Adult mice are more susceptible to high-fat diet-induced visceral adiposity and insulin resistance than juvenile mice.

Abstract

Purpose: Obesity that develops at different life stages may have distinct metabolic consequences, and the mechanisms distinguishing juvenile from adult-onset obesity remain incompletely defined. Thus, we examined how the timing of exposure to a high-fat diet (HFD) affects expansion, lipid metabolism, and insulin signaling in epididymal visceral adipose tissue (eVAT).

Methods: Male C57BL/6J mice were fed either a control diet or a 60% HFD, initiated immediately after weaning during the juvenile period (3 weeks of age) or at young adulthood (9 weeks of age), and continued until 17 weeks of age.

Results: HFD increased both total VAT and subcutaneous adipose tissue (SAT) mass regardless of exposure timing. However, when introduced during adulthood, it led to a higher total VAT to SAT ratio, greater total VAT mass, more severe hyperglycemia, and more pronounced eVAT adipocyte hypertrophy and reduction in PPARγ protein levels. Only adult mice exposed to HFD exhibited impaired eVAT insulin signaling, characterized by increased inhibitory IRS1 phosphorylation, reduced Akt phosphorylation, and lower GLUT4 protein levels. This was associated with increased fatty acid influx, indicated by higher lipoprotein lipase and Cd36 expression, reduced SREBP-1c protein levels, and a shift toward a pro-lipolytic profile with increased Hsl expression.

Conclusion: These findings indicate that adult exposure to HFD leads to more adverse effects on eVAT expansion, lipid metabolism, and insulin signaling than juvenile exposure, further supporting the concept that the developmental stage at which caloric overload is initiated shapes adipose tissue plasticity and influences the severity of obesity-related metabolic disturbances.