Adipocyte-specific Steap4 deficiency reduced thermogenesis and energy expenditure in mice

Summary: Six-transmembrane protein of prostate 4 (Steap4), highly expressed in adipose tissue, is associated with metabolic homeostasis. Dysregulated adipose and mitochondrial metabolism contributes to obesity, highlighting the need to understand their interplay. Whether and how Steap4 influences mi...

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Main Authors: Han Wang, Lizi Zhang, Xing Chen, Lingzi Hong, Junjie Zhao, Wen Qian, Lam Khue Pham, Belinda Willard, Xiaoxia Li, Katarzyna Bulek, Xiao Li
Format: Article
Language:English
Published: Elsevier 2025-02-01
Series:iScience
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Online Access:http://www.sciencedirect.com/science/article/pii/S2589004225001634
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author Han Wang
Lizi Zhang
Xing Chen
Lingzi Hong
Junjie Zhao
Wen Qian
Lam Khue Pham
Belinda Willard
Xiaoxia Li
Katarzyna Bulek
Xiao Li
author_facet Han Wang
Lizi Zhang
Xing Chen
Lingzi Hong
Junjie Zhao
Wen Qian
Lam Khue Pham
Belinda Willard
Xiaoxia Li
Katarzyna Bulek
Xiao Li
author_sort Han Wang
collection DOAJ
description Summary: Six-transmembrane protein of prostate 4 (Steap4), highly expressed in adipose tissue, is associated with metabolic homeostasis. Dysregulated adipose and mitochondrial metabolism contributes to obesity, highlighting the need to understand their interplay. Whether and how Steap4 influences mitochondrial function, adipocytes, and energy expenditure remain unclear. Adipocyte-specific Steap4-deficient mice exhibited increased fat mass and severe insulin resistance in our high-fat diet model. Mass spectrometry identified two classes of Steap4 interactomes: mitochondrial proteins and proteins involved in splicing. RNA sequencing (RNA-seq) analysis of white adipose tissue demonstrated that Steap4 deficiency altered RNA splicing patterns with enriched mitochondrial functions. Indeed, Steap4 deficiency impaired respiratory chain complex activity, causing mitochondrial dysfunction in white adipose tissue. Consistently, brown adipocyte-specific Steap4 deficiency impaired mitochondrial function, increased brown fat whitening, reduced energy expenditure, and exacerbated insulin resistance in a high-fat model. Overall, our study highlights Steap4’s critical role in modulating adipocyte mitochondrial function, thereby controlling thermogenesis, energy expenditure, and adiposity.
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institution Kabale University
issn 2589-0042
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publisher Elsevier
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series iScience
spelling doaj-art-c001d19f9e174e1198a4ea98643608872025-02-08T05:00:53ZengElsevieriScience2589-00422025-02-01282111903Adipocyte-specific Steap4 deficiency reduced thermogenesis and energy expenditure in miceHan Wang0Lizi Zhang1Xing Chen2Lingzi Hong3Junjie Zhao4Wen Qian5Lam Khue Pham6Belinda Willard7Xiaoxia Li8Katarzyna Bulek9Xiao Li10Department of Biochemistry, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA; Center for RNA Science and Therapeutics, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA; Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44106, USADepartment of Biochemistry, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA; Center for RNA Science and Therapeutics, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USADepartment of Biochemistry, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA; Center for RNA Science and Therapeutics, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USADepartment of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44106, USADepartment of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44106, USADepartment of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44106, USADepartment of Biochemistry, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA; Center for RNA Science and Therapeutics, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USAProteomics and Metabolomics Core, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44106, USADepartment of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44106, USADepartment of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44106, USADepartment of Biochemistry, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA; Center for RNA Science and Therapeutics, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA; Department of Computer and Data Sciences, School of Engineering, Case Western Reserve University, Cleveland,OH 44106, USA; Corresponding authorSummary: Six-transmembrane protein of prostate 4 (Steap4), highly expressed in adipose tissue, is associated with metabolic homeostasis. Dysregulated adipose and mitochondrial metabolism contributes to obesity, highlighting the need to understand their interplay. Whether and how Steap4 influences mitochondrial function, adipocytes, and energy expenditure remain unclear. Adipocyte-specific Steap4-deficient mice exhibited increased fat mass and severe insulin resistance in our high-fat diet model. Mass spectrometry identified two classes of Steap4 interactomes: mitochondrial proteins and proteins involved in splicing. RNA sequencing (RNA-seq) analysis of white adipose tissue demonstrated that Steap4 deficiency altered RNA splicing patterns with enriched mitochondrial functions. Indeed, Steap4 deficiency impaired respiratory chain complex activity, causing mitochondrial dysfunction in white adipose tissue. Consistently, brown adipocyte-specific Steap4 deficiency impaired mitochondrial function, increased brown fat whitening, reduced energy expenditure, and exacerbated insulin resistance in a high-fat model. Overall, our study highlights Steap4’s critical role in modulating adipocyte mitochondrial function, thereby controlling thermogenesis, energy expenditure, and adiposity.http://www.sciencedirect.com/science/article/pii/S2589004225001634Biological sciencesEndocrinologyNatural sciencesPhysiology
spellingShingle Han Wang
Lizi Zhang
Xing Chen
Lingzi Hong
Junjie Zhao
Wen Qian
Lam Khue Pham
Belinda Willard
Xiaoxia Li
Katarzyna Bulek
Xiao Li
Adipocyte-specific Steap4 deficiency reduced thermogenesis and energy expenditure in mice
iScience
Biological sciences
Endocrinology
Natural sciences
Physiology
title Adipocyte-specific Steap4 deficiency reduced thermogenesis and energy expenditure in mice
title_full Adipocyte-specific Steap4 deficiency reduced thermogenesis and energy expenditure in mice
title_fullStr Adipocyte-specific Steap4 deficiency reduced thermogenesis and energy expenditure in mice
title_full_unstemmed Adipocyte-specific Steap4 deficiency reduced thermogenesis and energy expenditure in mice
title_short Adipocyte-specific Steap4 deficiency reduced thermogenesis and energy expenditure in mice
title_sort adipocyte specific steap4 deficiency reduced thermogenesis and energy expenditure in mice
topic Biological sciences
Endocrinology
Natural sciences
Physiology
url http://www.sciencedirect.com/science/article/pii/S2589004225001634
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