bims-mimead 2024-12-22 papers

Issue of 2024–12–22
four papers selected by
Rachel M. Handy, University of Guelph

Cell Metab. 2024 Dec 11. pii: S1550-4131(24)00452-2. [Epub ahead of print]

Unveiling adipose populations linked to metabolic health in obesity.

Isabel Reinisch, Adhideb Ghosh, Falko Noé, Wenfei Sun, Hua Dong, Peter Leary, Arne Dietrich, Anne Hoffmann, Matthias Blüher, Christian Wolfrum.

Precision medicine is still not considered as a standard of care in obesity treatment, despite a large heterogeneity in the metabolic phenotype of individuals with obesity. One of the strongest factors influencing the variability in metabolic disease risk is adipose tissue (AT) dysfunction; however, there is little understanding of the link between distinct cell populations, cell-type-specific transcriptional programs, and disease severity. Here, we generated a comprehensive cellular map of subcutaneous and visceral AT of individuals with metabolically healthy and unhealthy obesity. By combining single-nucleus RNA-sequencing data with bulk transcriptomics and clinical parameters, we identified that mesothelial cells, adipocytes, and adipocyte-progenitor cells exhibit the strongest correlation with metabolic disease. Furthermore, we uncovered cell-specific transcriptional programs, such as the transitioning of mesothelial cells to a mesenchymal phenotype, that are involved in uncoupling obesity from metabolic disease. Together, these findings provide valuable insights by revealing biological drivers of clinical endpoints.

Keywords: adipocytes; adipose tissue; insulin resistance; insulin sensitivity; mesothelial cells; metabolically healthy obesity; obesity; precision medicine; snRNA-seq; visceral adipose tissue

DOI: https://doi.org/10.1016/j.cmet.2024.11.006

Cell Metab. 2024 Dec 11. pii: S1550-4131(24)00447-9. [Epub ahead of print]

FcRn-dependent IgG accumulation in adipose tissue unmasks obesity pathophysiology.

Immunoglobulin G (IgG) is traditionally recognized as a plasma protein that neutralizes antigens for immune defense. However, our research demonstrates that IgG predominantly accumulates in adipose tissue during obesity development, triggering insulin resistance and macrophage infiltration. This accumulation is governed by neonatal Fc receptor (FcRn)-dependent recycling, orchestrated in adipose progenitor cells and macrophages during the early and late stages of diet-induced obesity (DIO), respectively. Targeting FcRn abolished IgG accumulation and rectified insulin resistance and metabolic degeneration in DIO. By integrating artificial intelligence (AI) modeling with in vivo and in vitro experimental models, we unexpectedly uncovered an interaction between IgG's Fc-CH3 domain and the insulin receptor's ectodomain. This interaction hinders insulin binding, consequently obstructing insulin signaling and adipocyte functions. These findings unveil adipose IgG accumulation as a driving force in obesity pathophysiology, providing a novel therapeutic strategy to tackle metabolic dysfunctions.

Keywords: FcRn; IgG; adipose tissue remodeling; insulin receptor; insulin resistance; obesity

DOI: https://doi.org/10.1016/j.cmet.2024.11.001

Elife. 2024 Dec 20. pii: e105191. [Epub ahead of print]13

Mapping mitochondrial aging.

Alessandro Bitto.

Measuring mitochondrial respiration in frozen tissue samples provides the first comprehensive atlas of how aging affects mitochondrial function in mice.

Keywords: aging; cellular respiration; computational biology; mitochondria; mouse; respiration atlas; sex; systems biology

DOI: https://doi.org/10.7554/eLife.105191

Extracell Vesicles Circ Nucl Acids. 2024 ;5(3): 371-396

Extracellular vesicles in tumor-adipose tissue crosstalk: key drivers and therapeutic targets in cancer cachexia.

Cátia C Ramos, José Pires, Esperanza Gonzalez, Clara Garcia-Vallicrosa, Celso A Reis, Juan M Falcon-Perez, Daniela Freitas.

Cancer cachexia is a complex metabolic syndrome characterized by unintentional loss of skeletal muscle and body fat. This syndrome is frequently associated with different types of cancer and negatively affects the prognosis and outcome of these patients. It involves a dynamic interplay between tumor cells and adipose tissue, where tumor-derived extracellular vesicles (EVs) play a crucial role in mediating intercellular communication. Tumor cells release EVs containing bioactive molecules such as hormones (adrenomedullin, PTHrP), pro-inflammatory cytokines (IL-6), and miRNAs (miR-1304-3p, miR-204-5p, miR-155, miR-425-3p, miR-146b-5p, miR-92a-3p), which can trigger lipolysis and induce the browning of white adipocytes contributing to a cancer cachexia phenotype. On the other hand, adipocyte-derived EVs can reprogram the metabolism of tumor cells by transporting fatty acids and enzymes involved in fatty acid oxidation, resulting in tumor growth and progression. These vesicles also carry leptin and key miRNAs (miR-155-5p, miR-10a-3p, miR-30a-3p, miR-32a/b, miR-21), thereby supporting tumor cell proliferation, metastasis formation, and therapy resistance. Understanding the intricate network underlying EV-mediated communication between tumor cells and adipocytes can provide critical insights into the mechanisms driving cancer cachexia. This review consolidates current knowledge on the crosstalk between tumor cells and adipose tissue mediated by EVs and offers valuable insights for future research. It also addresses controversial topics in the field and possible therapeutic approaches to manage cancer cachexia and ultimately improve patient outcomes and quality of life.

Keywords: Cancer cachexia; adipose tissue transdifferentiation; cancer; exosome; extracellular vesicles; metabolism

DOI: https://doi.org/10.20517/evcna.2024.36