedly exacerbated hepatic steatosis in both experimental settings. Collectively, these observations indicate that the TFG plays essential roles in maintaining normal adipocyte functions, including an enlargement of adipose tissue, thyroid hormone function, and thermogenic gene expressions, and in preserving hypertrophic adipocytes.

Keywords: Trk-fused gene (TFG); adipogenesis; adipose expansion; carbohydrate responsive element binding protein (ChREBP); thyroid hormone.