bims-mimead 2025-03-02 papers

Issue of 2025–03–02
four papers selected by
Rachel M. Handy, University of Guelph

Res Sq. 2025 Feb 14. pii: rs.3.rs-5961609. [Epub ahead of print]

A Quantitative Approach to Mapping Mitochondrial Specialization and Plasticity.

Martin Picard, Anna Monzel, Jack Devine, Darshana Kapri, Jose Enriquez, Caroline Trumpff.

Mitochondria are a diverse family of organelles that specialize to accomplish complimentary functions 1-3. All mitochondria share general features, but not all mitochondria are created equal 4.Here we develop a quantitative pipeline to define the degree of molecular specialization among different mitochondrial phenotypes - or mitotypes. By distilling hundreds of validated mitochondrial genes/proteins into 149 biologically interpretable MitoPathway scores (MitoCarta 3.0 5) the simple mitotyping pipeline allows investigators to quantify and interpret mitochondrial diversity and plasticity from transcriptomics or proteomics data across a variety of natural and experimental contexts. We show that mouse and human multi-organ mitotypes segregate along two main axes of mitochondrial specialization, contrasting anabolic (liver) and catabolic (brain) tissues. In cultured primary human fibroblasts exhibiting robust time-dependent and treatment-induced metabolic plasticity 6-8, we demonstrate how the mitotype of a given cell type recalibrates i) over time in parallel with hallmarks of aging, and ii) in response to genetic, pharmacological, and metabolic perturbations. Investigators can now use MitotypeExplorer.org and the associated code to visualize, quantify and interpret the multivariate space of mitochondrial biology.

DOI: https://doi.org/10.21203/rs.3.rs-5961609/v1

medRxiv. 2025 Feb 12. pii: 2025.02.11.25322053. [Epub ahead of print]

Deep Learning Derived Adipocyte Size Reveals Adipocyte Hypertrophy is under Genetic Control.

Emil Jørsboe, Phil Kubitz, Julius Honecker, Andrea Flaccus, Dagmar Mvondo, Matthias Raggi, Torben Hansen, Hans Hauner, Matthias Blüher, Philip D Charles, Cecilia M Lindgren, Christoffer Nellåker, Melina Claussnitzer.

Fat distribution and macro structure of white adipose tissue are important factors in predicting obesity-associated diseases, but cellular microstructure of white adipose tissue has been less explored. To investigate the relationship between adipocyte size and obesity-related traits, and their underlying disease-driving genetic associations, we performed the largest study of automatic adipocyte phenotyping linking histological measurements and genetics to date. We introduce deep learning based methods for scalable and accurate semantic segmentation of subcutaneous and visceral adipose tissue histology samples (N=2,667) across 5 independent cohorts, including data from 9,000 whole slide images, with over 27 million adipocytes. Estimates of mean size of adipocytes were validated against Glastonbury et al. 2020. We show that adipocyte hypertrophy correlates with an adverse metabolic profile with increased levels of leptin, fasting plasma glucose, glycated hemoglobin and triglycerides, and decreased levels of adiponectin and HDL cholesterol. We performed the largest GWAS (N Subcutaneous = 2066, N Visceral = 1878) and subsequent meta-analysis of mean adipocyte area, and find two genome-wide significant loci (rs73184721, rs200047724) associated with increased 95%-quantile adipocyte size in respectively visceral and subcutaneous adipose tissue. Stratifying by sex, in females we find two genome-wide significant loci, with one variant (rs140503338) associated with increased mean adipocyte size in subcutaneous adipose tissue, and the other (rs11656704) is associated with decreased 95%-quantile adipocyte size in visceral adipose tissue.

DOI: https://doi.org/10.1101/2025.02.11.25322053

J Biomed Sci. 2025 Feb 28. 32(1): 31

Blocking the SIRPα-CD47 axis promotes macrophage phagocytosis of exosomes derived from visceral adipose tissue and improves inflammation and metabolism in mice.

Yun-Kai Lin, Yu-Fei Pan, Tian-Yi Jiang, Yi-Bin Chen, Tai-Yu Shang, Meng-You Xu, Hui-Bo Feng, Yun-Han Ma, Ye-Xiong Tan, Hong-Yang Wang, Li-Wei Dong.

