Maternal exercise intergenerationally drives muscle-based thermogenesis via activation of apelin-AMPK signaling

Abstract

Summary Background Sarcolipin and uncoupling protein 3 (UCP3) mediate muscle-based non-shivering thermogenesis (NST) to improve metabolic homeostasis. The impacts of maternal obesity (MO) and maternal exercise (ME) on NST in offspring muscle remain unexamined. Methods Female mice were fed with a control diet or high fat diet to induce obesity. Then, obese mice were further separated into two groups: obesity only (OB) and OB plus daily exercise (OB/Ex). Fetal muscle was collected at embryonic day 18.5 and offspring mice at 3-month-old. Apelin administration during pregnancy and apelin receptor (APJ) knockout mouse were further used for investigating the mediatory role of APJ on muscle-based thermogenesis. To explore the direct effects of exercise on AMP-activated protein kinase (AMPK) downstream targets, AMPK knockout mouse was used. Findings MO inhibited while ME activated AMPK and peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) in fetal muscle. AMPK activation increased sarcolipin expression, which inhibited the uptake of calcium ions into sarcoplasmic reticulum, thereby activating CaMKK2. Consistently, the expression of UCP3 and sarcolipin was suppressed due to MO but activated in ME fetal muscle. Importantly, changes of UCP3 and sarcolipin maintained in offspring muscle, showing the transgenerational effects. Furthermore, apelin administration during pregnancy mimicked the effects of ME on AMPK and CaMKK2 activation, and UCP3 and sarcolipin expression, underscoring the mediatory roles of apelin-AMPK signaling in improving fetal muscle development. Interpretation ME, via activation of apelin signaling-AMPK axis, enhances NST gene expression in fetal and offspring muscle impaired due to MO, which intergenerationally protects offspring from diet-induced obesity and metabolic disorders. Funding This work was supported by National Institutes of Health Grant R01-HD067449.

Modulation of Gut Microbiota and Metabolites by Berberine in Treating Mice With Disturbances in Glucose and Lipid Metabolism

“…Mice were placed in a restricted room, the temperature was controlled at 22-25 °C, and the photoperiod was 12 h of light and 12 h of darkness. C57BL/6 J mice were fed either a sterile maintenance feed (≥18% crude protein, ≥4% crude fat, ≤5% crude fiber, and ≤8% crude ash; SPF-F02-001; SPF (Beijing) Biotechnology Co., Ltd., Beijing, China) as the NC group or high fat diet (HFD; 60% energy from fat; D12492; Research Diets, Inc., New Brunswick, NJ, United states) ad libitum for 8 weeks to induce obese diabetic mice, defined as fasting blood glucose level ≥7.0 mmol/L and gaining more than 20% body weight compared to the NC group (Aye et al, 2015;Yang et al, 2016;Son et al, 2019;Son et al, 2022). Then, mice were randomized into three groups: the NC group (n = 8), the MC group (n = 8), and the BER group (n = 8).…”

The role of enriched environment in neural development and repair

“…A meta-analysis of the impact of prenatal exercise on neonatal and child outcomes showed that maternal exercise was associated with a reduced risk of macrosomia, not with neonatal complications or adverse child outcomes (Davenport et al, 2018 ). In addition to the changes in plasticity of the brain, maternal exercise-induced secretion of Apelin in the placental circulation may provide long-term metabolic benefits to offspring (Son et al, 2022 ; Wang and Zhu, 2022 ). These results manifest that prenatal exercise may promote positive development in neonates but may not be effective in inhibiting the occurrence of abnormal diseases, such as those caused by premature birth.…”

Possible roles of exercise and apelin against pregnancy complications

“…The prevalence of maternal obesity during pregnancy has been reported to be 7-25% and is associated with high birth weight and increases the risk of being overweight in the future ( 2 , 41 ). Overweight and obesity in pregnant mice predispose their children to obesity and metabolic diseases ( 42 ). In obese people, adipose tissue is composed of white adipose tissue (WAT) and brown adipose tissue (BAT).…”

“…Under conditions of hyperthermia, there is uncontrollable Ca2+ leakage with stimulation of the calcium cycle without muscle contraction and heat production ( 73 , 79 ). It is reported that exercise-induced apelin in mothers activates sarcolipin and uncoupling protein 3 (UCP3) in the muscles of children and protects them from obesity ( 2 ) because Sarcolipin and UCP3 regulate thermogenesis in muscles to improve metabolic homeostasis ( 42 ). In myogenic cells with apelin/APJ deficiency, a decrease in thermogenic genes (Sarcolipin and UCP3) indicates the effect of apelin/APJ on fetal muscle thermogenesis and lower muscle temperature ( 2 ).…”

“…After exercise, apelin activates Gαi and Gαq. Apelin activates CaMKK2 (calcium/calmodulin-dependent protein kinase kinase 2) as a downstream Gαq molecule in the fetal muscle of obese mothers and stimulates fetal muscle thermogenesis ( 42 ). In the fetal muscle of obese mothers, CaMKK2 is inactivated while it is regenerated by apelin administration.…”