Abstract
DJ-1 protein is involved in multiple physiological processes, including Parkinson’s disease. However, the role of DJ-1 in the metabolism is largely unknown. Here we found that DJ-1 maintained energy balance and glucose homeostasis via regulating brown adipose tissue (BAT) activity. DJ-1-deficient mice reduced body mass, increased energy expenditure and improved insulin sensitivity. DJ-1 deletion also resisted high-fat-diet (HFD) induced obesity and insulin resistance. Accordingly, DJ-1 transgene triggered autonomous obesity and glucose intolerance. Further BAT transplantation experiments clarified DJ-1 regulates energy and glucose homeostasis by modulating BAT function. Mechanistically, we found that DJ-1 promoted PTEN proteasomal degradation via an E3 ligase, mind bomb-2 (Mib2), which led to Akt activation and inhibited FoxO1-dependent Ucp1 (Uncoupling protein-1) expression in BAT. Consistently, ablation of Akt1 mitigated the obesity and BAT dysfunction induced by DJ-1 transgene. These findings define a new biological role of DJ-1 protein in regulating BAT function, with an implication of the therapeutic target in the treatment of metabolic disorders.
Highlights
Obesity occurs when energy intake exceeds energy expenditure [1]
Further examination showed that the reduction in the percentage of body fat in DJ-1 KO mice was mainly due to a reduction in the mass of epididymal white adipose tissue, subcutaneous white adipose tissue and brown adipose tissue (BAT), but not other tissues, without lower free fatty acid (FFA) in plasma (Supplementary Figure S1A–D)
These results indicate that deletion of DJ-1 affects adipose tissue composition
Summary
Obesity occurs when energy intake exceeds energy expenditure [1]. Obesity has reached epidemic proportions worldwide and is accompanied by a series of metabolic diseases including type II diabetes, hepatic steatosis and cardiovascular diseases [2]. Recent evidence indicates that mutations in the DJ-1 gene are associated with early-onset Parkinsonism [16]. DJ-1 could be connected with two other Parkinson disease-related genes; Parkin and Pten-induced putative kinase 1 (PINK1) to form the E3 ligase complex, thereby promoting the degradation of unfolded proteins and Parkinsonism [17]. Parkin and PINK1 are reported to be involved in the regulation of lipid metabolism [18, 19]
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