A newly identified compound activating UCP1 inhibits obesity and its related metabolic disorders
Ken Onodera
Division of Diabetes, Metabolism and Endocrinology, Department of Internal Medicine, Iwate Medical University, Yahaba, Japan
Search for more papers by this authorCorresponding Author
Yutaka Hasegawa
Division of Diabetes, Metabolism and Endocrinology, Department of Internal Medicine, Iwate Medical University, Yahaba, Japan
Correspondence Yutaka Hasegawa, Iwate Medical University, 2-1-1 Idaidori, Yahaba, Iwate, 028-3695, Japan
Email: [email protected]
Search for more papers by this authorNozomi Yokota
Division of Diabetes, Metabolism and Endocrinology, Department of Internal Medicine, Iwate Medical University, Yahaba, Japan
Search for more papers by this authorShukuko Tamura
Division of Diabetes, Metabolism and Endocrinology, Department of Internal Medicine, Iwate Medical University, Yahaba, Japan
Search for more papers by this authorHirofumi Kinno
Division of Diabetes, Metabolism and Endocrinology, Department of Internal Medicine, Iwate Medical University, Yahaba, Japan
Search for more papers by this authorIwao Takahashi
Division of Molecular and Cellular Pharmacology, Department of Pathophysiology and Pharmacology, School of Pharmacy, Iwate Medical University, Yahaba, Japan
Search for more papers by this authorHiraku Chiba
Division of Diabetes, Metabolism and Endocrinology, Department of Internal Medicine, Iwate Medical University, Yahaba, Japan
Search for more papers by this authorHirotatsu Kojima
Drug Discovery Initiative, The University of Tokyo, Tokyo, Japan
Search for more papers by this authorHideki Katagiri
Department of Diabetes and Metabolism, Tohoku University Graduate School of Medicine, Tohoku University Hospital, Sendai, Japan
Search for more papers by this authorKoji Nata
Division of Medical Biochemistry, School of Pharmacy, Iwate Medical University, Yahaba, Japan
Search for more papers by this authorYasushi Ishigaki
Division of Diabetes, Metabolism and Endocrinology, Department of Internal Medicine, Iwate Medical University, Yahaba, Japan
Search for more papers by this authorKen Onodera
Division of Diabetes, Metabolism and Endocrinology, Department of Internal Medicine, Iwate Medical University, Yahaba, Japan
Search for more papers by this authorCorresponding Author
Yutaka Hasegawa
Division of Diabetes, Metabolism and Endocrinology, Department of Internal Medicine, Iwate Medical University, Yahaba, Japan
Correspondence Yutaka Hasegawa, Iwate Medical University, 2-1-1 Idaidori, Yahaba, Iwate, 028-3695, Japan
Email: [email protected]
Search for more papers by this authorNozomi Yokota
Division of Diabetes, Metabolism and Endocrinology, Department of Internal Medicine, Iwate Medical University, Yahaba, Japan
Search for more papers by this authorShukuko Tamura
Division of Diabetes, Metabolism and Endocrinology, Department of Internal Medicine, Iwate Medical University, Yahaba, Japan
Search for more papers by this authorHirofumi Kinno
Division of Diabetes, Metabolism and Endocrinology, Department of Internal Medicine, Iwate Medical University, Yahaba, Japan
Search for more papers by this authorIwao Takahashi
Division of Molecular and Cellular Pharmacology, Department of Pathophysiology and Pharmacology, School of Pharmacy, Iwate Medical University, Yahaba, Japan
Search for more papers by this authorHiraku Chiba
Division of Diabetes, Metabolism and Endocrinology, Department of Internal Medicine, Iwate Medical University, Yahaba, Japan
Search for more papers by this authorHirotatsu Kojima
Drug Discovery Initiative, The University of Tokyo, Tokyo, Japan
Search for more papers by this authorHideki Katagiri
Department of Diabetes and Metabolism, Tohoku University Graduate School of Medicine, Tohoku University Hospital, Sendai, Japan
Search for more papers by this authorKoji Nata
Division of Medical Biochemistry, School of Pharmacy, Iwate Medical University, Yahaba, Japan
Search for more papers by this authorYasushi Ishigaki
Division of Diabetes, Metabolism and Endocrinology, Department of Internal Medicine, Iwate Medical University, Yahaba, Japan
Search for more papers by this authorKen Onodera and Yutaka Hasegawa contributed equally to this work.
Abstract
Objective
Promoting thermogenesis in adipose tissue has been a promising strategy against obesity and related metabolic complications. We aimed to identify compounds that promote thermogenesis in adipocytes and to elucidate their functions and roles in metabolism.
Methods
To identify compounds that directly promote thermogenesis from a structurally diverse set of 4800 compounds, we utilized a cell-based platform for high-throughput screening that induces uncoupling protein 1 (Ucp1) expression in adipocytes.
Results
We identified one candidate compound that activates UCP1. Additional characterization of this compound revealed that it induced cellular thermogenesis in adipocytes with negligible cytotoxicity. In a subsequent diet-induced obesity model, mice treated with this compound exhibited a slower rate of weight gain, improved insulin sensitivity, and increased energy expenditure. Mechanistic studies have revealed that this compound increases mitochondrial biogenesis by elevating maximal respiration, which is partly mediated by the protein kinase A (PKA)-p38 mitogen-activated protein kinase (MAPK) signaling pathway. A further comprehensive genetic analysis of adipocytes treated with these compounds identified two novel UCP1-dependent thermogenic genes, potassium voltage-gated channel subfamily C member 2 (Kcnc2) and predicted gene 5627 (Gm5627).
Conclusions
The identified compound can serve as a potential therapeutic drug for the treatment of obesity and its related metabolic disorders. Furthermore, our newly clarified thermogenic genes play an important role in UCP1-dependent thermogenesis in adipocytes.
CONFLICT OF INTEREST STATEMENT
The authors declared no conflict of interest.
Supporting Information
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| oby23948-sup-0001-supinfo.docxWord 2007 document , 693.9 KB | Data S1. Supporting Information |
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