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Obesity and Obesity-Associated Co-Morbidities: From Mechanisms to Mechanism-Based Therapies

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Endocrinology and Metabolism".

Deadline for manuscript submissions: 20 July 2026 | Viewed by 1721

Special Issue Editor


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Guest Editor
Laboratory of Experimental and Translational Medicine, National Bureau of Science and Technology, San Luis, Argentina
Interests: obesity; energy balance; adipose tissue inflammation; oxidative stress; macrophage phenotypic switch; gene expression; obesity-associated co-morbidity; non-communicable disease; aging; cancer

Special Issue Information

Dear Colleagues,

As the prevalence of obesity continues to increase, further research is needed to understand the pathways and mechanisms linking a chronic positive energy balance to non-communicable diseases (NCDs), cancer and ageing. A chronic energy balance leads to hyperplasia and hypertrophy of adipose tissue (AT), resulting in the recruitment of specific monocytes and other immune cells from the blood into the AT. The AT monocytes then differentiate into macrophages, which change their phenotype by activating specific signaling pathways and transcription factors. In healthy AT, free fatty acids (FFAs) are stored as triacylglycerol to prevent oxidative stress and activation of inflammatory gene expression. AT macrophages and other immune cells can be activated by pathogen-associated molecular patterns (PAMPs) that enter the blood from dysbiosis in the gut. FFAs, pro-inflammatory cytokines, oxidized macromolecules and PAMPs lead to systemic inflammation, the leading cause of obesity-associated NCDs, including neurodegenerative, metabolic and autoimmune diseases, as well as cancer and ageing, in genetically susceptible patients. Understanding the molecular basis controlling appetite, gut dysbiosis and AT inflammation will lead to better mechanism-based therapies against obesity-related NCDs. This Special Issue welcomes, but is not limited to, information on the molecular mechanisms and mechanism-based therapeutics against obesity-associated comorbidities.

This Special Issue is supervised by Dr. Dario C. Ramirez and assisted by Dr. Dra Sandra E. Gomez Mejiba (National University of San Luis).

Dr. Dario C. Ramirez
Guest Editor

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Keywords

  • obesity
  • adipose tissue inflammation
  • microbiota
  • oxidative stress
  • gene expression regulation
  • metabolism
  • obesity-associated co-morbidities
  • non-communicable disease
  • cancer
  • mechanism-based therapy

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Published Papers (2 papers)

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Research

13 pages, 2223 KB  
Article
Associations Between Klotho/FGF-Related Protein Expression in Peripheral Blood Mononuclear Cells, Inflammation, and Muscle Function in Middle-Aged Adults with Obesity: A Pilot Study
by Diana G. Ariadel-Cobo, Brisamar Estébanez, Elena González-Arnáiz, María Pilar García-Pérez, Marta Rivera Viloria, Alejandra Villasante Santos, Begoña Pintor de la Maza, David Emilio Barajas-Galindo, Diana García-Sastre, María José Cuevas González and María D. Ballesteros-Pomar
Int. J. Mol. Sci. 2026, 27(4), 1983; https://doi.org/10.3390/ijms27041983 - 19 Feb 2026
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Abstract
This pilot study aimed to investigate the role of the Klotho/FGF (fibroblast growth factor) system in biological features associated with premature aging, particularly inflammation and muscle dysfunction, focusing on its association with inflammatory markers, body composition, and muscle function in middle-aged adults. A [...] Read more.
This pilot study aimed to investigate the role of the Klotho/FGF (fibroblast growth factor) system in biological features associated with premature aging, particularly inflammation and muscle dysfunction, focusing on its association with inflammatory markers, body composition, and muscle function in middle-aged adults. A total of 45 participants aged 50–60 years were enrolled, including 30 patients with obesity (22F/8M) and 15 healthy controls (11F/4M). Comprehensive assessments were conducted, including body composition analysis and muscle function tests. Evaluations of protein expression of Klotho, β-Klotho, FGF19, FGF21, FGF23, TFN-α and IL-10 were assessed in peripheral blood mononuclear cells (PBMCs). A Principal Component Analysis (PCA) was carried out to explore the relationships among variables. Significant differences were observed between the obese and control groups, with obese individuals exhibiting lower levels of Klotho and higher levels of TFN-α. The PCA revealed that higher Klotho levels were positively associated with better muscle function and lower inflammatory markers. These associations suggest that Klotho-related alterations may reflect biological processes linked to inflammation and muscle dysfunction in obesity. These findings suggest that alterations in the Klotho/FGF system may reflect biological pathways commonly associated with aging-related phenotypes in obesity, rather than direct measures of chronological aging. Given the exploratory design and limited sample size, these findings should be interpreted as hypothesis-generating rather than evidence of causal mechanisms. Full article
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18 pages, 4285 KB  
Article
Restoring Lysosomes in Adipose Tissue Macrophages Mitigates Obesity-Induced Inflammation and Insulin Resistance
by Jiyeon Chang, Ellen Budiono, Shindy Soedono, Xaviera Riani Yasasilka, SungWan Chun and Kae Won Cho
Int. J. Mol. Sci. 2026, 27(4), 1755; https://doi.org/10.3390/ijms27041755 - 12 Feb 2026
Viewed by 756
Abstract
Adipose tissue macrophages (ATMs) are key mediators of obesity-induced inflammation and insulin resistance. However, the contribution of lysosomal dysfunction to ATM inflammatory activation remains poorly defined. Here, we characterized lysosomal structural and functional alterations in ATMs during obesity and examined whether pharmacological restoration [...] Read more.
Adipose tissue macrophages (ATMs) are key mediators of obesity-induced inflammation and insulin resistance. However, the contribution of lysosomal dysfunction to ATM inflammatory activation remains poorly defined. Here, we characterized lysosomal structural and functional alterations in ATMs during obesity and examined whether pharmacological restoration of lysosomal function using 2-hydroxypropyl-β-cyclodextrin (HPβCD) ameliorates metabolic inflammation. In diet-induced obese C57BL/6J male mice, adipose tissue exhibited increased lysosomal abundance, accompanied by reduced cathepsin L+V expression, modestly increased lysosomal acid lipase levels, and decreased expression of transcription factor EB (TFEB), a master regulator of lysosomal biogenesis. Despite expanded lysosomal content, ATMs displayed impaired lysosomal acidification, indicating functional lysosomal dysfunction. Intraperitoneal administration of HPβCD for two weeks significantly improved glucose tolerance and insulin sensitivity without affecting body weight. Flow cytometric analysis revealed reduced pro-inflammatory M1 ATMs and CD8+ T lymphocytes in visceral adipose tissue, whereas immune cell populations in subcutaneous adipose tissue, blood, and spleen remained unchanged. In vitro, HPβCD suppressed pro-inflammatory gene expression in both classically and metabolically activated macrophages and attenuated inflammatory responses induced by lysosomal stressors, including bafilomycin A1 and chloroquine, while restoring TFEB expression. Collectively, these findings demonstrate that obesity is associated with lysosomal dysfunction in ATMs and that restoration of lysosomal function alleviates adipose tissue inflammation and metabolic dysfunction, highlighting lysosomal regulation in ATMs as a potential therapeutic target for obesity-associated metabolic diseases. Full article
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