Sex-specific metabolic effects of Treg expansion in db/db mice

Abstract

Immunomodulation; Inflammation; Metabolism

Immunomodulació; Inflamació; Metabolisme

Inmunomodulación; Inflamación; Metabolismo

Introduction: Type 2 diabetes mellitus (T2D) is characterized by chronic, low-grade inflammation and immune dysregulation, contributing to insulin resistance and metabolic complications. Regulatory T cells (Tregs) are key modulators of immune homeostasis, and their therapeutic expansion has shown promise in limiting inflammation. Here, we investigated whether in vivo Treg expansion could modulate metabolic and inflammatory responses in T2D in a sex-specific manner. Methods: Male and female db/db and db/+ mice received intraperitoneal injections of IL-2/anti-IL-2 (JES6-1) complexes for six weeks to induce endogenous Treg expansion. Body weight, blood glucose, and insulin levels were monitored to calculate HOMA-IR. Plasma inflammatory and anti-inflammatory mediators (CRP, adiponectin, IL-10, IL-13, CCL3) were quantified by bead-based immunoassays. Hepatic triglycerides and gene expression of Foxp3, F4/80, Pparγ, Il10 and Il13 were analyzed by biochemical assays, western blot, and RT-qPCR. Results: Treg expansion reduced weight gain in db/db mice independently of food intake. Female mice displayed lower HOMA-IR, decreased CRP, and increased adiponectin, IL-10, and IL-13 levels, whereas males showed limited improvement. Hepatic triglycerides and F4/80 expression were reduced after Treg expansion, with restored Foxp3 and elevated Il10/Il13 expression, indicating diminished hepatic inflammation. Conclusion: Endogenous Treg expansion exerts sex-specific metabolic and anti-inflammatory benefits in db/db T2D mice, with females showing greater improvements in insulin resistance, inflammation, and hepatic lipid metabolism. These findings support Treg-based immunomodulation as a potential therapeutic approach for T2D and emphasize the need for sex-specific considerations in future research.

The author(s) declare financial support was received for the research and/or publication of this article. This work has been partially supported by Col•legi Oficial de Farmacèutics de Barcelona. ML-S.: Maria Zambrano fellowship from Spanish Ministry of Science, Innovation and Universities, financed by European Union “NextGenerationEU” (Universitat Autònoma de Barcelona), and Beatriu de Pinos fellowship, financed by Agència de Gestió d’Ajuts Universitaris i de Recerca (AGAUR,Generalitat de Catalunya).