vavilovВавиловский журнал генетики и селекцииVavilov Journal of Genetics and Breeding2500-3259Institute of Cytology and Genetics of Siberian Branch of the RAS10.18699/vjgb-25-88vavilov-4808Research ArticleГЕНЕТИКА ЖИВОТНЫХANIMAL GENETICSМетаболические эффекты трегалозы у мышей линии С57BL/6 с ожирением, вызванным диетой с высоким содержанием углеводов и жировMetabolic effects of trehalose in mice of the C57BL/6 strain with obesity induced by a high carbohydrate-fat dietПупышевА. Б.PupyshevA. B.

 Новосибирск 

 Novosibirsk 

pupyshevab@neuronm.ruБажанН. М.BazhanN. M.

 Новосибирск 

 Novosibirsk 

КазанцеваА. Ю.KazantsevaA. Yu.

 Новосибирск 

 Novosibirsk 

ЯковлеваТ. В.YakovlevaT. V.

 Новосибирск 

 Novosibirsk 

БеличенкоВ. М.BelichenkoV. M.

 Новосибирск 

 Novosibirsk 

ГончароваН. В.GoncharovaN. V.

 Новосибирск 

 Novosibirsk 

КороленкоТ. А.KorolenkoT. A.

 Новосибирск 

 Novosibirsk 

ТихоноваМ. А.TikhonovaM. A.

 Новосибирск 

 Novosibirsk 

Научно-исследовательский институт нейронаук и медициныРоссияScientific Research Institute of Neurosciences and MedicineRussian FederationФедеральный исследовательский центр Институт цитологии и генетики Сибирского отделения Российской академии наукРоссияInstitute of Cytology and Genetics of the Siberian Branch of the Russian Academy of SciencesRussian Federation202509102025296812818Copyright © Пупышев А.Б., Бажан Н.М., Казанцева А.Ю., Яковлева Т.В., Беличенко В.М., Гончарова Н.В., Короленко Т.А., Тихонова М.А., 20252025Пупышев А.Б., Бажан Н.М., Казанцева А.Ю., Яковлева Т.В., Беличенко В.М., Гончарова Н.В., Короленко Т.А., Тихонова М.А.Pupyshev A.B., Bazhan N.M., Kazantseva A.Y., Yakovleva T.V., Belichenko V.M., Goncharova N.V., Korolenko T.A., Tikhonova M.A.This work is licensed under a Creative Commons Attribution 4.0 License.https://vavilov.elpub.ru/jour/article/view/4808

Показано, что способность трегалозы улучшать метаболические показатели у животных с экспериментальным ожирением зависит от модели ожирения. У мышей линии db/db она снижает вес тела, уровни инсулина, глюкозы и холестерина в крови. У мышей с ожирением, вызванным потреблением высокожировой диеты, она не влияет на вес тела, но снижает уровень инсулина в крови, компенсаторно усиливая экспрессию генов инсулиновой сигнализации. Нами предпринято исследование действия трегалозы на вес и метаболические показатели у мышей линии C57BL/6 с избыточным весом, вызванным диетой с повышенным содержанием жиров и углеводов – «диетой кафетерия». Диета кафетерия включала свободный доступ на протяжении 18 недель к воде, стандартному корму, жирной пище (салу) и углеводам (сдобному печенью). Все мыши были рандомно разделены на четыре группы, содержавшиеся в разных условиях в течение 4 недель: 1) питье воды; 2) питье 3 % трегалозы; 3) диета кафетерия и питье воды; 4) диета кафетерия и питье 3 % трегалозы. Исследовали изменения массы тела, потребление корма, жидкости, пищевых калорий, биохимические показатели крови (уровень глюкозы, триглицеридов, холестерина, ЛПВП, АЛТ, креатинина), экспрессию генов углеводного обмена (Slc2a2, Insr) и аутофагии (Atg8, Becn1, Park2) в печени. Модель ожирения с помощью диеты кафетерия сопровождалась признаками метаболического синдрома, поскольку у этих мышей были повышены: масса тела (на 25 %), количество потребленных калорий (на 20 %), уровни в крови глюкозы (на 35 %), холестерина (на 66 %), триглицеридов (на 23 %). На контрольных мышей трегалоза действовала слабо, вызывая лишь снижение потребления стандартного корма и повышение потребления пищевых калорий на величину калорийности самой трегалозы. У мышей с ожирением трегалоза повышала общее число потребленных калорий и потребление печенья, но существенно не влияла на массу тела, метаболические показатели крови и экспрессию в печени генов, регулирующих транспорт глюкозы (Slc2a2), чувствительность к инсулину (Insr) и процессы аутофагии (Atg8, Becn1, Park2). Поскольку диета кафетерия является наиболее адекватной моделью формирования ожирения у людей, полученные нами результаты ставят под сомнение возможность использования трегалозы для коррекции моделируемого ожирения у людей.

