Prometheus’s Fire, Part I: The Flight of Icarus—Molecular Mechanisms Underlying Adipose Tissue Dysfunction in Obesity: From Adaptive Hyperplasia to Pathological Hypertrophy
5 affiliations
- 1Lux Med Medical Centre in Warsaw, 49 Komitetu Obrony Robotników Street, 02-146 Warsaw, Poland
- 2Department of Endocrinology, Centre of Postgraduate Medical Education, Marymoncka St. 99/103, 01-813 Warsaw, Poland
- 3Department of Neuroendocrinology, Centre of Postgraduate Medical Education, Marymoncka St. 99/103, 01-813 Warsaw, Poland
- 4Laboratory for Cell Research and Application, Medical University of Warsaw, 02-106 Warsaw, Poland
- 5Department of General Medicine and Geriatric Cardiology, Medical Centre of Postgraduate Education, 00-401 Warsaw, Poland
Abstract
Obesity is a heterogeneous disease in which cardiometabolic risk is shaped not only by adipose tissue mass but also by the capacity of adipose tissue to expand and remain metabolically functional. This narrative review provides an integrated, evidence-weighted molecular framework, the central original contribution of this work, for understanding how initially adaptive adipose tissue expansion transitions into pathological hypertrophy and self-sustaining immunometabolic dysfunction. We examine how impaired adipogenesis, angiogenesis and extracellular-matrix remodelling converge with mitochondrial and endoplasmic reticulum stress, oxidative stress, hypoxia and lipotoxicity to destabilise adipocyte homeostasis. Particular attention is given to the NLRP3 inflammasome, positioned within a broader network including JNK, IKKβ/NF-κB, TLR4 and cGAS–STING signalling, as a molecular integrator of metabolic danger signals. We further explore how adipokine remodelling, loss of adiponectin-mediated protection and enhanced leptin signalling interact with immune-cell recruitment to establish self-amplifying inflammatory circuits. Evidence is stratified across experimental, translational and human levels; a summary table maps each mechanism to its strength of evidence and current clinical relevance. This framework explains metabolic phenotype heterogeneity among individuals with comparable adiposity and establishes the molecular foundation for Parts II and III of the Prometheus’s Fire series.
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BibTeX
@article{grudniewska2026prometheuss,
title = {{Prometheus’s Fire, Part I: The Flight of Icarus—Molecular Mechanisms Underlying Adipose Tissue Dysfunction in Obesity: From Adaptive Hyperplasia to Pathological Hypertrophy}},
author = {Anna Grudniewska and Beata Mrozikiewicz-Rakowska and Kacper Wiszniewski and Wojciech Bik and Ilona Szabłowska-Gadomska and Alina Kuryłowicz},
journal = {International Journal of Molecular Sciences},
year = {2026},
month = oct,
doi = {10.3390/ijms27209055},
url = {https://www.mdpi.com/1422-0067/27/20/9055},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Prometheus’s Fire, Part I: The Flight of Icarus—Molecular Mechanisms Underlying Adipose Tissue Dysfunction in Obesity: From Adaptive Hyperplasia to Pathological Hypertrophy
AU - Anna Grudniewska
AU - Beata Mrozikiewicz-Rakowska
AU - Kacper Wiszniewski
AU - Wojciech Bik
AU - Ilona Szabłowska-Gadomska
AU - Alina Kuryłowicz
PY - 2026
DA - 2026/10/13
JO - International Journal of Molecular Sciences
DO - 10.3390/ijms27209055
UR - https://www.mdpi.com/1422-0067/27/20/9055
AB - Obesity is a heterogeneous disease in which cardiometabolic risk is shaped not only by adipose tissue mass but also by the capacity of adipose tissue to expand and remain metabolically functional. This narrative review provides an integrated, evidence-weighted molecular framework, the central original contribution of this work, for understanding how initially adaptive adipose tissue expansion transitions into pathological hypertrophy and self-sustaining immunometabolic dysfunction. We examine how impaired adipogenesis, angiogenesis and extracellular-matrix remodelling converge with mitochondrial and endoplasmic reticulum stress, oxidative stress, hypoxia and lipotoxicity to destabilise adipocyte homeostasis. Particular attention is given to the NLRP3 inflammasome, positioned within a broader network including JNK, IKKβ/NF-κB, TLR4 and cGAS–STING signalling, as a molecular integrator of metabolic danger signals. We further explore how adipokine remodelling, loss of adiponectin-mediated protection and enhanced leptin signalling interact with immune-cell recruitment to establish self-amplifying inflammatory circuits. Evidence is stratified across experimental, translational and human levels; a summary table maps each mechanism to its strength of evidence and current clinical relevance. This framework explains metabolic phenotype heterogeneity among individuals with comparable adiposity and establishes the molecular foundation for Parts II and III of the Prometheus’s Fire series.
SN - 1422-0067
ER -