Autophagy inhibition prevents glucocorticoid-increased adiposity via suppressing BAT whitening

Deng, Jiali; Guo, Yinlong; Yuan, Feixiang; Chen, Shanghai; Yin, Hanrui; Jiang, Xiaoxue; Jiao, Fangfang; Wang, Fenfen; Ji, Hongbin; Hu, Guohong; Ying, Hao; Chen, Yan; Zhai, Qiwei; Xiao, Fei; Guo, Feifan

doi:10.1080/15548627.2019.1628537

Cited by 57 publications

(60 citation statements)

References 51 publications

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“…The purpose of another study was to improve cell survival by increasing autophagy because glucocorticoids are a common drug used to alleviate inflammation in muscles and bones. In that study, the authors used 10-fold less glucocorticoids to treat the cells 42 . In contrast, glucocorticoids triggered defective mitophagy in this study.…”

Section: Discussionmentioning

confidence: 99%

BNIP3L/NIX-mediated mitophagy protects against glucocorticoid-induced synapse defects

et al. 2021

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Stress-induced glucocorticoids disturb mitochondrial bioenergetics and dynamics; however, instead of being removed via mitophagy, the damaged mitochondria accumulate. Therefore, we investigate the role of glucocorticoids in mitophagy inhibition and subsequent synaptic defects in hippocampal neurons, SH-SY5Y cells, and ICR mice. First, we observe that glucocorticoids decrease both synaptic density and vesicle recycling due to suppressed mitophagy. Screening data reveal that glucocorticoids downregulate BNIP3-like (BNIP3L)/NIX, resulting in the reduced mitochondrial respiration function and synaptic density. Notably, we find that glucocorticoids direct the glucocorticoid receptor to bind directly to the PGC1α promoter, downregulating its expression and nuclear translocation. PGC1α downregulation selectively decreases NIX-dependent mitophagy. Consistent with these results, NIX enhancer pre-treatment of a corticosterone-exposed mouse elevates mitophagy and synaptic density in hippocampus, improving the outcome of a spatial memory task. In conclusion, glucocorticoids inhibit mitophagy via downregulating NIX and that NIX activation represents a potential target for restoring synapse function.

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Section: Discussionmentioning

confidence: 99%

BNIP3L/NIX-mediated mitophagy protects against glucocorticoid-induced synapse defects

et al. 2021

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“…Several groups have reported increased mitochondrial mass upon genetic or pharmacological inhibition of autophagy and mitophagy in brite/beige or brown adipocytes [ 46 , 47 , 91 , 95 , 102 ]. While these models result in beneficial metabolic effects such as increased oxygen consumption, protection from diet-induced obesity, and insulin resistance, we did not observe advantageous effects on systemic metabolism caused by higher UCP1 levels and mitochondrial mass in BAT of the TFEB BAT KO mice.…”

Section: Discussionmentioning

confidence: 99%

TFEB deficiency attenuates mitochondrial degradation upon brown adipose tissue whitening at thermoneutrality

Sass

Schlein

Jaeckstein

et al. 2021

Molecular Metabolism

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Objective Brown adipose tissue (BAT) thermogenesis offers the potential to improve metabolic health in mice and humans. However, humans predominantly live under thermoneutral conditions, leading to BAT whitening, a reduction in BAT mitochondrial content and metabolic activity. Recent studies have established mitophagy as a major driver of mitochondrial degradation in the whitening of thermogenic brite/beige adipocytes, yet the pathways mediating mitochondrial breakdown in whitening of classical BAT remain largely elusive. The transcription factor EB (TFEB), a master regulator of lysosomal biogenesis and autophagy belonging to the MiT family of transcription factors, is the only member of this family that is upregulated during whitening, pointing toward a role of TFEB in whitening-associated mitochondrial breakdown. Methods We generated brown adipocyte-specific TFEB knockout mice, and induced BAT whitening by thermoneutral housing. We characterized gene and protein expression patterns, BAT metabolic activity, systemic metabolism, and mitochondrial localization using in vivo and in vitro approaches. Results Under low thermogenic activation conditions, deletion of TFEB preserves mitochondrial mass independently of mitochondriogenesis in BAT and primary brown adipocytes. However, this does not translate into elevated thermogenic capacity or protection from diet-induced obesity. Autophagosomal/lysosomal marker levels are altered in TFEB-deficient BAT and primary adipocytes, and lysosomal markers co-localize and co-purify with mitochondria in TFEB-deficient BAT, indicating trapping of mitochondria in late stages of mitophagy. Conclusion We identify TFEB as a driver of BAT whitening, mediating mitochondrial degradation via the autophagosomal and lysosomal machinery. This study provides proof of concept that interfering with the mitochondrial degradation machinery can increase mitochondrial mass in classical BAT under human-relevant conditions. However, it must be considered that interfering with autophagy may result in accumulation of non-functional mitochondria. Future studies targeting earlier steps of mitophagy or target recognition are therefore warranted.

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“…Lysosome-related autophagy regulates brown adipocyte function. Chloroquine, a weak lysosomotropic base that blocks the fusion of autophagosomes with lysosomes, blocked dexamethasoneinduced brown adipose tissue whitening and decreased the fat mass content in dexamethasone-treated mice (53,54). Bafilomycin, the autophagy repressor target of V-ATPase, increases UCP1 protein expression in primary preadipocytes (55).…”

Section: Discussionmentioning

confidence: 99%

Diphyllin Improves High-Fat Diet-Induced Obesity in Mice Through Brown and Beige Adipocytes

Duan

Jiang

et al. 2020

Front. Endocrinol.

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Brown adipose tissue (BAT) and beige adipose tissue dissipate metabolic energy and mediate nonshivering thermogenesis, thereby boosting energy expenditure. Increasing the browning of BAT and beige adipose tissue is expected to be a promising strategy for combatting obesity. Through phenotype screening of C3H10-T1/2 mesenchymal stem cells, diphyllin was identified as a promising molecule in promoting brown adipocyte differentiation. In vitro studies revealed that diphyllin promoted C3H10-T1/2 cell and primary brown/beige preadipocyte differentiation and thermogenesis, which resulted increased energy consumption. We synthesized the compound and evaluated its effect on metabolism in vivo. Chronic experiments revealed that mice fed a high-fat diet (HFD) with 100 mg/kg diphyllin had ameliorated oral glucose tolerance and insulin sensitivity and decreased body weight and fat content ratio. Adaptive thermogenesis in HFD-fed mice under cold stimulation and whole-body energy expenditure were augmented after chronic diphyllin treatment. Diphyllin may be involved in regulating the development of brown and beige adipocytes by inhibiting V-ATPase and reducing intracellular autophagy. This study provides new clues for the discovery of anti-obesity molecules from natural products.

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Autophagy inhibition prevents glucocorticoid-increased adiposity via suppressing BAT whitening

Cited by 57 publications

References 51 publications

BNIP3L/NIX-mediated mitophagy protects against glucocorticoid-induced synapse defects

BNIP3L/NIX-mediated mitophagy protects against glucocorticoid-induced synapse defects

TFEB deficiency attenuates mitochondrial degradation upon brown adipose tissue whitening at thermoneutrality

Diphyllin Improves High-Fat Diet-Induced Obesity in Mice Through Brown and Beige Adipocytes

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