The ability of trehalose to improve metabolic parameters in mice with experimental obesity has been shown to depend on the type of obesity model. In db/db mice, it reduced body weight, insulin, blood glucose, and cholesterol levels. In mice with obesity induced by high-fat dietary intake, it had no effect on body weight but reduced blood insulin levels with compensatory upregulation of insulin signaling gene expression. We studied the effect of trehalose on overweight and metabolic parameters in C57BL/6 inbred mice with obesity induced by a high carbohydrate-fat diet, the “cafeteria diet”. The cafeteria diet consisted of free access to water, standard chow, fatty foods (lard), and carbohydrates (biscuits) for 18 weeks. All mice were then randomly divided into four groups for four weeks of treatment: (1) water drinking, (2) drinking 3 % trehalose, (3) cafeteria diet and drinking water, (4) cafeteria diet and drinking 3 % trehalose. Alterations in body mass, food intake, fluid intake, dietary calories, blood biochemical parameters (glucose, triglyceride, cholesterol, HDL, ALT, creatinine levels), expression of carbohydrate metabolism (Slc2a2, Insr) and autophagy (Atg8, Becn1, Park2) genes in the liver were studied. The cafeteria diet obesity model was accompanied by some signs of metabolic syndrome as it induced an increase in body weight (by 25 %), calorie intake (by 25 %), blood levels of glucose (by 35 %), cholesterol (by 66 %), and triglycerides (by 23 %) in mice. Trehalose had little effect on control mice, causing a decrease in standard food intake and an increase in dietary caloric intake by the number of calories from trehalose itself. In obese mice, trehalose increased total caloric intake and biscuit consumption but had no substantial effect on body weight gain, blood metabolic parameters, or expression of liver genes regulating glucose transport (Slc2a2), insulin sensitivity (Insr), and autophagy processes (Atg8, Becn1, Park2). Since the cafeteria diet is the most adequate model of alimentary obesity development in humans, our results question the use of trehalose to correct the dietary type of obesity in humans.

