Abstract Mutations in the Trk-fused gene (TFG) cause hereditary motor and sensory neuropathy with proximal dominant involvement (HMSN-P), which reportedly has high co-incidences with diabetes and dyslipidemia, suggesting critical roles of 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 mice (AiTFG KO). While marked downregulation of the PPARγ target, de novo lipogenesis (DNL) and mitochondria-related gene expressions were observed in subcutaneous WAT (scWAT) from AiTFG KO, these effects were blunted in SVF-derived adipocytes when TFG was deleted after differentiation into adipocytes, implying cell-nonautonomous effects. Intriguingly, expressions of thyroid hormone receptors as well as ChREBPβ, which mediates the metabolic actions of thyroid hormone, were drastically downregulated in scWAT from AiTFG KO. Reduced DNL and thermogenic gene expressions in AiTFG KO 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 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 TFG plays essential roles in maintaining normal adipocyte functions, including enlargement of adipose tissue, thyroid hormone function and thermogenic gene expressions, and in preserving hypertrophic adipocytes.