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.

Individual evaluation of aging- and caloric restriction-related changes to distinct multimeric complexes of circulating adiponectin by immunoblotting.

Adiponectin (APN), a major adipokine secreted from white adipose tissue, prevents inflammation and improves insulin sensitivity. APN exists as distinct multimeric complexes with different physiological activities, including low, middle and high molecular weight complexes (LMW, MMW and HMW, respectively) in peripheral blood. Caloric restriction (CR), an intervention that suppresses aging-related pathophysiological changes and extends lifespan, reportedly elevates the expression levels of Adipoq (encoding APN) and total circulating APN. Circulating APN levels have generally been measured using ELISA, but ELISA fails to directly and separately detect APN multimeric complexes other than HMW. Here, we aimed to evaluate the association of aging and CR with oligomerization of APN in rodent models, using immunoblotting to distinguish multimeric complexes based on molecular sizes. In mice, aging elevated plasma levels of HMW and MMW, while CR only elevated HMW. In contrast, LMW and monomeric APN levels were unchanged, suggesting that aging and CR can induce the assembly of APN oligomers in adipocytes. In rats, plasma levels of all multimeric complexes and monomeric APN were not significantly changed by aging or CR. Collectively, levels of circulating APN in mice were consistent with previous findings, whereas those of rats were partially inconsistent, probably because of experimental differences. Moreover, aging reduced Adipoq mRNA levels in mice and rats, while CR prevented this reduction only in rats. Such a discrepancy between Adipoq expression and circulating APN levels may be attributed to proteasomal regulation in adipocytes or tissue accumulation of APN. In conclusion, this study provides new findings of aging- and CR-related changes of each APN multimeric complex and underscores the importance of qualitative approaches for a greater understanding of physiological changes in APN.

Trehalose induces SQSTM1/p62 expression and enhances lysosomal activity and antioxidative capacity in adipocytes.

Adipocytes, which comprise the majority of white adipose tissue (WAT), are involved in obesity-related pathology via various mechanisms, including disturbed lysosomal enzymatic activity and accumulation of oxidative stress. Sequestosome 1 (SQSTM1/p62) is an autophagy marker that participates in antioxidative responses via the activation of nuclear factor erythroid-derived 2-like 2 (NRF2). Trehalose is a non-reducing disaccharide reported to suppress adipocyte hypertrophy in obese mice and improve glucose tolerance in humans. We recently revealed that trehalose increases SQSTM1 levels and enhances antioxidative capacity in hepatocytes. Here, to further evaluate the mechanism behind the beneficial effects of trehalose on metabolism, we examined SQSTM1 levels, autophagy, and oxidative stress in trehalose-treated adipocytes. We initially confirmed that trehalose increases SQSTM1 transcription and protein levels without affecting autophagy in adipocytes. Trehalose also elevated transcription of several lysosomal genes and the activity of cathepsin L, a lysosomal enzyme, independently of the transcription factor EB. In agreement with our data from hepatocytes, trehalose induced the nuclear translocation of NRF2 and the transcription of its downstream antioxidative genes, resulting in reduced cellular reactive oxygen species levels. Moreover, some cellular trehalose was detected in trehalose-treated adipocytes, implying that extracellular trehalose is taken into cells. These observations reveal the mechanism behind the beneficial effects of trehalose on metabolism and suggest its potential for preventing or treating obesity-related pathology.