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KMID : 0620920220540081250
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Experimental & Molecular Medicine
2022 Volume.54 No. 8 p.1250 ~ p.1261
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KLHL3 deficiency in mice ameliorates obesity, insulin resistance, and nonalcoholic fatty liver disease by regulating energy expenditure
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Jang Ju-Hong
Lee Jeong-Woong
Cho Min-Ji
Hwang Byung-Tae
Kwon Min-Gi
Kim Dong-Hwan
Lee Nam-Kyung
Lee Jang-Wook
Park Young-Jun
Yang Yong-Ryoul
Kim Jin-Chul
Kim Yong-Hoon
An Tae-Hyeon
Oh Kyoung-Jin
Bae Kwang-Hee
Park Jong-Gil
Min Jeong-Ki
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Abstract
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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 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.
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KEYWORD
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Homeostasis, Obesity
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