Background: In-utero exposure to a low-protein (LP) diet is a well-established model of developmental programming linked to increased risk of chronic metabolic diseases, including lean Type 2 Diabetes (T2D).
Objective: In this study, we investigated the long-term effects of maternal LP diet on hepatic lipid metabolism and mitochondrial dynamics in adult lean T2D male rat offspring.
Methods: Pregnant Wistar rats were fed either a control (20% protein) or isocaloric low-protein (6% protein) diet during gestation, and male offspring were examined in adulthood. Hepatic lipid accumulation, mitochondrial function, and related signaling pathways were analyzed using integrated histological, metabolomic, and molecular methods. Student's t-test and two-way ANOVA were used for statistical analyses.
Results: In LP-programmed livers, Oil Red O staining and TEM revealed increased lipid accumulation, with a 55% increase in lipid droplet area compared with controls. Further, relative levels of carnitine and acylcarnitines were elevated (carnitine 66%, deoxycarnitine 33%, glutarylcarnitine 37%, malonylcarnitine 44%, methylglutarylcarnitine 83%; p ≤ 0.05), consistent with disrupted fatty-acid handling. Transcriptionally, β-oxidation genes (Acadm, Acads, Cact) were ∼2-fold downregulated, and the lipogenic gene Acaca was ∼1.5-fold upregulated (p ≤ 0.05), indicating a shift toward lipid synthesis and reduced mitochondrial fatty-acid oxidation. TCA-cycle intermediates were lower (p ≤ 0.05) in LP, with citrate (∼2.5-fold), succinate (∼1.5-fold), and malate (∼1.2-fold), suggesting impaired oxidative metabolism. Mitochondrial remodeling was evident with increased OPA1 (115%) and decreased FIS1 (35%), alongside reduced mitophagy regulators LC3B (45%) and BNIP3L (41%) (all, p ≤ 0.05), suggesting compromised mitochondrial quality control. mtDNA copy number was unchanged, but multiple PKC isoforms were increased (p ≤ 0.05), consistent with altered intracellular insulin signaling.
Conclusion: Our findings collectively demonstrate that in-utero protein restriction induces persistent impairments in hepatic mitochondrial function and lipid metabolism, contributing to the developmental origins of insulin resistance and metabolic dysfunction.
扫码关注我们
求助内容:
应助结果提醒方式:
