Suppression of Brown Adipocyte Autophagy Improves Energy Metabolism by Regulating Mitochondrial Turnover

Kim, Dong Hwan; Kim, Jihye; Kang, Youngho; Kim, Je Seong; Yun, Sung‐Cheol; Kang, Sang‐Wook; Song, Youngsup

doi:10.3390/ijms20143520

Cited by 23 publications

(24 citation statements)

References 71 publications

(86 reference statements)

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“…It has been reported that deletion of the gene essential for autophagosome assembly, Atg7, in brown adipose tissue results in elevated levels of UCP1 [ 95 , 96 ] and improved metabolic health, as does deletion of the mitophagy-initiating protein Parkin [ 91 ]. Similarly, the whitening of brite/beige adipocytes is an autophagy-dependent process [ 46 , 47 , 70 ], and deletion or inhibition of key components of the autophagy pathway such as Atg5, Atg12, or Park2 results in elevated mitochondrial content and UCP1 levels [ 46 , 47 , 70 , 92 , [96] , [97] , [98] ].…”

Section: Discussionmentioning

confidence: 99%

“…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%

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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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Section: Discussionmentioning

confidence: 99%

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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“…Compared with the control mice, PHA-treated mice showed a sizeable increase in oxygen consumption during the dark cycle (active phase), and there was no significant difference between PHA and control groups during the light cycle (non-active phase). BAT activity is positively correlated with energy expenditure and can improve glucose metabolism ( Kim et al . 2019 ).…”

Section: Discussionmentioning

confidence: 99%

Phytohemagglutinin ameliorates HFD-induced obesity by increasing energy expenditure

Zhang

Jin

et al. 2021

Journal of Molecular Endocrinology

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Despite all modern advances in medicine, there are few reports of effective and safe drugs to treat obesity. Our objective was to screen anti-obesity natural compounds, and to verify whether they can reduce the body weight gain and investigate their molecular mechanisms. By using drug-screening methods, Phytohemagglutinin (PHA) was found to be the most anti-obesity candidate natural compound. Six-week-old C57BL/6J mice were fed with high-fat diet (HFD) and intraperitoneally injected with 0.25mg/kg PHA every day for 8 weeks. The body weight, glucose homeostasis, oxygen consumption and physical activity were assessed. We also measured the heat intensity, body temperature and the gene expression of key regulators of energy expenditure. Prevention study results showed PHA treatment not only reduced the body weight gain, but also maintained glucose homeostasis in HFD-fed mice. Further study indicated energy expenditure and uncoupling protein 1 (UCP-1) expression of brown adipose tissue (BAT) and white adipose tissue (WAT) in HFD-fed mice were significantly improved by PHA. In the therapeutic study, the similar effect was observed. PHA inhibited lipid droplet formation and up-regulated mitochondrial related genes expression during adipogenesis in vitro. UCP-1 KO mice displayed no differences in body weight, glucose homeostasis and core body temperature between PHA and control groups. Our results suggest that PHA prevent and treat obesity by increasing energy expenditure though up-regulation of BAT thermogenesis.

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“…Upon adipose-specific deletion of Atg7, WAT acquires functional (but not transcriptional) features of BAT, including an increase in the mitochondrial content and oxidative metabolism [ 82 ]. Similarly, the suppression of autophagy in BAT improves energy usage, while limiting the obese phenotype [ 83 ]. Mechanistically, these effects can be attributed to the inhibition of mitophagy, which in turn restrains the WAT to BAT conversion while reinforcing BAT metabolic peculiarities.…”

Section: Autophagy Between Obesity and Oxidative Stressmentioning

confidence: 99%

Targeting Autophagy to Counteract Obesity-Associated Oxidative Stress

Pietrocola

Pedro

2021

Antioxidants

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Reactive oxygen species (ROS) operate as key regulators of cellular homeostasis within a physiological range of concentrations, yet they turn into cytotoxic entities when their levels exceed a threshold limit. Accordingly, ROS are an important etiological cue for obesity, which in turn represents a major risk factor for multiple diseases, including diabetes, cardiovascular disorders, non-alcoholic fatty liver disease, and cancer. Therefore, the implementation of novel therapeutic strategies to improve the obese phenotype by targeting oxidative stress is of great interest for the scientific community. To this end, it is of high importance to shed light on the mechanisms through which cells curtail ROS production or limit their toxic effects, in order to harness them in anti-obesity therapy. In this review, we specifically discuss the role of autophagy in redox biology, focusing on its implication in the pathogenesis of obesity. Because autophagy is specifically triggered in response to redox imbalance as a quintessential cytoprotective mechanism, maneuvers based on the activation of autophagy hold promises of efficacy for the prevention and treatment of obesity and obesity-related morbidities.

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Suppression of Brown Adipocyte Autophagy Improves Energy Metabolism by Regulating Mitochondrial Turnover

Cited by 23 publications

References 71 publications

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

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

Phytohemagglutinin ameliorates HFD-induced obesity by increasing energy expenditure

Targeting Autophagy to Counteract Obesity-Associated Oxidative Stress

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