Nemoto Shino, Uchida Kazuyo, Kubota Tetsuya, Nakayama Manabu, Han Yong-Woon, Koyasu Shigeo, Ohno Hiroshi
Laboratory for Intestinal Ecosystem, RIKEN Center for Integrative Medical Sciences, Yokohama, Kanagawa, Japan.
Laboratory for Intestinal Ecosystem, RIKEN Center for Integrative Medical Sciences, Yokohama, Kanagawa, Japan.
Mol Metab. 2025 Jul;97:102168. doi: 10.1016/j.molmet.2025.102168. Epub 2025 May 12.
We previously identified tetraspanin 7 (Tspan7) as a candidate gene influencing body weight in an obesity-related gene screening study. However, the mechanisms underlying its involvement in body weight regulation remained unclear. This study aims to investigate the role of TSPAN7 from a metabolic perspective.
We utilized genetically modified mice, including adipose tissue-specific Tspan7-knockout and Tspan7-overexpressing models, as well as human adipose-derived stem cells with TSPAN7 knockdown and overexpression. Morphological, molecular, and omics analyses, including proteomics and transcriptomics, were performed to investigate TSPAN7 function. Physiological effects were assessed by measuring blood markers associated with lipid regulation under metabolic challenges, such as high-fat feeding and aging.
We show that TSPAN7 is involved in regulating lipid droplet formation and stabilization. Tspan7-knockout mice exhibited an increased proportion of small-sized adipocytes and a reduced visceral-to-subcutaneous fat ratio. This shift in fat distribution was associated with improved insulin sensitivity and altered branched-chain amino acid metabolism, as evidenced by increased expression of the branched-chain α-keto acid dehydrogenase complex subunit B in Tspan7-modified mice. Mechanistically, TSPAN7 deficiency promoted subcutaneous fat expansion, alleviating metabolic stress on visceral fat, a major contributor to insulin resistance.
TSPAN7 influences lipid metabolism by modulating adipose tissue remodeling, particularly under metabolic challenges, such as high-fat diet exposure and aging. Its modulation enhances subcutaneous fat storage capacity while mitigating visceral fat accumulation, leading to improved insulin sensitivity. These findings position TSPAN7 as a potential target for therapeutic interventions aimed at improving metabolic health and preventing obesity-related diseases.
在一项肥胖相关基因筛查研究中，我们之前将四跨膜蛋白7（Tspan7）鉴定为影响体重的候选基因。然而，其参与体重调节的潜在机制仍不清楚。本研究旨在从代谢角度探究TSPAN7的作用。
我们利用了基因改造小鼠，包括脂肪组织特异性Tspan7基因敲除和Tspan7过表达模型，以及TSPAN7基因敲低和过表达的人脂肪来源干细胞。进行了形态学、分子和组学分析，包括蛋白质组学和转录组学，以研究TSPAN7的功能。通过在高脂喂养和衰老等代谢挑战下测量与脂质调节相关的血液标志物来评估生理效应。
我们发现TSPAN7参与调节脂滴的形成和稳定。Tspan7基因敲除小鼠表现出小尺寸脂肪细胞比例增加，内脏脂肪与皮下脂肪比例降低。这种脂肪分布的变化与胰岛素敏感性改善和支链氨基酸代谢改变有关，Tspan7基因改造小鼠中支链α-酮酸脱氢酶复合体亚基B的表达增加证明了这一点。从机制上讲，TSPAN7缺乏促进皮下脂肪扩张，减轻了对内脏脂肪的代谢应激，而内脏脂肪是胰岛素抵抗的主要促成因素。
TSPAN7通过调节脂肪组织重塑影响脂质代谢，特别是在高脂饮食暴露和衰老等代谢挑战下。其调节增强了皮下脂肪储存能力，同时减轻了内脏脂肪堆积，从而改善了胰岛素敏感性。这些发现使TSPAN7成为旨在改善代谢健康和预防肥胖相关疾病的治疗干预的潜在靶点。