BACKGROUND: Adipose tissue plays a pivotal role in systemic metabolism and maintaining bodily homeostasis. Exosomes from adipose tissues, known as AT-Exos, are recognized as important messengers in the communication between adipose tissue and other organs. Despite this, the alterations in exosome composition and the functional disparities among depot-specific AT-Exos in obesity remain elusive.
METHODS: In this work, we utilized lipidomics and microRNA (miRNA) sequencing to elucidate the lipid and miRNA profiles of AT-Exos in a diet-induced obesity model. We identified obesity-related miRNAs in AT-Exos and further explored their mechanisms using gain- and loss-of-function experiments. To evaluate the metabolic effects of AT-Exos on adipocytes, we conducted RNA-sequencing (RNA-seq) and confirmed our findings through Quantitative Real-time PCR (qPCR) and Western bolt analyses. Meanwhile, a mouse model with intraperitoneal injections was utilized to validate the role of exosomes derived from visceral white adipose tissue (vWAT-Exos) in obesity progression in vivo. Finally, we explored potential therapeutic intervention strategies targeting AT-Exos, particularly focusing on modulating the SIRPα-CD47 axis to enhance macrophage phagocytosis using Leptin-deficient (ob/ob) mice and SIRPα knock-out mice.
RESULTS: Our study revealed that obesity-related metabolism affects the biological processes of AT-Exos, with depot-specific secretion patterns. In obesity, the lipidome profile of AT-Exos was significantly altered, and diet can modify the miRNA content and function within these exosomes, influencing lipid metabolism and inflammatory pathways that contribute to metabolic dysregulation. Specifically, we identified that miR-200a-3p and miR-200b-3p promoted lipid accumulation in 3T3L1 cells partly through the PI3K/AKT/mTOR pathway. RNA-Seq analysis revealed that AT-Exos from different fat depots exerted distinct effects on adipocyte metabolism, with obese vWAT-Exos being notably potent in triggering inflammation and lipid accumulation in diet-induced obesity. Additionally, we found that inhibiting the SIRPα-CD47 axis can mitigate metabolic disorders induced by obese vWAT-Exos or ob/ob mice, partly due to the enhanced clearance of vWAT-Exos. Consistent with this, SIRPα-deficient mice exhibited a reduction in vWAT-Exos and displayed greater resistance to obesity.
CONCLUSIONS: This study elucidates that diet-induced obesity altered the lipid and miRNA profiles of AT-Exos, which involved in modulating adipocyte inflammation and metabolic balance. The SIRPα-CD47 axis emerges as a potential therapeutic target for obesity and its associated complications.

Keywords: Adipose tissue; Exosomes; Macrophages; Obesity; SIRPα-CD47; miRNAs

DOI: https://doi.org/10.1186/s12929-025-01124-y

Mol Metab. 2025 Feb 25. pii: S2212-8778(25)00021-3. [Epub ahead of print] 102114

Adipocyte Septin-7 attenuates obesogenic adipogenesis and promotes lipolysis to prevent obesity.

OBJECTIVE: The white adipose tissue (WAT) expansion plays a significant role in the development of obesity. Cytoskeletal remodeling directly impacts adipogenic program, however, the precise mechanism remains poorly understood. Here, we identified a crucial role of Septin-7 (SEPT7), a cytoskeleton component, in the regulation of diet-induced processes of adipogenesis, lipogenesis, and lipolysis in WAT.
METHODS: A high-fat diet (HFD)-induced obesity model was constructed using mice with inducible adipocyte-specific SEPT7 deficiency. The impact of SEPT7 on adipocyte morphology, cell number and metabolism capacity were evaluated with immunofluorescence, isoproterenol induced lipolysis assay, glucose tolerance test and insulin tolerance test. Adipocyte mTmG reporter line was established to trace in vivo adipogenesis. The preadipocyte 3T3-L1 cell was induced for exploring role of SEPT7 in adipocyte differentiation. qRT-PCR and Western-blot were used to investigate the expression of PPARγ, C/EBPα, and HSL in 3T3-L1 cell with siRNA-mediated SEPT7 knockdown.
RESULTS: SEPT7 expression was greatly induced in obesogenic human and murine adipocytes. Mice lacking SEPT7 in mature white adipocytes demonstrated defective differentiation of preadipocyte into mature adipocytes when fed HFD resulting in larger adipocytes, increased WAT inflammation and reduced lipolysis, which leading to increased WAT mass, liver fat accumulation and impaired glucose tolerance. Mechanistically, we identified SEPT7 restrains store-operated Ca2+ entry (SOCE) and regulates adipocyte adipogenesis and lipolysis by targeting PPARγ, C/EBPα and HSL.
CONCLUSION: We demonstrated that SEPT7 negatively regulates adipogenesis while promotes lipolysis and its repression drives WAT expansion and impaired metabolic health.

Keywords: Septin-7; adipocyte; adipogenensis; obesity

DOI: https://doi.org/10.1016/j.molmet.2025.102114