Maternal Physical Activity and Sex Impact Markers of Hepatic Mitochondrial Health

Cunningham, Rory P.; Moore, Mary; Meers, Grace M.; Ruegsegger, Gregory N.; Booth, Frank W.; Rector, R. Scott

doi:10.1249/mss.0000000000001675

Cited by 10 publications

(20 citation statements)

References 38 publications

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“…However, despite the lack of effect on fetal growth, we have shown previously that the exercise intervention used in this study prevented the development of placental hypoxia and lipidemia, as well as male offspring insulin resistance, cardiac hypertrophy, and cardiac dysfunction due to maternal obesity (Fernandez‐Twinn et al ; Beeson et al ). Similar beneficial effects of exercise on the cardiovascular and metabolic health of the offspring have been reported in overweight or obese women (Barakat et al ; Patel et al ) and in other experimental animals (Carter et al ; Carter et al ; Rajia et al ; Laker et al ; Blaize et al ; Raipuria et al ; Vega et al ; Stanford et al ; Quiclet et al ; Ribeiro et al ; Stanford et al ; Cunningham et al ). Our previous work has shown that maternal hyperinsulinemia is a predictor of offspring cardiometabolic health in obese pregnancies (Fernandez‐Twinn et al ).…”

Section: Discussionsupporting

confidence: 63%

“…In mice, exercise also ameliorates the increased levels of maternal oxidative stress (Vega et al ) and placental hypoxia and lipid accumulation associated with maternal obesity (Fernandez‐Twinn et al ). Furthermore, there is accumulating evidence that maternal exercise has beneficial effects on cardiometabolic outcomes of the offspring in overweight or obese women (Barakat et al ; Patel et al ) and in experimental animals (Carter et al ; Carter et al ; Rajia et al ; Laker et al ; Blaize et al ; Raipuria et al ; Vega et al ; Stanford et al ; Fernandez‐Twinn et al ; Quiclet et al ; Ribeiro et al ; Stanford et al ; Beeson et al ; Cunningham et al ). However, the physiological and molecular impact of exercise on the metabolically active tissues of the mother, which may lead to improved pregnancy outcomes, remain unknown.…”

Section: Introductionmentioning

confidence: 99%

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Exercise alters the molecular pathways of insulin signaling and lipid handling in maternal tissues of obese pregnant mice

et al. 2019

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Obesity during gestation adversely affects maternal and infant health both during pregnancy and for long afterwards. However, recent work suggests that a period of maternal exercise during pregnancy can improve metabolic health of the obese mother and her offspring. This study aimed to identify the physiological and molecular impact of exercise on the obese mother during pregnancy that may lead to improved metabolic outcomes. To achieve this, a 20‐min treadmill exercise intervention was performed 5 days a week in diet‐induced obese female mice from 1 week before and up to day 17 of pregnancy. Biometric, biochemical and molecular analyses of maternal tissues and/or plasma were performed on day 19 of pregnancy. We found exercise prevented some of the adverse changes in insulin signaling and lipid metabolic pathways seen in the liver, skeletal muscle and white adipose tissue of sedentary‐obese pregnant dams (p110 β , p110 α , AKT, SREBP). Exercise also induced changes in the insulin and lipid signaling pathways in obese dams that were different from those observed in control and sedentary‐obese dams. The changes induced by obesity and exercise were tissue‐specific and related to alterations in tissue lipid, protein and glycogen content and plasma insulin, leptin and triglyceride concentrations. We conclude that the beneficial effects of exercise on metabolic outcomes in obese mothers may be related to specific molecular signatures in metabolically active maternal tissues during pregnancy. These findings highlight potential metabolic targets for therapeutic intervention and the importance of lifestyle in reducing the burden of the current obesity epidemic on healthcare systems.

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Section: Discussionsupporting

confidence: 63%

Section: Introductionmentioning

confidence: 99%

Exercise alters the molecular pathways of insulin signaling and lipid handling in maternal tissues of obese pregnant mice

et al. 2019

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“…As we have published previously (66,67), male mice had elevated hepatic steatosis compared to female mice regardless of other conditions, with no effect of sex on inflammation and NAS (Fig. 3.1A-B).…”

Section: 1a-b)supporting

confidence: 76%

“…Despite this, the mechanisms conferring this protection against NAFLD development is unresolved. Our group has demonstrated that female mice are not only protected from hepatic steatosis compared to male mice, but also displayed elevated markers of mitochondrial biogenesis and mitophagy, regardless of maternal condition (66). Similarly, we have shown that female rats have higher markers of mitochondrial biogenesis (TFAM), mitophagy (LC3-II/I, ATG12:5), and cellular energy homeostasis (AMPK) compared to males, regardless of diet (67).…”