мыши С57BL/6углеводножировая диетадиета кафетерияожирениетрегалозааутофагияПЦРглюкозатриглицеридыхолестеринC57BL/6 micecarbohydrate-fat dietcafeteria dietobesitytrehaloseautophagyqPCRglucosetriglyceridescholesterolThe work was supported by the funds of the federal budget for SRINM (theme No. 122042700001-9) and the budget project of ICG SB RAS (No. FWNR-2022-0021).ReferencesArai C., Arai N., Mizote A., Kohno K., Iwaki K., Hanaya T., Arai S., Ushio S., Fukuda S. Trehalose prevents adipocyte hypertrophy and mitigates insulin resistance. Nutr Res. 2010;30(12):840-848. doi 10.1016/j.nutres.2010.10.009Arai C., Arai N., Mizote A., Kohno K., Iwaki K., Hanaya T., Arai S., Ushio S., Fukuda S. Trehalose prevents adipocyte hypertrophy and mitigates insulin resistance. Nutr Res. 2010;30(12):840-848. doi 10.1016/j.nutres.2010.10.009Arai C., Miyake M., Matsumoto Y., Mizote A., Yoshizane C., Hanaya Y., Koide K., Yamada M., Hanaya T., Arai S., Fukuda S. Trehalose prevents adipocyte hypertrophy and mitigates insulin resistance in mice with established obesity. J Nutr Sci Vitaminol (Tokyo). 2013;59(5):393-401. doi 10.3177/jnsv.59.393Arai C., Miyake M., Matsumoto Y., Mizote A., Yoshizane C., Hanaya Y., Koide K., Yamada M., Hanaya T., Arai S., Fukuda S. Trehalose prevents adipocyte hypertrophy and mitigates insulin resistance in mice with established obesity. J Nutr Sci Vitaminol (Tokyo). 2013;59(5):393-401. doi 10.3177/jnsv.59.393Arai C., Arai N., Arai S., Yoshizane C., Miyata S., Mizote A., Suyama A., Endo S., Ariyasu T., Mitsuzumi H., Ushio S. Continuous intake of trehalose induces white adipose tissue browning and enhances energy metabolism. Nutr Metab. 2019;16:45. doi 10.1186/s12986-019-0373-4Arai C., Arai N., Arai S., Yoshizane C., Miyata S., Mizote A., Suyama A., Endo S., Ariyasu T., Mitsuzumi H., Ushio S. Continuous intake of trehalose induces white adipose tissue browning and enhances energy metabolism. Nutr Metab. 2019;16:45. doi 10.1186/s12986-019-0373-4DeBosch B.J., Heitmeier M.R., Mayer A.L., Higgins C.B., Crowley J.R., Kraft T.E., Chi M., Newberry E.P., Chen Z., Finck B.N., Davidson N.O., Yarasheski K.E., Hruz P.W., Moley K.H. Trehalose inhibits solute carrier 2A (SLC2A) proteins to induce autophagy and prevent hepatic steatosis. Sci Signal. 2016;9(416):ra21. doi 10.1126/scisignal.aac5472DeBosch B.J., Heitmeier M.R., Mayer A.L., Higgins C.B., Crowley J.R., Kraft T.E., Chi M., Newberry E.P., Chen Z., Finck B.N., Davidson N.O., Yarasheski K.E., Hruz P.W., Moley K.H. Trehalose inhibits solute carrier 2A (SLC2A) proteins to induce autophagy and prevent hepatic steatosis. Sci Signal. 2016;9(416):ra21. doi 10.1126/scisignal.aac5472Goncharova N.V., Pupyshev A.B., Filyushina E.E., Loktev K.V., Korolenko E.Ts., Lushnikova E.L., Molodykh O.P., Korolenko T.A., Churin B.V. Depression of macrophages modifies serum lipid profile in hyperlipidemia. Bull Exp Biol Med. 2016;160(5):617-621. doi 10.1007/s10517-016-3231-7Goncharova N.V., Pupyshev A.B., Filyushina E.E., Loktev K.V., Korolenko E.Ts., Lushnikova E.L., Molodykh O.P., Korolenko T.A., Churin B.V. Depression of macrophages modifies serum lipid profile in hyperlipidemia. Bull Exp Biol Med. 2016;160(5):617-621. doi 10.1007/s10517-016-3231-7Higgins C.B., Zhang Y., Mayer A.L., Fujiwara H., Stothard A.I., Graham M.J., Swarts B.M., DeBosch B.J. Hepatocyte ALOXE3 is induced during adaptive fasting and enhances insulin sensitivity by activating hepatic PPARγ. JCI Insight. 