Mitophagy deficiency increases NLRP3 to induce brown fat dysfunction in mice.

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.Abbreviations ACTB actin, beta; BAPs brown adipocyte precursors; BAT brown adipose tissue; BMDMs bone marrow-derived macrophages; CASP1 caspase 1; CEBPA CCAAT/enhancer binding protein (C/EBP), alpha; ChIP chromatin immunoprecipitation; EE energy expenditure; HFD high-fat diet; IL1B interleukin 1 beta; ITT insulin tolerance test; KO knockout; LPS lipopolysaccharide; NLRP3 NLR family, pyrin domain containing 3; PINK1 PTEN induced putative kinase 1; PRKN parkin RBR E3 ubiquitin protein ligase; RD regular diet; ROS reactive oxygen species; RT room temperature; UCP1 uncoupling protein 1 (mitochondrial, proton carrier); WT wild-type.