TEAD1, MYO7A and NDUFC2 are novel functional genes associated with glucose metabolism in BXD recombinant inbred population DOI
Yingying Wu, Chao Zhang,

Shaofei Duan

et al.

Diabetes Obesity and Metabolism, Journal Year: 2024, Volume and Issue: 26(5), P. 1775 - 1788

Published: Feb. 22, 2024

Abstract Aim The liver is an important metabolic organ that governs glucolipid metabolism, and its dysfunction may cause non‐alcoholic fatty disease, type 2 diabetes mellitus, dyslipidaemia, etc. We aimed to systematic investigate the key factors related hepatic glucose which be beneficial for understanding underlying pathogenic mechanisms obesity mellitus. Materials methods Oral tolerance test (OGTT) phenotypes transcriptomes of BXD mice under chow high‐fat diet conditions were collected from GeneNetwork. QTL mapping was conducted pinpoint genomic regions associated with homeostasis. Candidate genes further nominated using a multi‐criteria approach validated confirm their functional relevance in vitro. Results Our results demonstrated plasma levels OGTT significantly affected by both genetic background, six regulating loci mapped on chromosomes 1, 4, 7. Moreover, TEAD1, MYO7A NDUFC2 identified as candidate genes. Functionally, siRNA‐mediated knockdown decreased uptake inhibited transcription insulin metabolism pathways. Conclusions study contributes novel insights demonstrating impact mitochondrial function regulatory role maintaining

Language: Английский

Sex differences in energy metabolism: natural selection, mechanisms and consequences DOI
Franck Mauvais‐Jarvis

Nature Reviews Nephrology, Journal Year: 2023, Volume and Issue: 20(1), P. 56 - 69

Published: Nov. 3, 2023

Language: Английский

Citations

51
Adipose Tissue and Metabolic Health DOI Creative Commons
Sung‐Min An, Seung‐Hee Cho, John C. Yoon

et al.

Diabetes & Metabolism Journal, Journal Year: 2023, Volume and Issue: 47(5), P. 595 - 611

Published: Sept. 26, 2023

In this review, we provide a brief synopsis of the connections between adipose tissue and metabolic health highlight some recent developments in understanding exploiting adipocyte biology. Adipose plays critical roles regulation systemic glucose lipid metabolism secretes bioactive molecules possessing endocrine, paracrine, autocrine functions. Dysfunctional has detrimental impact on is intimately involved key aspects diseases such as insulin resistance, overload, inflammation, organelle stress. Differences distribution fat depots characteristics relate to divergent degrees dysfunction found metabolically healthy unhealthy obese individuals. Thermogenic adipocytes increase energy expenditure via mitochondrial uncoupling or adenosine triphosphate-consuming futile substrate cycles, while functioning sink participating crosstalk with other organs. Manipulation provides wealth opportunities intervene combat progression associated diseases. We discuss current treatment modalities for obesity including incretin hormone analogs touch upon emerging strategies therapeutic potential exosome-based therapy, pharmacological activation brown beige thermogenesis, administration inhibition adipocyte-derived factors.

Language: Английский

Citations

47
Sex differences in the intergenerational inheritance of metabolic traits DOI
Ionel Sandovici, Denise S. Fernandez‐Twinn, Antonia Hufnagel

et al.

Nature Metabolism, Journal Year: 2022, Volume and Issue: 4(5), P. 507 - 523

Published: May 30, 2022

Language: Английский

Citations

52
Transferrin receptor 1-mediated iron uptake regulates bone mass in mice via osteoclast mitochondria and cytoskeleton DOI Creative Commons
Bhaba Krishna Das, Lei Wang, Toshifumi Fujiwara

et al.

