Parkin controls brown adipose tissue plasticity in response to adaptive thermogenesis

Cairó, Montserrat; Campderrós, Laura; Gavaldà‐Navarro, Aleix; Cereijo, Rubén; Delgado‐Anglés, Alejandro; Quesada‐López, Tania; Giralt, Marta; Villarroya, Joan; Villarroya, Francesc

doi:10.15252/embr.201846832

Cited by 32 publications

(36 citation statements)

References 51 publications

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“…In parallel with the repression of autophagy, an increased UCP1 level and mitochondrial content were observed ( Figure 1 A–D), suggesting that this fast regulatory mechanism contributes to preserving cellular components that are necessary for effective thermogenesis. Our results for human beige adipocytes are consistent with the recent study in mouse BAT, claiming that the regulation of autophagy/mitophagy and thermogenesis are inverse processes [ 44 , 45 ].…”

Section: Discussionsupporting

confidence: 92%

“…Parkin is one of the major mediators of mitophagy; during the adipogenesis of immortalized 3T3-L1 adipocytes [ 52 ] and in differentiating mouse beige [ 28 ] and brown [ 45 ] adipocytes, its expression was increased. However, the exact role of Parkin in beige adipocytes has not been clarified yet, and contradictory results have been reported.…”

Section: Discussionmentioning

confidence: 99%

“…However, the exact role of Parkin in beige adipocytes has not been clarified yet, and contradictory results have been reported. Recently, Cairó et al found the downregulation of Parkin in response to thermogenic induction in mouse BAT, and the exhibition of high thermogenic activity in Parkin knockout (KO) mice [ 45 ]. Moreover, an inefficient beige-to-white adipocyte transition of inguinal WAT was found in PARK2 KO mice [ 28 ].…”

Section: Discussionmentioning

confidence: 99%

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Thermogenic Activation Downregulates High Mitophagy Rate in Human Masked and Mature Beige Adipocytes

Szatmári-Tóth

Shaw

Csomós

et al. 2020

IJMS

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Thermogenic brown and beige adipocytes oxidize metabolic substrates producing heat, mainly by the mitochondrial uncoupling protein UCP1, and can thus counteract obesity. Masked beige adipocytes possess white adipocyte-like morphology, but can be made thermogenic by adrenergic stimuli. We investigated the regulation of mitophagy upon thermogenic activation of human masked and mature beige adipocytes. Human primary abdominal subcutaneous adipose-derived stromal cells (hASCs) and Simpson–Golabi–Behmel syndrome (SGBS) preadipocytes were differentiated to white and beige adipocytes, then their cAMP-induced thermogenic potential was assessed by detecting increased expressions of UCP1, mitochondrial DNA content and respiratory chain complex subunits. cAMP increased the thermogenic potential of white adipocytes similarly to beige ones, indicating the presence of a masked beige population. In unstimulated conditions, a high autophagic flux and mitophagy rates (demonstrated by LC3 punctae and TOM20 co-immunostaining) were observed in white adipocytes, while these were lower in beige adipocytes. Silencing and gene expression experiments showed that the ongoing mitophagy was Parkin-independent. cAMP treatment led to the downregulation of mitophagy through PKA in both types of adipocytes, resulting in more fragmented mitochondria and increased UCP1 levels. Our data indicates that mitophagy is repressed upon encountering a short-term adrenergic stimulus, as a fast regulatory mechanism to provide high mitochondrial content for thermogenesis.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Thermogenic Activation Downregulates High Mitophagy Rate in Human Masked and Mature Beige Adipocytes

Szatmári-Tóth

Shaw

Csomós

et al. 2020

IJMS

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“…Accordingly, in contrast to activating brown or brite/beige mitochondrial biogenesis as a potential therapeutic strategy, mitochondrial mass may also be increased by lowering mitochondrial degradation during BAT whitening, thereby shifting the balance toward increased mitochondrial mass [ 70 ]. The major pathway of mitochondrial degradation, mitophagy, is downregulated upon cold activation of brown tissue [ 90 , 91 ] and recruitment of brite/beige adipose tissue [ 92 ]. It should however be noted that others reported elevated mitophagy under conditions of cold-induced BAT recruitment [ 77 ].…”

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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“…Non-shivering thermogenesis is a critical characteristic of cold acclimation and plays a key role in facilitating cold adaptation [7]. Brown and browning white fat are a major source of heat production from non-shivering thermogenesis [8,9]. Indeed, fat tissue can be divided into brown, white, and brown-like adipose.…”

Section: Introductionmentioning

confidence: 99%

Mitochondrial-Derived Peptide MOTS-c Increases Adipose Thermogenic Activation to Promote Cold Adaptation

Tang

Xue

et al. 2019

IJMS

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Cold exposure stress causes hypothermia, cognitive impairment, liver injury, and cardiovascular diseases, thereby increasing morbidity and mortality. Paradoxically, cold acclimation is believed to confer metabolic improvement to allow individuals to adapt to cold, harsh conditions and to protect them from cold stress-induced diseases. However, the therapeutic strategy to enhance cold acclimation remains less studied. Here, we demonstrate that the mitochondrial-derived peptide MOTS-c efficiently promotes cold adaptation. Following cold exposure, the improvement of adipose non-shivering thermogenesis facilitated cold adaptation. MOTS-c, a newly identified peptide, is secreted by mitochondria. In this study, we observed that the level of MOTS-c in serum decreased after cold stress. MOTS-c treatment enhanced cold tolerance and reduced lipid trafficking to the liver. In addition, MOTS-c dramatically upregulated brown adipose tissue (BAT) thermogenic gene expression and increased white fat “browning”. This effect might have been mediated by MOTS-c-activated phosphorylation of the ERK signaling pathway. The inhibition of ERK signaling disturbed the up-regulatory effect of MOTS-c on thermogenesis. In summary, our results indicate that MOTS-c treatment is a potential therapeutic strategy for defending against cold stress by increasing the adipose thermogenesis via the ERK pathway.

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Parkin controls brown adipose tissue plasticity in response to adaptive thermogenesis

Cited by 32 publications

References 51 publications

Thermogenic Activation Downregulates High Mitophagy Rate in Human Masked and Mature Beige Adipocytes

Thermogenic Activation Downregulates High Mitophagy Rate in Human Masked and Mature Beige Adipocytes

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

Mitochondrial-Derived Peptide MOTS-c Increases Adipose Thermogenic Activation to Promote Cold Adaptation

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