The obesity rate is rapidly increasing, which has been attributed to lack of exercise and excessive energy intake. Here, we found a previously unidentified explanation, due to lack of maternal exercise. In this study, healthy maternal mice were assigned either to a sedentary lifestyle or to exercise daily, and fetal brown adipose tissue (BAT) development and offspring metabolic health were analyzed. Compared to the sedentary group, maternal exercise enhanced DNA demethylation of Prdm16 promoter and BAT development and prevented obesity of offspring when challenged with a high-energy diet. Apelin, an exerkine, was elevated in both maternal and fetal circulations due to exercise, and maternal administration of apelin mimicked the beneficial effects of exercise on fetal BAT development and offspring metabolic health. Together, maternal exercise enhances thermogenesis and the metabolic health of offspring mice, suggesting that the sedentary lifestyle during pregnancy contributes to the obesity epidemic in modern societies.

Key pointsr Maternal exercise improves the metabolic health of maternal mice challenged with a high-fat diet.r Exercise intervention of obese mothers prevents fetal overgrowth. r Exercise intervention reverses impaired placental vascularization in obese mice. r Maternal exercise activates placental AMP-activated protein kinase, which was inhibited as a result of maternal obesity.Abstract More than one-third of pregnant women in the USA are obese and maternal obesity (MO) negatively affects fetal development, which predisposes offspring to metabolic diseases. The placenta mediates nutrient delivery to fetuses and its function is impaired as a result of MO. Exercise ameliorates metabolic dysfunction resulting from obesity, although its effect on placental function of obese mothers has not been explored. In the present study, C57BL/6J female mice were randomly assigned into two groups fed either a control or a high-fat diet (HFD) and then the mice on each diet were further divided into two subgroups with/without exercise. In HFD-induced obese mice, daily treadmill exercise during pregnancy reduced body weight gain, lowered serum glucose and lipid concentration, and improved insulin sensitivity of maternal mice. Importantly, maternal exercise prevented fetal overgrowth (macrosomia) induced by MO. To further examine the preventive effects of exercise on fetal overgrowth, placental vascularization and nutrient transporters were analysed. Vascular density and the expression of vasculogenic factors were reduced as a result of MO but were recovered by maternal exercise. On the other hand, the contents of nutrient transporters were not substantially altered by MO or exercise, suggesting that the protective effects of exercise in MO-induced fetal overgrowth were primarily a result of the alteration of placental vascularization and improved maternal metabolism. Furthermore, exercise enhanced downstream insulin signalling and activated AMP-activated protein kinase in HFD placenta. In sum, maternal exercise prevented fetal overgrowth induced by MO, which was Jun Seok Son received MS Degree in Kinesiology from Seoul National University. Currently, Jun Seok is a PhD student in the . His research interests focus on the impacts of maternal obesity, exercise, nutrition and other physiological conditions on fetal development and offspring health, especially the epigenetic mechanisms linking nutrients/metabolites to progenitor cell differentiation into myocytes/adipocytes. Ultimately, he aims to translate his work into clinical practice with respect to improving health outcomes for mothers and children affected by obesity.

SUMMARY Although maternal exercise (ME) becomes increasingly uncommon, the effects of ME on offspring muscle metabolic health remain largely undefined. Maternal mice are subject to daily exercise during pregnancy, which enhances mitochondrial biogenesis during fetal muscle development; this is correlated with higher mitochondrial content and oxidative muscle fibers in offspring muscle and improved endurance capacity. Apelin, an exerkine, is elevated due to ME, and maternal apelin administration mirrors the effect of ME on mitochondrial biogenesis in fetal muscle. Importantly, both ME and apelin induce DNA demethylation of the peroxisome proliferator-activated receptor γ coactivator-1α ( Ppargc1a ) promoter and enhance its expression and mitochondrial biogenesis in fetal muscle. Such changes in DNA methylation were maintained in offspring, with ME offspring muscle expressing higher levels of PGC-1α1/4 isoforms, explaining improved muscle function. In summary, ME enhances DNA demethylation of the Ppargc1a promoter in fetal muscle, which has positive programming effects on the exercise endurance capacity and protects offspring muscle against metabolic dysfunction.

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.

Myokines, known to mediate metabolism, inflammation, and other pathophysiological conditions, have been widely investigated, including myokines induced by exercise. However, among published literature, there is substantial inconsistency in the quantification of exercise-induced myokines. Here, we summarized and compared published data regarding the effects of exercise on commonly studied myokines including apelin, Brain-derived neurotrophic factor (BDNF), Interleukin-15 (IL-15), irisin, and Secreted protein acidic and rich in cysteine (SPARC) during the last decade and discussed possible reasons for discrepancy in these reports. Areas covered: A search on PubMed for original articles published in this decade was conducted, focusing on the impacts of exercises on myokines and metabolic and age-related disorders. Beneficial relationship between skeletal muscle plasticity and myokines due to exercise is also discussed. Expert commentary: Based on these analyses, exercise induces the secretion of a number of myokines, which has positive effects on metabolic diseases or age-related muscle atrophy (sarcopenia). However, among published reports, there is wide discrepancy in the quantification of myokines induced by exercise, which could be due to timing of sample collection, pre-analytic sample processing, analytical method, and calculation and other factors. Thus, these factors need to be considered in future studies on exercise induced myokines.

gestational diabetes mellitus (GDM); glucose transporters (GLUTs); G protein-coupled receptor (GPCR); human chorionic gonadotropin (hCG); hypoxia inducible factor-1a (HIF-1a); luteinizing hormone/choriogonadotropin receptor (LHCGR); maternal exercise (ME); maternal obesity (MO); maximal oxygen consumption rates (VO 2 max); metastatic lymph node 64 (MLN64); superoxide dismutase 3 (SOD3); mitochondrial transcription factor A (TFAM); peroxisome proliferator-activated receptor  coactivator-1 (PGC-1); placental lactogen (PL); placental growth hormone (PGH); protein kinase A (PKA); vascular endothelial growth factor (VEGFA); voluntary wheel running (VWR).

A role for exercise-induced apelin in improving metabolism indicates the possibility of a new drug target for the treatment of metabolic diseases and repairing skeletal muscle damage. Muscle Nerve 56: 1155-1163, 2017.

Maternal exercise (ME) protects against adverse effects of maternal obesity (MO) on fetal development. As a cytokine stimulated by exercise, apelin is elevated due to ME, but its roles in mediating the effects of ME on placental development remain to be defined. Two studies were conducted. In the first study, eighteen female mice were assigned to control (CON), high fat diet-induced obesity (OB) or OB with exercise (OB/Ex) groups (n = 6); in the second study, the same number of female mice were assigned to three groups; CON with PBS injection (CD/PBS), OB/PBS or OB with apelin injection (OB/APN). In the exercise study, daily treadmill exercise during pregnancy significantly elevated the expression of PRDM16 (P < 0.001) which correlated with enhanced oxidative metabolism and mitochondrial biogenesis in placenta (P < 0.05). More importantly, these changes were partially mirrored in the apelin study. Apelin administration upregulated PRDM16 protein level (P < 0.001), mitochondrial biogenesis (P < 0.05), placental nutrient transporter expression (P < 0.001) and placental vascularization (P < 0.01), which were impaired due to MO (P < 0.05). In summary, MO impairs oxidative phosphorylation in the placenta which is improved by ME; apelin administration partially mimics the beneficial effects of exercise on improving placental function, which prevents placental dysfunction due to MO.