Obesity-induced PARIS (ZNF746) accumulation in adipose progenitor cells leads to attenuated mitochondrial biogenesis and impaired adipogenesis.

White adipose tissue (WAT) is critical for whole-body energy metabolism, and its dysfunction leads to various metabolic disorders. In recent years, many studies have suggested that impaired mitochondria may contribute to obesity-related decline in adipose tissue function, but the detailed mechanisms remain unclear. To investigate these mechanisms, we carried out a comprehensive analysis of WAT from mice with diet-induced obesity. We discovered the transcription factor Parkin interactive substrate (PARIS or ZNF746), which suppresses the expression of peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α), a key regulator of mitochondrial biogenesis, to be accumulated in adipose progenitor cells from obese mice. Furthermore, we demonstrated that 3T3-L1 preadipocytes with overexpression of PARIS protein exhibited decreased mitochondrial biogenesis and impaired adipogenesis. Our results suggest that the accumulation of PARIS protein may be a novel component in the pathogenesis of obesity-related dysfunction in WAT.

Non-degradable autophagic vacuoles are indispensable for cell competition.

Cell competition is a process by which unwanted cells are eliminated from tissues. Apical extrusion is one mode whereby normal epithelial cells remove transformed cells, but it remains unclear how this process is mechanically effected. In this study, we show that autophagic and endocytic fluxes are attenuated in RasV12-transformed cells surrounded by normal cells due to lysosomal dysfunction, and that chemical manipulation of lysosomal activity compromises apical extrusion. We further find that RasV12 cells deficient in autophagy initiation machinery are resistant to elimination pressure exerted by normal cells, suggesting that non-degradable autophagic vacuoles are required for cell competition. Moreover, in vivo analysis revealed that autophagy-ablated RasV12 cells are less readily eliminated by cell competition, and remaining transformed cells destroy ductal integrity, leading to chronic pancreatitis. Collectively, our findings illuminate a positive role for autophagy in cell competition and reveal a homeostasis-preserving function of autophagy upon emergence of transformed cells.