Mitochondrial homeostasis in adipose tissue remodeling

Altshuler-Keylin, Svetlana; Kajimura, Shingo

doi:10.1126/scisignal.aai9248

Cited by 80 publications

(80 citation statements)

References 107 publications

(113 reference statements)

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“…For instance, the transforming growth factor β (TGF β) and Notch signaling pathways were shown to react as negative regulators of thermogenesis in obese mice [34]. Furthermore, autophagy was found to dysregulate beige adipogenesis, as inhibiting autophagy through deletion of Atg7 in adipocytes led to increased beige adipocyte differentiation in DIO mice [35, 36]. Our group also has observed that autophagy profoundly contributes to LPS-induced beige fat inhibition [13].…”

Section: Discussionmentioning

confidence: 99%

Inhibitory Effects of Toll-Like Receptor 4, NLRP3 Inflammasome, and Interleukin-1β on White Adipocyte Browning

et al. 2017

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Adipose tissue expansion is accompanied by infiltration and accumulation of pro-inflammatory macrophages, which links obesity to pathologic conditions such as type 2 diabetes. However, little is known regarding the role of pro-inflammatory adipose tissue remodeling in the thermogenic activation of brown/beige fat. Here, we investigated the effect of pattern recognition receptors (PRR) activation in macrophages, especially the toll-like receptor 4 (TLR4) and Nod-like receptor 3 (NLRP3), on white adipocyte browning. We report that TLR4 activation by lipopolysaccharide repressed white adipocyte browning in response to β3-adrenergic receptor activation and caused ROS production and mitochondrial dysfunction, while genetic deletion of TLR4 protected mitochondrial function and thermogenesis. In addition, activation of NLRP3 inflammasome in macrophages attenuated UCP1 induction and mitochondrial respiration in cultures of primary adipocytes, while the absence of NLRP3 protected UCP1 in adipocytes. The effect of NLRP3 inflammasome activation on browning was mediated by IL-1β signaling, as blocking IL-1 receptor in adipocytes protected thermogenesis. We also report that IL-1β interferes with thermogenesis via oxidative stress stimulation and mitochondrial dysfunction as we observed a statistically significant increase in ROS production, decrease in SOD enzyme activity, and increase in mitochondrial depolarization in adipocytes treated with IL-1β. Collectively, we demonstrated that inflammatory response to obesity, such as TLR4 and NLRP3 inflammasome activation as well as IL-1β secretion, attenuates β3-adrenoreceptor-induced beige adipocyte formation via oxidative stress and mitochondrial dysfunction. Our findings provide insights into targeting innate inflammatory system for enhancement of the adaptive thermogenesis against obesity.

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Section: Discussionmentioning

confidence: 99%

Inhibitory Effects of Toll-Like Receptor 4, NLRP3 Inflammasome, and Interleukin-1β on White Adipocyte Browning

et al. 2017

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“…The control of cellular mitochondrial content and oxidative capacity is important for cellular and organismal energy homeostasis 25 . For example, brown and beige adipocytes generate new mitochondria and increase their oxidative and thermogenic capacity in response to norepinephrine (NE), which is secreted locally when the organism senses a cold environment 26 .…”

Section: Bench Validation Use Case 3: the Murine Err Ppargc And Adipmentioning

confidence: 99%

The Signaling Pathways Project: an integrated ‘omics knowledgebase for mammalian cellular signaling pathways

Ochsner

Abraham

Martin

et al. 2018

Preprint

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Integrated mining of public transcriptomic and ChIP-Seq datasets has the potential to illuminate facets of mammalian cellular signaling pathways not yet explored in the research literature.Here, we designed a web knowledgebase, the Signaling Pathways Project (SPP), which incorporates stable community classifications of the four major categories of signaling pathway node (receptors, enzymes, transcription factors and co-nodes) and their cognate bioactive small molecules (BSMs). We then mapped over 10,000 public transcriptomic or cistromic experiments to their relevant signaling pathway node, BSM or biosample of study. To provide for prediction of pathway node-target transcriptional regulatory relationships, we generated consensus 'omics signatures, or consensomes, based on measures of significant differential expression of genomic targets across all underlying transcriptomic experiments. To expose the SPP knowledgebase to researchers, a web browser interface accommodates a variety of routine data mining strategies. Consensomes were validated using alignment with literature-based knowledge, gene target-level integration of transcriptomic and ChIP-Seq data points, and in bench experiments that confirmed previously uncharacterized node-gene target regulatory relationships. SPP is freely accessible at https://beta.signalingpathways.org.Individual dataset pages enable integration of SPP with the research literature via digital object identifier (DOI)-driven links from external sites, as well as for citation of datasets to enhance their FAIR status 3,4 .

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“…For example, obesity impairs MT biogenesis. [19][20][21] MT dysfunction has been also implicated in the development of insulin resistance. [22][23][24] Thus, our study prioritized obesity and insulin resistance pathways to CVD.…”

Section: Introductionmentioning

confidence: 99%

Associations of Mitochondrial and Nuclear Mitochondrial Variants and Genes with Seven Metabolic Traits

Kraja¹,

Liu

Fetterman

et al. 2019

The American Journal of Human Genetics

109

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Mitochondria (MT), the major site of cellular energy production, are under dual genetic control by 37 mitochondrial DNA (mtDNA) genes and numerous nuclear genes (MT-nDNA). In the CHARGEmtDNAþ Consortium, we studied genetic associations of mtDNA and MT-nDNA associations with body mass index (BMI), waist-hip-ratio (WHR), glucose, insulin, HOMA-B, HOMA-IR, and HbA1c. This 45-cohort collaboration comprised 70,775 (insulin) to 170,202 (BMI) pan-ancestry individuals. Validation and imputation of mtDNA variants was followed by single-variant and gene-based association testing. We report two significant common variants, one in MT-ATP6 associated (p % 5EÀ04) with WHR and one in the D-loop with glucose. Five rare variants in MT-ATP6, MT-ND5, and MT-ND6 associated with BMI, WHR, or insulin. Gene-based meta-analysis identified MT-ND3 associated with BMI (p % 1EÀ03). We considered 2,282 MT-nDNA candidate gene associations compiled from online summary results for our traits (20 unique studies with 31 dataset consortia's genome-wide associations [GWASs]). Of these, 109 genes associated (p % 1EÀ06) with at least 1 of our 7 traits. We assessed regulatory features of variants in the 109 genes, cis-and trans-gene expression regulation, and performed enrichment and protein-protein interactions analyses. Of the identified mtDNA and MT-nDNA genes, 79 associated with adipose measures, 49 with glucose/insulin, 13 with risk for type 2 diabetes, and 18 with cardiovascular disease, indicating for pleiotropic effects with health implications. Additionally, 21 genes related to cholesterol, suggesting additional important roles for the genes identified. Our results suggest that mtDNA and MT-nDNA genes and variants reported make important contributions to glucose and insulin metabolism, adipocyte regulation, diabetes, and cardiovascular disease.

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Mitochondrial homeostasis in adipose tissue remodeling

Cited by 80 publications

References 107 publications

Inhibitory Effects of Toll-Like Receptor 4, NLRP3 Inflammasome, and Interleukin-1β on White Adipocyte Browning

Inhibitory Effects of Toll-Like Receptor 4, NLRP3 Inflammasome, and Interleukin-1β on White Adipocyte Browning

The Signaling Pathways Project: an integrated ‘omics knowledgebase for mammalian cellular signaling pathways

Associations of Mitochondrial and Nuclear Mitochondrial Variants and Genes with Seven Metabolic Traits

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