Tetraspanin7 in adipose tissue remodeling and its impact on metabolic health.

OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.