Endocrine Abstracts

JOINT1996

Background: Obesity is a significant risk factor for developing cardio-metabolic diseases and is associated with increased mortality. However, there is substantial variability in the severity of metabolic abnormalities among obese individuals. The exact mechanisms contributing to this heterogeneity remain unclear.

Objective: This study aims to investigate whether differences in stress response affect metabolic health and to explore underlying mechanisms, hypothesizing that impaired stress resilience affects adipose tissue function.

Methods: The study utilized a selectively bred mouse model with inherent social dominance (Dom) and submissiveness (Sub), representing stress resilience and vulnerability, respectively. Mice were fed either a high-fat diet (HFD) or standard diet (STD), followed by physiological and molecular analyses. To manipulate stress response, a stress inoculation paradigm involving chronic mild stress (CMS) was employed (14 days of 5-minute daily restraint)¹. Epididymal and inguinal white adipose tissue (eWAT and iWAT, respectively) were isolated for RNA-seq analysis, insulin sensitivity assessment, and determination of adipogenic potential.

Results: HFD-fed Sub mice exhibited hyperinsulinemia, hyperleptinemia, severe glucose intolerance, and fatty liver, whereas Dom mice showed minimal effects. CMS reduced HFD-induced glucose intolerance in stress-vulnerable mice, with similar positive effects observed in C57BL/6 mice. Adipose tissue analysis revealed impaired adipokine expression in HFD-fed Sub mice, with higher leptin and lower adiponectin mRNA levels compared to Dom mice. Additionally, an impaired pro-inflammatory gene expression profile was observed in Sub mice. Further investigation focused on differences in adipose tissue function between Sub and Dom mice, showing impaired insulin-induced Akt phosphorylation and glucose uptake in Sub mice. RNA-seq analysis demonstrated distinct clustering of genes in WAT of Sub and Dom mice, even under STD-feeding conditions, indicating fundamental differences in adipose tissue function between strains. Pathway analysis revealed that adipogenic pathways were enriched in eWAT but reduced in iWAT of lean Sub mice, suggesting impaired adipogenic potential in iWAT of Sub. Functional analysis of adipogenesis in isolated stroma-vascular fraction (SVF) from iWAT confirmed lower proliferation and differentiation rates in Sub mice compared to Dom mice. Furthermore, differentiated adipocytes from Dom mice exhibited a higher UCP1 and adiponectin-to-leptin expression ratio, compared to adipocytes from Sub.

Conclusion: Stress vulnerability contributes to increased susceptibility to metabolic alterations, with impaired adipogenic potential and impaired function in stress-vulnerable mice, potentially exacerbating metabolic abnormalities observed in this model.Reference1. Ayash, S., et al., Stress inoculation in mice induces global resilience. Translational Psychiatry, 2020. 10 (1): p. 200.