Metabolic imprinting due to small litter size mitigates insulin resistance through the interscapular brown adipose tissue activation in a high-sucrose diet model.

Abstract

Metabolic imprinting refers to lasting metabolic changes from early-life environmental exposures, especially nutritional, that impact adult health and chronic disease risk. We investigated whether metabolic imprinting by small litter size (SL) activates interscapular brown adipose tissue (iBAT) and affects glucose and lipid metabolism, oxidative damage, and insulin resistance (IR) in young rats exposed to a high-sucrose diet (HSD) over eight weeks. Male Wistar rats (n = 48) were assigned to control (eight pups/ dam; CL) and small litter (four pups/ dam; SL) groups. Post-weaning (21 days), they were divided into four dietary groups: (i) standard diet (STD, chow diet) from CL, or (ii) SL; (iii) HSD (30% sucrose) from CL, or (iv) SL, for eight weeks. Afterward, animals were euthanized for analysis of iBAT and serum samples. HSD caused hypertrophy, IR, and oxidative damage in iBAT. However, the SL model attenuated HSD-induced IR by up-regulating p-AKT (Ser 473) and activating iBAT thermogenesis, resulting in decreased PGC1-α expression and up-regulating UCP1 expression, which contributed to iBAT hyperplasia. Additionally, SL reduced PKA activation and free fatty acid (FFA) release, decreasing the lipid oxidative damage observed in HSD-fed iBAT. These findings suggest that SL-induced metabolic imprinting enhances iBAT thermogenesis through p-AKT (Ser 473) and PGC1-α signaling, increases UCP1 expression, and reduces PKA substrates phosphorylation, decreasing FFA levels and oxidative damage following HSD exposure. While our results challenge the existing literature, we propose that the metabolic plasticity from the SL model allows rats to adapt to dietary variations and may protect against HSD-induced IR in adulthood.