KLHL3 deficiency in mice ameliorates obesity, insulin resistance, and nonalcoholic fatty liver disease by regulating energy expenditure
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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.
Abstract
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.
참고문헌 (34)
- Narayanaswami, V., "Obesity : current and potential pharmacotherapeutics and targets", Pharmacol. Ther, 170, pp.116~147 (2017)
- Saltiel, A. R., "New therapeutic approaches for the treatment of obesity", Sci. Transl. Med, 8, pp.323rv322~ (2016)
- Bessesen, D. H., "Progress and challenges in anti-obesity pharmacotherapy", Lancet Diabetes Endocrinol, 6, pp.237~248 (2018)
- Tilg, H., "NAFLD and diabetes mellitus", Nat. Rev. Gastroenterol. Hepatol, 14, pp.32~42 (2017)
- Eguchi, Y., "Visceral fat accumulation and insulin resistance are important factors in nonalcoholic fatty liver disease", J. Gastroenterol, 41, pp.462~469 (2006)
- Rogge, M. M., "Biology of obesity and weight regain: implications for clinical practice", J. Am. Assoc. Nurse Pr, 29, pp.S15~S29 (2017)
- Goodpaster, B. H., "Metabolic flexibility in health and disease", Cell Metab, 25, pp.1027~1036 (2017)
- Liu, R., "Gut microbiome and serum metabolome alterations in obesity and after weight-loss intervention", Nat. Med, 23, pp.859~868 (2017)
- Shimomura, I., "Leptin reverses insulin resistance and diabetes mellitus in mice with congenital lipodystrophy", Nature, 401, pp.73~76 (1999)
- Bournat, J. C., "Mitochondrial dysfunction in obesity", Curr. Opin. Endocrinol. Diabetes Obes, 17, pp.446~452 (2010)
- Jayashankar, V., "Drug-like sphingolipid SH-BC-893 opposes ceramideinduced mitochondrial fission and corrects diet-induced obesity", EMBO Mol. Med, 13, pp.e13086~ (2021)
- Boyden, L. M., "Mutations in kelch-like 3 and cullin 3 cause hypertension and electrolyte abnormalities", Nature, 482, pp.98~102 (2012)
- Ohta, A., "The CUL3-KLHL3 E3 ligase complex mutated in Gordon’s hypertension syndrome interacts with and ubiquitylates WNK isoforms : diseasecausing mutations in KLHL3 and WNK4 disrupt interaction", Biochem. J, 451, pp.111~122 (2013)
- McCormick, J. A., "Hyperkalemic hypertension-associated cullin 3 promotes WNK signaling by degrading KLHL3", J. Clin. Invest, 124, pp.4723~4736 (2014)
- Pathare, G., "A molecular update on pseudohypoaldosteronism type II", Am. J. Physiol. Ren. Physiol, 305, pp.F1513~F1520 (2013)
- Takahashi, D., "WNK4 is an adipogenic factor and its deletion reduces dietinduced obesity in mice", EBioMedicine, 18, pp.118~127 (2017)
- Sasaki, E., "KLHL3 knockout mice reveal the physiological role of KLHL3 and the pathophysiology of pseudohypoaldosteronism type II caused by mutant KLHL3", Mol. Cell Biol, 37, pp.e00508~e00516 (2017)
- Uhlen, M., "Proteomics. Tissue-based map of the human proteome", Science, 347, pp.1260419~ (2015)
- Park, J. G., "CREBH-FGF21 axis improves hepatic steatosis by suppressing adipose tissue lipolysis", Sci. Rep, 6, pp.27938~ (2016)
- Suski, J. M., "Isolation of plasma membrane-associated membranes from rat liver", Nat. Protoc, 9, pp.312~322 (2014)
- Susa, K., "Impaired degradation of WNK1 and WNK4 kinases causes PHAII in mutant KLHL3 knock-in mice", Hum. Mol. Genet, 23, pp.5052~5060 (2014)
- De Lorenzo, A., "Why primary obesity is a disease?", J. Transl. Med, 17, pp.169~ (2019)
- Jastreboff, A. M., "Obesity as a disease : the obesity society 2018 position statement", Obes. (Silver Spring), 27, pp.7~9 (2019)
- Bays, H. E., "Pathogenic potential of adipose tissue and metabolic consequences of adipocyte hypertrophy and increased visceral adiposity", Expert Rev. Cardiovasc. Ther, 6, pp.343~368 (2008)
- Bays, H., "Adiposopathy is a more rational treatment target for metabolic disease than obesity alone", Curr. Atheroscler. Rep, 8, pp.144~156 (2006)
- Council of the Obesity, S., "Obesity as a disease : the Obesity Society Council resolution", Obes. (Silver Spring), 16, pp.1151~ (2008)
- Finkelstein, E. A., "Obesity and severe obesity forecasts through 2030", Am. J. Prev. Med, 42, pp.563~570 (2012)
- Jequier, E., "Leptin signaling, adiposity, and energy balance", Ann. N. Y. Acad. Sci, 967, pp.379~388 (2002)
- Masayuki Saito, "Brown Adipose Tissue as a Regulator of Energy Expenditure and Body Fat in Humans", Diabetes and Metabolism Journal, 37(1), pp.22~29 (2013), 대한당뇨병학회[DOI]
- Minokoshi, Y., "Leptin stimulates fatty-acid oxidation by activating AMPactivated protein kinase", Nature, 415, pp.339~343 (2002)
- Yamauchi, T., "Adiponectin stimulates glucose utilization and fatty-acid oxidation by activating AMP-activated protein kinase", Nat. Med, 8, pp.1288~1295 (2002)
- Minokoshi, Y., "AMP-kinase regulates food intake by responding to hormonal and nutrient signals in the hypothalamus", Nature, 428, pp.569~574 (2004)
- Kahn, B. B., "AMP-activated protein kinase : ancient energy gauge provides clues to modern understanding of metabolism", Cell Metab, 1, pp.15~25 (2005)
- Louis-Dit-Picard, H., "KLHL3 mutations cause familial hyperkalemic hypertension by impairing ion transport in the distal nephron", Nat. Genet, 44, pp.S451~S453 (2012)