KLHL3 deficiency in mice ameliorates obesity, insulin resistance, and nonalcoholic fatty liver disease by regulating energy expenditure.

Experimental & molecular medicine 2022 Aug

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Obesity is a growing global epidemic that can cause serious adverse health consequences, including insulin resistance (IR) and nonalcoholic fatty liver disease (NAFLD). Obesity development can be attributed to energy imbalance and metabolic inflexibility. Here, we demonstrated that lack of Kelch-like protein 3 (KLHL3) mitigated the development of obesity, IR, and NAFLD by increasing energy expenditure. KLHL3 mutations in humans cause Gordon's hypertension syndrome; however, the role of KLHL3 in obesity was previously unknown. We examined differences in obesity-related parameters between control and Klhl3-/- mice. A significant decrease in body weight concomitant with fat</a> mass loss and improved IR and NAFLD were observed in Klhl3-/- mice fed a high-fat (HF) diet and aged. KLHL3 deficiency inhibited obesity, IR, and NAFLD by increasing energy expenditure with augmentation of O2 consumption and CO2 production. Delivering dominant-negative (DN) Klhl3 using adeno-associated virus into mice, thereby dominantly expressing DN-KLHL3 in the liver, ameliorated diet-induced obesity, IR, and NAFLD. Finally, adenoviral overexpression of DN-KLHL3, but not wild-type KLHL3, in hepatocytes revealed an energetic phenotype with an increase in the oxygen consumption rate. The present findings demonstrate a novel function of KLHL3 mutation in extrarenal tissues, such as the liver, and may provide a therapeutic target against obesity and obesity-related diseases. © 2022. The Author(s).

Citation

Ju-Hong Jang, Jeong Woong Lee, Min Ji Cho, Byungtae Hwang, Min-Gi Kwon, Dong-Hwan Kim, Nam-Kyung Lee, Jangwook Lee, Young-Jun Park, Yong Ryoul Yang, Jinchul Kim, Yong-Hoon Kim, Tae Hyeon An, Kyoung-Jin Oh, Kwang-Hee Bae, Jong-Gil Park, Jeong-Ki Min. KLHL3 deficiency in mice ameliorates obesity, insulin resistance, and nonalcoholic fatty liver disease by regulating energy expenditure. Experimental & molecular medicine. 2022 Aug;54(8):1250-1261