Abstract
Brown adipose tissue (BAT), an organ that burns energy through uncoupling thermogenesis, is a promising therapeutic target for obesity. However, there are still no safe anti-obesity drugs that target BAT in the market. In the current study, we performed large scale screening of 636 compounds which were approved by Food and Drug Administration (FDA) to find drugs that could significantly increase uncoupling protein 1 (UCP1) mRNA expression by real-time PCR. Among those UCP1 activators, most of them were antibiotics or carcinogenic compounds. We paid particular attention to fluvastatin sodium (FS), because as an inhibitor of the cellular hydroxymethyl glutaryl coenzyme A (HMG-CoA) reductase, FS has already been approved for treatment of hypercholesteremia. We found that in the cellular levels, FS treatment significantly increased UCP1 expression and BAT activity in human brown adipocytes. Consistently, the expression of oxidative phosphorylation-related genes was significantly increased upon FS treatment without differences in adipogenic gene expression. Furthermore, FS treatment resisted to high-fat diet (HFD)-induced body weight gain by activating BAT in the mice model. In addition, administration of FS significantly increased energy expenditure, improved glucose homeostasis and ameliorated hepatic steatosis. Furthermore, we reveal that FS induced browning in subcutaneous white adipose tissue (sWAT) known to have a beneficial effect on energy metabolism. Taken together, our results clearly demonstrate that as an effective BAT activator, FS may have great potential for treatment of obesity and related metabolic disorders.
Highlights
Obesity, an increasing and serious worldwide problem, is mainly responsible for the development of type 2 diabetes and metabolic syndrome
To discover safe brown adipose tissue (BAT) activators, we screened 636 compounds that have already been approved by Food and Drug Administration (FDA) for treating various diseases that could induce uncoupling protein 1 (UCP1) expression examined by qRT-PCR in human primary BAT cells
BAT is characterized by abundant mitochondria, which are the main implementor of thermogenesis
Summary
An increasing and serious worldwide problem, is mainly responsible for the development of type 2 diabetes and metabolic syndrome. Many studies have shown that obesity can induce a series of metabolic diseases, such as insulin resistance, type 2 diabetes, fatty liver, high cholesterol, high blood pressure, cardiovascular disease, polycystic ovary syndrome, inflammation, and cancer [1,2,3,4]. Improving BAT activity via small molecules may be feasible for clinical application. Cold stimulation [11], sympathetic input, catecholamine neurotransmission, thyroid hormones, cytokines, and small molecules, such as rutin [12], have been reported as activators of BAT [13,14,15]. Rutin is a BAT activator that we have recently discovered, whereas its low solubility and bioavailability limit its clinical application
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