Maternal Exercise Mediates Hepatic Metabolic Programming via Activation of AMPK-PGC1α Axis in the Offspring of Obese Mothers

Abstract

Maternal obesity is associated with an increased risk of hepatic metabolic dysfunction for both mother and offspring and targeted interventions to address this growing metabolic disease burden are urgently needed. This study investigates whether maternal exercise (ME) could reverse the detrimental effects of hepatic metabolic dysfunction in obese dams and their offspring while focusing on the AMP-activated protein kinase (AMPK), representing a key regulator of hepatic metabolism. In a mouse model of maternal western-style-diet (WSD)-induced obesity, we established an exercise intervention of voluntary wheel-running before and during pregnancy and analyzed its effects on hepatic energy metabolism during developmental organ programming. ME prevented WSD-induced hepatic steatosis in obese dams by alterations of key hepatic metabolic processes, including activation of hepatic ß-oxidation and inhibition of lipogenesis following increased AMPK and peroxisome-proliferator-activated-receptor-γ-coactivator-1α (PGC-1α)-signaling. Offspring of exercised dams exhibited a comparable hepatic metabolic signature to their mothers with increased AMPK-PGC1α-activity and beneficial changes in hepatic lipid metabolism and were protected from WSD-induced adipose tissue accumulation and hepatic steatosis in later life. In conclusion, this study demonstrates that ME provides a promising strategy to improve the metabolic health of both obese mothers and their offspring and highlights AMPK as a potential metabolic target for therapeutic interventions.

Brain-Restricted Inhibition of IL-6 Trans-Signaling Mildly Affects Metabolic Consequences of Maternal Obesity in Male Offspring

“…As expected from previous experiments by our group and others [43,44], WSD and GFAPsgp130 WSD dams displayed signs of impaired glucose tolerance prior to mating. Importantly, entering pregnancy, transgenic and WT dams on WSD were significantly heavier than the respective SD groups with no significant differences in-between WT and transgenic dams on the same diets, marking no significant effect of body weight differences entering the perinatal period.…”

Developmental programming by maternal obesity: Lessons from animal models

“…Maternal exercise was also shown to prevent adiposity and hepatic steatosis in 4-month-old offspring of Western-diet fed obese mouse dams. 42 Gestational exercise also prevented the hyperinsulinaemia and insulin resistance observed in 12-month-old female mouse offspring of HFD-fed dams. 27 Moreover, although training in gestation alone was sufficient to improve glucose tolerance in young adult males, both male and female offspring were protected against glucose intolerance and adiposity until 12 months of age when the exercise intervention was initiated 2-week pre-gestation, illustrating the importance of the timing of interventions.…”

Perinatal Obesity Induces Hepatic Growth Restriction with Increased DNA Damage Response, Senescence, and Dysregulated Igf-1-Akt-Foxo1 Signaling in Male Offspring of Obese Mice

“…The histological analysis of liver samples was performed as previously described [ 16 , 56 ]. In brief, upon sacrificing the mice at P21, the liver tissue was excised and immediately fixed in 4% PFA.…”

“…Inflammation induces insulin resistance and promotes the development of cardiovascular as well as chronic hepatic diseases, such as non-alcoholic fatty liver disease, and converges with aging processes [ 14 , 15 ]. For instance, our research group has recently demonstrated that perinatal obesity causes hepatic steatosis and imbalanced metabolic signaling later in life [ 16 ]. However, the early postnatal molecular mechanisms by which maternal obesity determines liver health remain poorly understood.…”