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Obesity is an increasingly serious epidemic worldwide characterized by an increase in the number and size of adipocytes. Adipose tissue maintains the balance between lipid storage and energy utilization. Therefore, adipose metabolism is of great significance for the prevention, treatment and intervention of obesity. Asprosin, a novel adipokine, is a circulating hormone mainly secreted by white adipose tissue. Previous studies have shown that asprosin plays a role in fasting-induced homeostasis, insulin resistance, and glucose tolerance. However, whether it can regulate the metabolism of adipose tissue itself has not been studied. This study intended to examine the roles and potential mechanisms of asprosin in adipose regulation. We first demonstrated that the expression level of asprosin was significantly downregulated in subcutaneous white adipose tissue (scWAT) of high-fat diet (HFD)-fed or cold-stimulated mice. Overexpression of asprosin in scWAT reduced heat production, decreased expression of the browning marker uncoupling protein 1 (UCP1) and other browning-related genes, along with upregulation of adipogenic gene expression. Mechanistically, we found that Nrf2 was activated upon cold exposure, but this activation was suppressed after asprosin overexpression. In primary cultured adipocytes, adenovirusmediated asprosin overexpression inhibited adipose browning and aggravated lipid deposition, while Nrf2 agonist oltipraz could reverse these changes. Our findings suggest that novel adipokine asprosin negatively regulated browning and elevate lipid deposition in adipose tissue via a Nrf2-mediated mechanism. Asprosin may be a promising target for the prevention and treatment of obesity and other metabolic diseases.

The browning of white adipose tissue predominantly emerges as an adaptation to environmental cues, such as cold exposure. The enhanced browning of adipose tissue results in improved energy and glucose homeostasis and reduced fat mass and body weight, which is greatly beneficial for the treatment of obesity and other metabolic diseases. C1q/TNF-related protein 5 (CTRP5) is a novel adipokine associated with a variety of endocrine and metabolic diseases; however, whether it can regulate the metabolism of adipose tissue itself remains unknown. In this study, we demonstrated that the expression of CTRP5 in murine subcutaneous white adipose tissue (scWAT) was significantly decreased when the mice were exposed to cold temperatures. The lentivirus-mediated overexpression of CTRP5 in mice repressed the adipose tissue browning, leading to reduced heat production, decreased expression of the browning marker uncoupling protein 1 (UCP1) and decreased browning-related gene expression. Mechanistically, we found that autophagy was inhibited after cold exposure, but this inhibition was alleviated after CTRP5 overexpression. In primary cultured adipocytes, CTRP5 suppressed UCP1 expression, whereas 3-MA (an autophagy inhibitor) rescued the suppression. All of these results demonstrated that CTRP5 is a negative regulator of adipose browning. CTRP5 exerts its effect, at least in part, by suppressing adipocyte autophagy. Our findings indicated that CTRP5 is a novel promising therapeutic target for obesity and other metabolic diseases.

Nonalcoholic steatohepatitis (NASH) is a common metabolic disorder that is a major contributor to health care expenditures worldwide. Enoyl coenzyme A hydratase 1 (ECH1) is initially recognized as a key component in mitochondrial fatty acid β-oxidation, and subsequent studies have demonstrated that it regulates multiple pathophysiological processes. However, the relationship between ECH1 and NASH has remained largely unknown. Herein, we investigated the role of ECH1 in NASH progression. Adeno-associated virus-mediated genetic engineering was used to investigate the role of ECH1. Alterations in hepatic steatosis, inflammation, fibrogenesis, oxidative stress, apoptosis, and liver injury were monitored using liver or serum samples from mice. ECH1 expression was significantly higher in human NASH biopsy specimens and in methionine choline-deficient (MCD) diet-fed mice. ECH1 overexpression significantly alleviated hepatic steatosis, inflammation, fibrogenesis, apoptosis, and oxidative stress in livers of mice. In addition, ECH1 overexpression also reduced alanine aminotransferase and proinflammatory cytokine levels in serum and triglyceride levels in livers. Consistently, ECH1 knockdown suppressed this beneficial phenotype. Mechanistically, ECH1-knockdown mice treated with ferrostatin-1 (Fer-1) showed an alleviated NASH phenotype compared with the untreated knockdown mice. Meanwhile, we detected changes in Erk signaling pathway when ECH1 was overexpressed or knocked down, which may partially explain the potential mechanism of ECH1 regulation of ferroptosis.In summary, ECH1 may ameliorate steatohepatitis by inhibiting ferroptosis. Pharmacological or genetic ECH1 activation may have potential as a future therapy for NASH.NEW & NOTEWORTHY Enoyl coenzyme A hydratase 1 (ECH1) is a key component in mitochondrial fatty acid β-oxidation and is also a well-known enzyme for lipid metabolism. However, the biological role of ECH1 in the development of NASH is still unclear. Herein, we demonstrated that ECH1 inhibits NASH by inhibiting ferroptosis, thus providing a novel target for therapeutic intervention for future treatment of NASH.

Browning of white adipose tissue (WAT) has been recognized as an important strategy for the treatment of obesity, insulin resistance, and diabetes. Enoyl coenzyme A hydratase 1 (ECH1) is a widely known enzyme involved in lipid metabolism. However, whether and how ECH1 is implicated in browning of WAT remain obscure. Adeno-associated, virus-mediated genetic engineering of ECH1 in adipose tissue was used in investigations in mouse models of obesity induced by a high-fat diet (HFD) or browning induced by cold exposure. Metabolic parameters showed that ECH1 overexpression decreased weight gain and improved insulin sensitivity and lipid profile after 8 wk of an HFD. Further work revealed that these changes were associated with enhanced energy expenditure and increased appearance of brown-like adipocytes in inguinal WAT, as verified by a remarkable increase in uncoupling protein 1 and thermogenic gene expression. In vitro, ECH1 induced brown fat-related gene expression in adipocytes differentiated from primary stromal vascular fractions, whereas knockdown of ECH1 reversed this effect. Mechanistically, ECH1 regulated the thermogenic program by inhibiting mammalian target of rapamycin signaling, which may partially explain the potential mechanism for ECH1 regulating adipose browning. In summary, ECH1 may participate in the pathology of obesity by regulating browning of WAT, which probably provides us with a new therapeutic strategy for combating obesity.