In Utero Protein Deficiency Leads to Impaired Hepatic Lipid Metabolism in Adult Male Rats.

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).

OBJECTIVES

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 LP (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 2-way analysis of variance were used for statistical analyses.

RESULTS

In LP-programmed livers, Oil Red O staining and transmission electron microscopy revealed increased lipid accumulation, with a 55% increase in lipid droplet area compared with controls. Furthermore, relative levels of carnitine and acylcarnitines were elevated (carnitine 66%, deoxycarnitine 33%, glutarylcarnitine 37%, malonylcarnitine 44%, and methylglutarylcarnitine 83%; P ≤ 0.05), consistent with disrupted fatty acid handling. Transcriptionally, β-oxidation genes (Acadm, Acads, and 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. Tricarboxylic acid-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 optic atrophy 1 (115%) and decreased mitochondrial fission 1 protein (35%), alongside reduced mitophagy regulators LC3B (45%) and BCL2 interacting protein 3-like (41%) (all, P ≤ 0.05), suggesting compromised mitochondrial quality control. Mitochondrial deoxyribonucleic acid copy number was unchanged, but multiple protein kinase C isoforms were increased (P ≤ 0.05), consistent with altered intracellular insulin signaling.

CONCLUSIONS

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.