Section: Sex Differences With Hepatic Mitophagymentioning

confidence: 53%

“…Our group has demonstrated that female rodents are not only protected from hepatic steatosis compared to male mice, but also displayed elevated markers of hepatic mitochondrial biogenesis and mitophagy (66,67). Additionally, female mice possessed elevated hepatic mitochondrial content, respiratory capacity, and lower reactive oxygen species emission compared to male mice, regardless of physical activity status (68)(69)(70).…”

Section: Introductionmentioning

confidence: 84%

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The role of hepatocellular eNOS in NAFLD development and hepatic mitochondrial adaptations to exercise

Cunningham¹

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Whole body loss of endothelial nitric oxide synthase (eNOS) worsens hepatic mitochondrial function and exacerbates nonalcoholic fatty liver disease/steatohepatitis (NAFLD/NASH) development and progression. However, the precise role of eNOS in hepatocytes in the contribution to NAFLD has not been established. Here, we use gain- and loss- of-function approaches including a hepatocyte-specific eNOS knockout mouse model (eNOShep-/-), and lifestyle interventions (diet and exercise), to investigate the role of hepatocellular eNOS in NAFLD/NASH development and hepatic mitochondrial adaptations to exercise. Ablation of hepatocellular eNOS via genetic and viral knockout exacerbated hepatic steatosis and inflammation, decreased hepatic mitochondrial fatty acid oxidation and respiration, and impaired mitophagy. Conversely, overexpressing hepatocellular eNOS via viral approaches increased hepatocyte respiration, markers of mitophagy, while attenuating NASH progression. Interestingly, these detriments were not rescued by BNIP3 overexpression or nitric oxide (NO) donors in eNOS deficient hepatocytes. In addition, elevated H2O2 emission and hepatic steatosis in eNOShep-/- mice was completely ablated with 10 weeks of voluntary wheel running exercise. Interestingly, eNOShep-/- male mice had a blunted exercise-induced increase in hepatic fatty acid oxidation. eNOShep-/- mice also had impaired markers of energy sensing ability of the cell and attenuated activation of the autophagy initiating factor ULK1. While mitochondrial respiration and markers of mitochondrial content were not increased with exercise, female mice showed markers of mitochondrial biogenesis. Collectively, these data uncover the important and novel role of hepatocellular eNOS in exercise-induced hepatic mitochondrial adaptations, and help to further the understanding behind the mechanistic role of eNOS in NAFLD development.

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Hepatocyte‐specific eNOS deletion impairs exercise‐induced adaptations in hepatic mitochondrial function and autophagy

Cunningham

Moore

Dashek

et al. 2022

Obesity

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Objective: Endothelial nitric oxide synthase (eNOS) is a potential mediator of exerciseinduced hepatic mitochondrial adaptations.Methods: Here, male and female hepatocyte-specific eNOS knockout (eNOS hep−/− ) and intact hepatic eNOS (eNOS fl/fl ) mice performed voluntary wheel-running exercise (EX) or remained in sedentary cage conditions for 10 weeks.Results: EX resolved the exacerbated hepatic steatosis in eNOS hep−/− male mice. Elevated hydrogen peroxide emission (~50% higher in eNOS hep−/− vs. eNOS fl/fl mice) was completely ablated with EX. Interestingly, EX increased [1-14 C] palmitate oxidation in eNOS fl/fl male mice, but this was blunted in the eNOS hep−/− male mice. eNOS hep−/− mice had lower markers of the energy sensors AMP-activated protein kinase (AMPK)/ phospho-(p)AMPK and mammalian target of rapamycin (mTOR) and p-mTOR, as well as the autophagy initiators serine/threonine-protein kinase ULK1 and pULK1, compared with eNOS fl/fl mice. Females showed elevated electron transport chain protein content and markers of mitochondrial biogenesis (transcription factor A, mitochondrial, peroxisome proliferator-activated receptor-gamma coactivator 1α). Conclusions:Collectively, this study demonstrates for the first time, to the authors' knowledge, the requirement of eNOS in hepatocytes in the EX-induced increases in hepatic fatty acid oxidation in male mice. Deletion of eNOS in hepatocytes also appears to impair the energy-sensing ability of the cell and inhibit the activation of the autophagy initiating factor ULK1. These data uncover the important and novel role of hepatocyte eNOS in EX-induced hepatic mitochondrial adaptations.

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Maternal Physical Activity and Sex Impact Markers of Hepatic Mitochondrial Health

Cited by 10 publications

References 38 publications

Exercise alters the molecular pathways of insulin signaling and lipid handling in maternal tissues of obese pregnant mice

Exercise alters the molecular pathways of insulin signaling and lipid handling in maternal tissues of obese pregnant mice

The role of hepatocellular eNOS in NAFLD development and hepatic mitochondrial adaptations to exercise

Hepatocyte‐specific eNOS deletion impairs exercise‐induced adaptations in hepatic mitochondrial function and autophagy

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