eLife, Journal Year: 2022, Volume and Issue: 11

Published: June 27, 2022

Increased intracellular iron spurs mitochondrial biogenesis and respiration to satisfy high-energy demand during osteoclast differentiation bone-resorbing activities. Transferrin receptor 1 (Tfr1) mediates cellular uptake through endocytosis of iron-loaded transferrin, its expression increases differentiation. Nonetheless, the precise functions Tfr1 Tfr1-mediated in biology skeletal homeostasis remain incompletely understood. To investigate role lineage cells vivo vitro, we crossed Tfrc (encoding Tfr1)-floxed mice with Lyz2 (LysM)- Cre Cathepsin K ( Ctsk )-Cre generate conditional knockout myeloid precursors (Tfr1 ΔLysM ) or differentiated osteoclasts ΔCtsk ), respectively. Skeletal phenotyping by µCT histology unveiled a significant increase trabecular bone mass normal number long bones 10-week-old young 6-month-old adult female but not male mice. Although high volume was observed both mice, this phenotype more pronounced Consistent gender-dependent phenomena, estrogen deficiency induced ovariectomy decreased Mechanistically, disruption attenuated metabolism cytoskeletal organization mature vitro attenuating activation Src-Rac1-WAVE regulatory complex axis, respectively, leading resorption little impact on These results indicate that is specifically required for function indispensable remodeling manner.

Language: Английский

Citations

45
Mitochondrial heterogeneity in diseases DOI Creative Commons
Long Chen,

Mengnan Zhou,

Hao Li

et al.

Signal Transduction and Targeted Therapy, Journal Year: 2023, Volume and Issue: 8(1)

Published: Aug. 23, 2023

Abstract As key organelles involved in cellular metabolism, mitochondria frequently undergo adaptive changes morphology, components and functions response to various environmental stresses demands. Previous studies of research have gradually evolved, from focusing on morphological change analysis systematic multiomics, thereby revealing the mitochondrial variation between cells or within population a single cell. The phenomenon features is defined as heterogeneity. Moreover, heterogeneity has been reported influence variety physiological processes, including tissue homeostasis, repair, immunoregulation, tumor progression. Here, we comprehensively review different tissues under pathological states, involving variant DNA, RNA, protein lipid components. Then, mechanisms that contribute are also summarized, such mutation genome import proteins result DNA Additionally, multiple perspectives investigated better comprehend mysteries cells. Finally, summarize prospective heterogeneity-targeting therapies terms alleviating oxidative damage, reducing carbon stress enhancing biogenesis relieve conditions. possibility recent technological advances targeted gene editing discussed.

Language: Английский

Citations

37
PHB2 ameliorates Doxorubicin-induced cardiomyopathy through interaction with NDUFV2 and restoration of mitochondrial complex I function DOI Creative Commons

Mingjie Yang,

Miyesaier Abudureyimu, Xiang Wang

et al.

Redox Biology, Journal Year: 2023, Volume and Issue: 65, P. 102812 - 102812

Published: July 12, 2023

Doxorubicin (DOX) is among the most widely employed antitumor agents, although its clinical applications have been largely hindered by severe cardiotoxicity. Earlier studies described an essential role of mitochondrial injury in pathogenesis DOX cardiomyopathy. PHB2 (Prohibitin 2) perceived as regulator for dynamics and oxidative phosphorylation (OXPHOS) involvement cardiomyopathy remains elusive.To decipher possible cardiomyopathy, tamoxifen-induced cardiac-specific conditional knockout mice were generated subjected to challenge. Cardiac function profiles examined. Screening downstream mediators was performed using proteomic profiling bioinformatic analysis, further verified co-immunoprecipitation pulldown assays.Our data revealed significantly downregulated expression DOX-challenged mouse hearts. PHB2CKO more susceptible cardiotoxicity compared with PHB2flox/flox mice, evidenced pronounced cardiac atrophy, interstitial fibrosis decrease left ventricular ejection fraction fractional shortening. Mechanistically, deficiency resulted impairment bioenergetics Proteomic interactome analyses that interacted NDUFV2 (NADH-ubiquinone oxidoreductase core subunit V2), a key respiratory Complex I mediate regulatory property on metabolism. governed promoting stabilization, while overexpression alleviated defects both vivo vitro.Our study defined novel energetic metabolism through interacting Forced may be considered promising therapeutic approach patients

Language: Английский

Citations

27
Hepatotoxic effects of chronic exposure to environmentally relevant concentrations of Di-(2-ethylhexyl) phthalate (DEHP) on crucian carp: Insights from multi-omics analyses DOI
Yingjie Liu, Shijie You, Lu Ding

et al.

The Science of The Total Environment, Journal Year: 2024, Volume and Issue: 923, P. 171447 - 171447

Published: March 4, 2024

Language: Английский

Citations

12
Aberrant mitochondrial DNA synthesis in macrophages exacerbates inflammation and atherosclerosis DOI Creative Commons
Niranjana Natarajan, Jonathan Florentin, Ebin Johny

et al.

