Mitophagy Deficiency Increases NLRP3 To Induce Brown Fat Dysfunction in Mice

Authors

Myoung Seok Ko
Ji Young Yun
In-Jeoung Baek
Jung Eun Jang
Jung Jin Hwang
Seung Eun Lee
Seung-Ho Heo
David A Bader
Chul-Ho Lee
Jaeseok Han
Jong-Seok Moon
Jae Man Lee
Eun-Gyoung Hong
In-Kyu Lee
Seong Who Kim
Joong Yeol Park
Sean M Hartig
Un Jung Kang
David D Moore
Eun Hee Koh
Ki-Up Lee

Publication Date

5-1-2021

Journal

Autophagy

DOI

10.1080/15548627.2020.1753002

PMID

32400277

PMCID

PMC8143238

PubMedCentral® Posted Date

5-17-2021

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes

Keywords

Adipocytes, Adipose Tissue, Brown, Animals, Autophagy, Energy Metabolism, Inflammasomes, Mice, Knockout, Mitochondria, Mitophagy, NLR Family, Pyrin Domain-Containing 3 Protein, Reactive Oxygen Species, Mice. Brown adipocyte, inflammasome, pink1, transcriptional activation, white adipocyte

Abstract

Although macroautophagy/autophagy deficiency causes degenerative diseases, the deletion of essential autophagy genes in adipocytes paradoxically reduces body weight. Brown adipose tissue (BAT) plays an important role in body weight regulation and metabolic control. However, the key cellular mechanisms that maintain BAT function remain poorly understood. in this study, we showed that global or brown adipocyte-specific deletion of pink1, a Parkinson disease-related gene involved in selective mitochondrial autophagy (mitophagy), induced BAT dysfunction, and obesity-prone type in mice. Defective mitochondrial function is among the upstream signals that activate the NLRP3 inflammasome. NLRP3 was induced in brown adipocyte precursors (BAPs) from pink1 knockout (KO) mice. Unexpectedly, NLRP3 induction did not induce canonical inflammasome activity. Instead, NLRP3 induction led to the differentiation of pink1 KO BAPs into white-like adipocytes by increasing the expression of white adipocyte-specific genes and repressing the expression of brown adipocyte-specific genes. nlrp3 deletion in pink1 knockout mice reversed BAT dysfunction. Conversely, adipose tissue-specific atg7 KO mice showed significantly lower expression of Nlrp3 in their BAT. Overall, our data suggest that the role of mitophagy is different from general autophagy in regulating adipose tissue and whole-body energy metabolism. Our results uncovered a new mitochondria-NLRP3 pathway that induces BAT dysfunction. The ability of the nlrp3 knockouts to rescue BAT dysfunction suggests the transcriptional function of NLRP3 as an unexpected, but a quite specific therapeutic target for obesity-related metabolic diseases.

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