Project description:Signaling pathways that promote adipose tissue thermogenesis are well characterized, but the physiologic limiters of energy expenditure are largely unknown. Here we show that ablation of the anti-inflammatory cytokine IL-10 improves insulin sensitivity, protects against diet-induced obesity, and elicits the browning of white adipose tissue. Mechanistic studies define bone marrow cells as the source of the IL-10 signal and mature adipocytes as the target cell type mediating these effects. IL-10 receptor alpha is highly enriched in mature adipocytes and is induced in response to cold, obesity and aging. ATAC-seq and RNA-seq reveal that IL-10 represses the transcription of thermogenic genes in adipocytes by altering chromatin accessibility and inhibiting ATF and PGC-1alpha recruitment to key enhancer regions. These findings identify the IL-10 axis as a critical and potentially targetable regulator of thermogenesis, and expand our understanding of the links between inflammatory signaling and adipose tissue function in the setting of obesity.
Project description:Signaling pathways that promote adipose tissue thermogenesis are well characterized, but the physiologic limiters of energy expenditure are largely unknown. Here we show that ablation of the anti-inflammatory cytokine IL-10 improves insulin sensitivity, protects against diet-induced obesity, and elicits the browning of white adipose tissue. Mechanistic studies define bone marrow cells as the source of the IL-10 signal and mature adipocytes as the target cell type mediating these effects. IL-10 receptor alpha is highly enriched in mature adipocytes and is induced in response to cold, obesity and aging. ATAC-seq and RNA-seq reveal that IL-10 represses the transcription of thermogenic genes in adipocytes by altering chromatin accessibility and inhibiting ATF and PGC-1alpha recruitment to key enhancer regions. These findings identify the IL-10 axis as a critical and potentially targetable regulator of thermogenesis, and expand our understanding of the links between inflammatory signaling and adipose tissue function in the setting of obesity.
Project description:Signaling pathways that promote adipose tissue thermogenesis are well characterized, but the physiologic limiters of energy expenditure are largely unknown. Here we show that ablation of the anti-inflammatory cytokine IL-10 improves insulin sensitivity, protects against diet-induced obesity, and elicits the browning of white adipose tissue. Mechanistic studies define bone marrow cells as the source of the IL-10 signal and mature adipocytes as the target cell type mediating these effects. IL-10 receptor alpha is highly enriched in mature adipocytes and is induced in response to cold, obesity and aging. ATAC-seq and RNA-seq reveal that IL-10 represses the transcription of thermogenic genes in adipocytes by altering chromatin accessibility and inhibiting ATF and PGC-1alpha recruitment to key enhancer regions. These findings identify the IL-10 axis as a critical and potentially targetable regulator of thermogenesis, and expand our understanding of the links between inflammatory signaling and adipose tissue function in the setting of obesity.
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.
Project description: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.
Project description:Signaling pathways that promote adipose tissue thermogenesis are well characterized, but the limiters of energy expenditure are largely unknown. Here, we show that ablation of the anti-inflammatory cytokine IL-10 improves insulin sensitivity, protects against diet-induced obesity, and elicits the browning of white adipose tissue. Mechanistic studies define bone marrow cells as the source of the IL-10 signal and adipocytes as the target cell type mediating these effects. IL-10 receptor alpha is highly enriched in mature adipocytes and is induced in response to differentiation, obesity, and aging. Assay for transposase-accessible chromatin sequencing (ATAC-seq), ChIP-seq, and RNA-seq reveal that IL-10 represses the transcription of thermogenic genes in adipocytes by altering chromatin accessibility and inhibiting ATF and C/EBPβ recruitment to key enhancer regions. These findings expand our understanding of the relationship between inflammatory signaling pathways and adipose tissue function and provide insight into the physiological control of thermogenesis that could inform future therapy.