Introduction: Obesity leads to massive death worldwide by initiating numerous illnesses like Nonalcoholic Steatohepatitis (NASH), liver disease, and cardiovascular diseases. Developing new therapeutics against obesity is an emergency need. Targeting mitochondrial uncoupling protein 1 (UCP1) will provide new therapeutic strategies for drug discovery research against obesity and obesity-related disorders.  Methods: We screened UCP1 up-regulators from epigenetic drug libraries by using a previously developed Ucp1-A-GFP cellular GFP screening platform, ATP production, and mitochondrial DNA quantification.  Results: We discovered that the histone methyltransferase G9a inhibitor UNC0631 has a considerable effect on the expression of UCP1 in adipocytes when used in vitro. Here, we discovered that UNC0631 is crucial for controlling mitochondrial activity and anti-obesity. The UNC0631-treated fat cells have higher UCP1 expression at the cellular level. Taken together, in our studies, we have established an efficient in vitro cell experiment system to study the metabolic regulation of UCP1. Enhanced mitochondrial DNA, ATP synthesis, and cell survival showed that UNC0631 had a benign impact on the HEK293T cell line. As a result, UNC0631 reveals a promising therapeutic option for the treatment of diseases associated with obesity and metabolic disorders. Conclusion: In this study, we make a list of potent drug candidates from epigenetic drug libraries that can upregulate mitochondrial UCP1 gene expression and promote thermogenesis. UNC0631 improves mitochondrial function and would be an effective drug candidate to treat metabolic diseases and obesity-related diseases. Further investigation will require both the human and animal models to reveal new insight into the mechanism against obesity, metabolic diseases, or mitochondrial dysfunction-related diseases.

Background: Pioglitazone increases insulin sensitivity and improves glycemic control in type 2 diabetics. In this study, we evaluated the effects of pioglitazone on the uncoupling protein 1 (UCP1) expression in mouse brown adipose tissue (BAT), and on recovery from oxidative stress due to a high-fat diet. Methods: 30 mice were divided into three groups: group 1 received a normal diet, group 2 received a high-fat diet, and group 3 received a high-fat diet plus 30 mg kg pioglitazone. After treatment, the cholesterol, triglyceride, paraoxonase 1 (PON1), total serum antioxidant capacity (TAC), malondialdehyde (MDA), and specific activity of hepatic catalase were measured. BAT UCP1 expression was evaluated at both the mRNA and protein levels. Results: The weights differed between the groups (p<0. 05). Serum MDA was greater and TAC, liver catalase, and PON1 were less than in group 2 than in group 1 (p<0. 05). In Serum MDA was less and catalase activity was greater in group 3 than in group 2 (p<0. 05). UCP1 gene expression was less in group 2 than in group 1 (p<0. 05) but greater than in group 3 (p<0. 05). Conclusions: Pioglitazone may have a protective role in high-fat-diet-induced oxidative stress by increasing the antioxidant capacity. Moreover, it can induce weight loss by increasing UCP1 mRNA and protein expression.