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Steap4 controls adipocyte thermogenesis and energy expenditure by modulating mitochondrial function

ABSTRACT: Steap4, a highly expressed protein in adipose tissue, has been implicated in metabolic homeostasis. In this study, we generated adipocyte-specific Steap4-deficient mice and observed that Steap4 deficiency led to increased fat mass and severe insulin resistance in a high-fat diet model. Mass spectrometry analysis revealed two classes of Steap4 interactomes: mitochondrial proteins and proteins involved in spliceosome. RNA-seq analysis of white adipose tissue demonstrated that Steap4 deficiency altered RNA splicing patterns with enriched functions in mitochondria. While interactome and transcriptome data implicate a role of Steap4 in mitochondria, Steap4 deficiency indeed impaired mitochondrial respiratory chain complex activity resulting in mitochondrial dysfunction in white adipose tissue. Consistently, brown adipocyte-specific Steap4-deficient mice also showed impaired mitochondrial function, increased whitening of brown adipose tissue, reduced energy expenditure, and exacerbated insulin resistance under HFD conditions. Overall, our findings elucidate the critical role of Steap4 in regulating adipocyte thermogenesis and energy expenditure by modulating mitochondrial function.

INSTRUMENT(S): timsTOF Pro 2

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): White Adipose Tissue, Cell Culture

SUBMITTER: Belinda Willard

LAB HEAD: Xiao Li, Ph.D

PROVIDER: PXD046997 | Pride | 2025-02-03

REPOSITORIES: pride

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			Action	DRS
	Lane2_WT0_Area1.d.zip	Other
	Lane2_WT0_Area1.mzML	Mzml
	Lane2_WT0_Area1.pepXML	Pepxml
	Lane2_WT0_Area2.d.zip	Other
	Lane2_WT0_Area2.mzML	Mzml

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

Project description:Steap4, highly expressed in adipose tissue, is associated with metabolic homeostasis. Dysregulated adipose and mitochondrial metabolism contribute to obesity, highlighting the need to understand their interplay. Whether and how Steap4 influences mitochondrial function, adipocytes, and energy expenditure remains 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-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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