The hepatic metabolism pattern of MASLD in rats with double burden of malnutrition

Aim: The double burden of malnutrition (DBM) combines early-life undernutrition with later metabolic risks, potentially driving metabolic dysfunction-associated steatotic liver disease (MASLD) according to epidemiological evidence. Early-life undernutrition, though protective in adulthood, may disrupt metabolic programming in critical developmental stages, exacerbating metabolic dysfunction. However, DBM-specific hepatic energy metabolism adaptations remain unclear. This study investigates metabolic pathways in DBM-induced liver steatosis in a rat model, aiming to clarify how DBM promote fatty liver disease.

Method: Rats were fed with early life semistarvation (50 % normal chow diet, 50 %NCD) and subsequent high-fat diet (HFD) in adulthood to build the model of MASLD induced by DBM. Multilayer omics (metabolome, transcriptome, proteome and phosphoproteome) were used to generally assess the metabolic states of DBM rats.

Results: MASLD rats induced by DBM developed hepatic steatosis, liver dysfunction, and systemic inflammation. The processes of glycogenolysis, gluconeogenesis, aerobic oxidation, and fatty acid synthesis were upregulated in semistarvation + HFD (i.e. DBM) compared with HFD rats. To explore other potential changes of metabolic changes, untargeted metabolome was performed, and the main pathway enrichments of differential relative levels of hepatic metabolites between the two groups may be related to glycerophospholipid metabolism, oxidative phosphorylation, bile secretion, primary bile acid biosynthesis, fatty acid biosynthesis. Liver transcriptome, proteome and phosphoproteome analysis focused on AMP-activated protein kinase (AMPK) signaling pathway; compared with simple NCD group and HFD group, early life semistarvation (including NCD and HFD in adulthood) can lead to the downregulation of liver AMPK signal and upregulation of its downstream de novo lipogenesis.

Conclusion: We uncovered a concurrent hypercatabolism-hyperanabolism pattern in the rat model of DBM. AMPK inactivation was the center linking early-life undernutrition to adulthood overnutrition in the development of MASLD induced by DBM. Future work is called for AMPK-based therapeutic biologics for the treatment of hypermetabolism MASLD induced by DBM.