The hidden impact of intrauterine growth restriction in the pathogenesis of metabolic syndrome: Functional and structural alterations in rat visceral adipose tissue

Individuals born after intrauterine growth restriction (IUGR) have a higher risk of developing metabolic syndrome (MetS) in adulthood. In a rat model, male IUGR offspring exhibit MetS features-including elevated systolic blood pressure, glucose intolerance, non-alcoholic fatty liver disease, and increased visceral adipose tissue (VAT)-by 6 months of age. Female offspring, however, do not. While higher VAT is associated with MetS, its role in IUGR-induced metabolic disorders remains unclear. The objective is to examine structural changes and mechanisms in VAT associated with metabolic disorders in IUGR rats. IUGR was induced via a maternal low-protein (9% casein) and compared to a control diet (23% casein). VAT was collected from 6-month-old offspring. Adipocyte hyperplasia and hypertrophy were analyzed using Ki-67 and hematoxylin/eosin (H/E) staining. Adipogenesis (PPAR-γ by Western blot; ZFP423 by RT-qPCR), inflammation (IL-6, TNF-α by RT-qPCR), macrophage markers (CD68, ITGAM, ITGAX by RT-qPCR), oxidative stress (superoxide anion via hydroethidine; Cu/Zn SOD, catalase by Western blot), and senescence (lipofuscin via autofluorescence, crown-like structures by H/E, p16INK4a, p21WAF1, Sirtuin-1 by Western blot) were evaluated. IUGR males showed increased adipocyte proliferation, hypertrophy, and upregulated adipogenic markers (PPAR-γ, ZFP423; P<.05, P<.001). Inflammatory and macrophage markers were elevated (P<.05), along with superoxide anion production, Cu/Zn SOD and catalase protein expression (P<.05). Senescence indicators-including lipofuscin, crown-like structures, p16INK4a, p21WAF1, and Sirtuin-1 were also upregulated (all P<.05). No significant changes were observed in females. VAT from male IUGR offspring exhibits increased adipogenesis, inflammation, oxidative stress, and premature senescence, suggesting a mechanistic link to their higher MetS susceptibility.