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: Aug. 26, 2024

There is a large body of evidence that cellular metabolism governs inflammation, and inflammation contributes to the progression atherosclerosis. However, whether mitochondrial DNA synthesis affects macrophage function atherosclerosis pathology not fully understood. Here we show, by transcriptomic analyzes plaque macrophages, spatial single cell transcriptomics atherosclerotic plaques, functional experiments, (mtDNA) in macrophages are triggered vascular adhesion molecule 1 (VCAM-1) under inflammatory conditions both humans mice. Mechanistically, VCAM-1 activates C/EBPα, which binds promoters key biogenesis genes - Cmpk2 Pgc1a. Increased CMPK2 PGC-1α expression triggers mtDNA synthesis, STING-mediated inflammation. Consistently, less severe Apoe

Language: Английский

Citations

12
Sarcopenic obesity is part of obesity paradox in dementia development: evidence from a population-based cohort study DOI Creative Commons
Junhan Zhang, Xiaona Na, Zhihui Li

et al.

BMC Medicine, Journal Year: 2024, Volume and Issue: 22(1)

Published: March 22, 2024

Abstract Background Sarcopenic obesity, a clinical and functional condition characterized by the coexistence of obesity sarcopenia, has not been investigated in relation to dementia risk its onset. Methods We included 208,867 participants from UK biobank, who aged 60 69 years at baseline. Dementia diagnoses were identified using hospital records death register data. Hazard ratios (HRs) 95% confidence intervals (CIs) estimated Cox proportional hazards models evaluate associations sarcopenic with risk, stratified sex. Stratified analyses performed across dementia-related polygenic score (PRS). Restricted mean survival time established estimate difference 95%CIs onset different status. Additionally, linear regression employed status brain imaging parameters. The mediation effects chronic diseases also examined. Results Obese women high PRS had decreased (HR = 0.855 [0.761–0.961]), but obese men low an increased 1.223 [1.045–1.431]). sarcopenia was associated elevated 1.323 [1.064–1.644]; HR 2.144 [1.753–2.621]) those PRS. Among PRS, however, association only significant early-life 1.679 [1.355–2.081]; 2.069 [1.656–2.585]). Of note, higher 1.424 [1.227–1.653]; 1.989 [1.702–2.323]), results remained similar Considering onset, 1.114 delayed women, 0.170 advanced men. Sarcopenia (women: 0.080 years; men: 0.192 years) 0.109 0.511 respectively Obesity, related alterations regions. Association between mediated diseases. Conclusions vary degree. role may differ sex genetic background.

Language: Английский

Citations

9
Genetic variation of putative myokine signaling is dominated by biological sex and sex hormones DOI Creative Commons
Leandro M Velez, Cassandra Van, Timothy M. Moore

et al.

eLife, Journal Year: 2022, Volume and Issue: 11

Published: April 13, 2022

Skeletal muscle plays an integral role in coordinating physiological homeostasis, where signaling to other tissues via myokines allows for coordination of complex processes. Here, we aimed leverage natural genetic correlation structure gene expression both within and across understand how interacts with metabolic tissues. Specifically, performed a survey correlations focused on myokine regulation, cell composition, cross-tissue signaling, interactions sex humans. While levels majority proportions skeletal showed little relative differences between males females, nearly all significant enrichments operated sex-specific or hormone-dependent fashion; particular, estradiol. These sex- hormone-specific effects were consistent key tissues: liver, pancreas, hypothalamus, intestine, heart, visceral, subcutaneous adipose tissue. To characterize the estradiol receptor expression, generated male female mice which lack estrogen α specifically (MERKO) integrated human data. analyses highlighted potential mechanisms sex-dependent conserved species, such as myostatin enriched divergent substrate utilization pathways sexes. Several putative uncovered, muscle-derived tumor necrosis factor alpha ( TNFA ) stronger inflammatory females compared GPX3 male-specific link glycolytic fiber abundance hepatic inflammation. Collectively, provide population genetics framework inferring We further highlight critical variables when assaying functions changes composition are predicted impact organs.

Language: Английский

Citations

28