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Published on: July 1, 2021
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Mitophagy deficiency increases NLRP3 to induce brown fat dysfunction in mice
Myoung Seok Ko1, Ji Young Yun1,2, In-Jeoung Baek1
1Biomedical Research Center, Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
Autophagy
|May 14, 2020
Summary
Mice lacking the Parkinson disease-related gene PINK1 in brown adipose tissue develop obesity. This study reveals a new mitochondria-NLRP3 pathway driving brown adipose tissue dysfunction, highlighting NLRP3 as a therapeutic target for metabolic diseases.
Area of Science:
- Cellular and Molecular Biology
- Metabolic and Endocrine Disorders
- Immunology
Background:
- Autophagy deficiency typically causes degenerative diseases, but its absence in adipocytes paradoxically reduces body weight.
- Brown adipose tissue (BAT) is crucial for metabolic control, yet the mechanisms maintaining its function are not fully understood.
- PTEN induced putative kinase 1 (PINK1) is involved in selective mitochondrial autophagy (mitophagy) and linked to Parkinson disease.
Purpose of the Study:
- To investigate the role of PINK1 and mitophagy in maintaining brown adipose tissue (BAT) function and whole-body energy metabolism.
- To elucidate the cellular mechanisms by which PINK1 deficiency impacts BAT and contributes to obesity.
- To identify potential therapeutic targets for obesity-related metabolic diseases.
Main Methods:
- Generated global and brown adipocyte-specific PINK1 knockout (KO) mouse models.
- Analyzed BAT dysfunction, adipocyte differentiation, and gene expression profiles in PINK1 KO mice.
- Investigated the role of the NLRP3 inflammasome by generating and studying nlrp3 deletion in PINK1 KO mice and atg7 KO mice.
Main Results:
- PINK1 deletion in adipocytes induced BAT dysfunction and an obesity-prone phenotype in mice.
- NLRP3 was induced in brown adipocyte precursors (BAPs) lacking PINK1, leading to white-like adipocyte differentiation and repression of brown adipocyte markers.
- NLRP3 deletion reversed BAT dysfunction in PINK1 KO mice, while ATG7 deletion in adipose tissue reduced NLRP3 expression in BAT.
Conclusions:
- Mitophagy, regulated by PINK1, plays a distinct role in adipose tissue function compared to general autophagy.
- A novel mitochondria-NLRP3 pathway was identified that promotes BAT dysfunction and obesity.
- NLRP3 exhibits a specific transcriptional function in adipocyte differentiation, presenting a potential therapeutic target for obesity and related metabolic diseases.
