Dataset Information

Mitochondrial biogenesis in white adipose tissue mediated by JMJD1A-PGC-1 axis limits age-related metabolic disease.

ABSTRACT: Mitochondria play a vital role in non-shivering thermogenesis in both brown and subcutaneous white adipose tissues (BAT and scWAT, respectively). However, specific regulatory mechanisms driving mitochondrial function in these tissues have been unclear. Here we demonstrate that prolonged activation of β-adrenergic signaling induces epigenetic modifications in scWAT, specifically targeting the enhancers for the mitochondria master regulator genes Pgc1a/b. This is mediated at least partially through JMJD1A, a histone demethylase that in response to β-adrenergic signals, facilitates H3K9 demethylation of the Pgc1a/b enhancers, promoting mitochondrial biogenesis and the formation of beige adipocytes. Disruption of demethylation activity of JMJD1A in mice impairs activation of Pgc1a/b driven mitochondrial biogenesis and limits scWAT beiging, contributing to reduced energy expenditure, obesity, insulin resistance, and metabolic disorders. Notably, JMJD1A demethylase activity is not required for Pgc1a/b dependent thermogenic capacity of BAT especially during acute cold stress, emphasizing the importance of scWAT thermogenesis in overall energy metabolism.

SUBMITTER: Ito R

PROVIDER: S-EPMC10966194 | biostudies-literature | 2024 Apr

REPOSITORIES: biostudies-literature

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Mitochondrial biogenesis in white adipose tissue mediated by JMJD1A-PGC-1 axis limits age-related metabolic disease.

Ito Ryo R Xie Shiyu S Tumenjargal Myagmar M Sugahara Yuto Y Yang Chaoran C Takahashi Hiroki H Arai Makoto M Inoue Shin-Ichi SI Uchida Aoi A Nakano Kenji K Choi Hyunmi H Yang Ge G Zhao Yanan Y Yamaguchi Rei R Jin Hitomi H Sagae Hina H Wada Youichiro Y Tanaka Toshiya T Kimura Hiroshi H Kodama Tatsuhiko T Aburatani Hiroyuki H Takeda Kazuhisa K Inagaki Takeshi T Osborne Timothy F TF Yoneshiro Takeshi T Matsumura Yoshihiro Y Sakai Juro J

iScience 20240301 4

Mitochondria play a vital role in non-shivering thermogenesis in both brown and subcutaneous white adipose tissues (BAT and scWAT, respectively). However, specific regulatory mechanisms driving mitochondrial function in these tissues have been unclear. Here we demonstrate that prolonged activation of β-adrenergic signaling induces epigenetic modifications in scWAT, specifically targeting the enhancers for the mitochondria master regulator genes <i>Pgc1a/b</i>. This is mediated at least partially ...[more]

PMID: 38544573

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Project description:The purpose of this study was to determine whether exercise or/and cold exposure regulate mitochondria biogenesis-related gene expression in soleus and inguinal adipose tissue of mice.Forty ICR 5-week old male mice were divided into four groups: thermoneutrality-untrained (23 ± 1 °C in room temperature, n=10), cold-water immersion (24 ± 1 °C, n=10), exercise in neutral temperature (34 ± 1 °C, n=10), and exercise in cold temperature (24 ± 1 °C, n=10). The mice performed swimming exercise (30 min to 60 min, 5 times) for 8 weeks. After 8 weeks, we confirmed mitochondrial biogenesis-related gene expression changes for peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α), nuclear respiratory factors 1 (NRF1), and mitochondrial transcription factor A (Tfam) in soleus muscle and inguinal adipose tissue, and the related protein expression in soleus muscle.In soleus muscle, PGC-1α expression significantly increased in response to cold exposure (p = 0.006) and exercise (p = 0.05). There was also significant interaction between exercise and cold exposure (p = 0.005). Only exercise had a significant effect on NRF1 relative expression (p=0.001). Neither cold exposure nor the interaction showed significant effects (p = 0.1222 and p = 0.875, respectively). Relative Tfam expression did not show any significant effect from exercise. In inguinal adipose tissue, relative PGC-1α expression did not significantly change in any group. NRF1 expression showed a significant change from exercise (p = 0.01) and cold exposure (p = 0.011). There was also a significant interaction between exercise and cold exposure (p = 0.000). Tfam mRNA expression showed a significant effect from exercise (p=0.000) and an interaction between exercise and cold exposure (p=0.001). Only temperature significantly affected PGC-1α protein levels (p=0.045). Neither exercise nor the interaction were significant (p = 0.397 and p = 0.292, respectively). NRF1 protein levels did not show a significant effect in any experimental treatments. Tfam protein levels showed a significant effect in the exercise group (p=0.012), but effects of neither cold exposure nor the interaction were significant (p = 0.085 and p=0.374, respectively).Exercise and cold exposure promoted increased expression of mitochondrial biogenesis- related genes in soleus muscle. Only cold exposure had a significant effect on PGC-1α protein expression and only exercise had a significant effect on Tfam protein expression. In inguinal adipose tissue, there was interaction between exercise and cold exposure in expression of mitochondrial biogenesis-related genes.

Project description:Exercise has beneficial effects on energy balance and also improves metabolic health independently of weight loss. Adipose tissue function is a critical denominator of a healthy metabolism but the adaptation of adipocytes in response to exercise is insufficiently well understood. We have previously shown that one aerobic exercise session was associated with increased expression of antioxidant and cytoprotective genes in white adipose tissue (WAT). In the present study, we evaluate the chronic effects of physical exercise on WAT redox homeostasis and mitochondrial function. Adult male Wistar rats were separated into two groups: a control group that did not exercise and a group that performed running exercise sessions on a treadmill for 30 min, 5 days per week for 9 weeks. Reactive oxygen species (ROS) generation, antioxidant enzyme activities, mitochondrial function, markers of oxidative stress and inflammation, and proteins related to DNA damage response were analyzed. In WAT from the exercise group, we found higher mitochondrial respiration in states I, II, and III of Complex I and Complex II, followed by an increase in ATP production, and the ROS/ATP ratio when compared to tissues from control rats. Regarding redox homeostasis, NADPH oxidase activity, protein carbonylation, and lipid peroxidation levels were lower in WAT from the exercise group when compared to control tissues. Moreover, antioxidant enzymatic activity, reduced glutathione/oxidized glutathione ratio, and total nuclear factor erythroid-2, like-2 (NFE2L2/NRF2) protein levels were higher in the exercise group compared to control. Finally, we found that exercise reduced the phosphorylation levels of H2AX histone (γH2AX), a central protein that contributes to genome stability through the signaling of DNA damage. In conclusion, our results show that chronic exercise modulates redox homeostasis in WAT, improving antioxidant capacity, and mitochondrial function. This hormetic remodeling of adipocyte redox balance points to improved adipocyte health and seems to be directly associated with the beneficial effects of exercise.

Dataset Information

Mitochondrial biogenesis in white adipose tissue mediated by JMJD1A-PGC-1 axis limits age-related metabolic disease.

Publications

Mitochondrial biogenesis in white adipose tissue mediated by JMJD1A-PGC-1 axis limits age-related metabolic disease.

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