Mitochondrial dysfunction charachterizes the multigenerational effects of maternal obesity on MASLD

Although maternal obesity is an independent risk factor for metabolic dysfunction-associated steatotic liver disease (MASLD), the pathogenesis remains unclear. We aimed to evaluate the effect and mechanisms of multigenerational maternal western diet (WD) on MASLD progression, and test drug candidates in a preclinical model. Female mice were fed WD from 8 weeks before breeding initiation with a normal chow (NC)-fed male, throughout pregnancy and lactation. Male offspring were weaned onto NC or WD and assessed at the age of 16 weeks. Maternal WD feeding aggravated body weight gain, insulin resistance, steatosis and inflammation. Fibrosis was only observed in offspring exposed to maternal WD. Mechanistically, the latter exhibited reduced OXPHOS activity. Maternal WD aggravates MASLD in male offspring, with mitochondrial dysfunction contributing to disease severity. 8-week-old female C57BL/6J mice were fed either Western diet (WD) or normal chow (NC) control for 8 weeks before breeding to a NC-fed male. Diet was maintained during breeding and lactation. Female offspring were weaned onto NC and used to produce the next generation in the same way as the first generation. Offspring from the second generation were weaned onto WD or NC. In this way, four groups of offspring were generated: NC-fed offspring without maternal obesity (healthy controls, NC/NC), WD-fed offspring without maternal obesity (NC/WD), and WD-fed offspring with one or two generations of maternal obesity (WD/WD and WD/WD/WD respectively).