Maternal exercise protects offspring mice from nonalcoholic fatty liver disease by promoting AMPK-mediated autophagy

Maternal exercise (ME) protects offspring from fatty liver induced by high-fat diet (HFD) challenge. Here, we have shown that ME enhances fetal hepatic autophagy, including lipophagy, which promotes degradation of lipid droplets, thereby leading to reduction of lipid accumulation in the liver. This process helps maintain liver homeostasis in lipid metabolism and prevents the progression of HFD-induced nonalcoholic fatty liver disease (NAFLD). In this study, eight-week-old female C57BL/6J mice were fed either a control diet or a HFD (60% energy from fat) for 8 weeks to induce obesity, resulting in a 20% increase in body weight compared to the control group. Additionally, mice were randomized into two groups with/without exercise: Control (CON, n=6), Control with exercise (COEX, n=6), Obese (OB, n=6), and Obese with exercise (OBEX, n=6). All mice were acclimated to treadmill running for one week, and COEX and OBEX mice trained daily during pregnancy until embryonic day (e) 16.5. Fetal liver samples were collected at e18.5 for further biochemical and histochemical analyses. Moreover, AMPKα1 knockout (KO) mice were used to investigate the role of the AMPK pathway on ME-induced hepatic autophagy. We observed that the OB group exhibits an increase of expression of SREBP-1, a key regulator of fat accumulation, compared to the CON and OBEX which suppressed proper autophagy. In contrast, exercise increased LC-3 expression, a marker of autophagy. COEX showed higher levels of LC-3 compared to CON, while the OB group showed significantly lower levels compared to both CON and OBEX. To investigate the role of AMPK deficiency in hepatic autophagy, we utilized AMPK KO mice. While a single bout of exercise increased LC-3 levels in control mice, no change in LC3 expression was observed in the AMPK-deficient mice, indicating that AMPK activation is essential for hepatic autophagy in response to exercise stimulation. These results suggest that ME enhances autophagy through the AMPK pathway, leading to improvement of liver pathological conditions, such as steatosis, in offspring. In conclusion, ME and maternal obesity (MO) significantly reprogram offspring biological conditions in ways that can either benefit or harm in liver function, potentially influencing the offspring’s ability to adapt to western diets. This work was supported by the National Institutes of Health (NIH) grants (R01-HD067449; R21-AG084142). This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.