2018;3(16):e120794. doi 10.1172/jci.insight.120794Higgins C.B., Zhang Y., Mayer A.L., Fujiwara H., Stothard A.I., Graham M.J., Swarts B.M., DeBosch B.J. Hepatocyte ALOXE3 is induced during adaptive fasting and enhances insulin sensitivity by activating hepatic PPARγ. JCI Insight. 2018;3(16):e120794. doi 10.1172/jci.insight.120794Hosseinpour-Moghaddam K., Caraglia M., Sahebkar A. Autophagy induction by trehalose: molecular mechanisms and therapeutic impacts. J Cell Physiol. 2018;233(9):6524-6543. doi 10.1002/jcp.26583Hosseinpour-Moghaddam K., Caraglia M., Sahebkar A. Autophagy induction by trehalose: molecular mechanisms and therapeutic impacts. J Cell Physiol. 2018;233(9):6524-6543. doi 10.1002/jcp.26583Kobayashi M., Yasukawa H., Arikawa T., Deguchi Y., Mizushima N., Sakurai M., Onishi S., Tagawa R., Sudo Y., Okita N., Higashi K., Higami Y. Trehalose induces SQSTM1/p62 expression and enhances lysosomal activity and antioxidative capacity in adipocytes. FEBS Open Bio. 2021;11(1):185-194. doi 10.1002/2211-5463.13055Kobayashi M., Yasukawa H., Arikawa T., Deguchi Y., Mizushima N., Sakurai M., Onishi S., Tagawa R., Sudo Y., Okita N., Higashi K., Higami Y. Trehalose induces SQSTM1/p62 expression and enhances lysosomal activity and antioxidative capacity in adipocytes. FEBS Open Bio. 2021;11(1):185-194. doi 10.1002/2211-5463.13055Korolenko T.A., Dubrovina N.I., Ovsyukova M.V., Bgatova N.P., Tenditnik M.V., Pupyshev A.B., Akopyan A.A., Goncharova N.V., Lin C.L., Zavjalov E.L., Tikhonova M.A., Amstislavskaya T.G. Treatment with autophagy inducer trehalose alleviates memory and behavioral impairments and neuroinflammatory brain processes in db/db mice. Cells. 2021;10(10):2557. doi 10.3390/cells10102557Korolenko T.A., Dubrovina N.I., Ovsyukova M.V., Bgatova N.P., Tenditnik M.V., Pupyshev A.B., Akopyan A.A., Goncharova N.V., Lin C.L., Zavjalov E.L., Tikhonova M.A., Amstislavskaya T.G. Treatment with autophagy inducer trehalose alleviates memory and behavioral impairments and neuroinflammatory brain processes in db/db mice. Cells. 2021;10(10):2557. doi 10.3390/cells10102557Liu M., Zhang M., Ye H., Lin S., Yang Y., Wang L., Jones G., Trang H. Multiple toxicity studies of trehalose in mice by intragastric admini­ stration. Food Chem. 2013;136(2):485-490. doi 10.1016/j.foodchem. 2012.09.031Liu M., Zhang M., Ye H., Lin S., Yang Y., Wang L., Jones G., Trang H. Multiple toxicity studies of trehalose in mice by intragastric admini­ stration. Food Chem. 2013;136(2):485-490. doi 10.1016/j.foodchem. 2012.09.031Makarova E.N., Chepeleva E.V., Panchenko P.E., Bazhan N.M. Influence of abnormally high leptin levels during pregnancy on metabolic phenotypes in progeny mice. Am J Physiol Regul Integr Comp Physiol. 2013;305(11):R1268-R1280. doi 10.1152/ajpregu.00162.2013Makarova E.N., Chepeleva E.V., Panchenko P.E., Bazhan N.M. Influence of abnormally high leptin levels during pregnancy on metabolic phenotypes in progeny mice. Am J Physiol Regul Integr Comp Physiol. 2013;305(11):R1268-R1280. doi 10.1152/ajpregu.00162.2013Mayer A.L., Higgins C.B., Heitmeier M.R., Kraft T.E., Qian X., Crowley J.R., Hyrc K.L., Beatty W.L., Yarasheski K.E., Hruz P.W., DeBosch B.J. SLC2A8 (GLUT8) is a mammalian trehalose transporter required for trehalose-induced autophagy. Sci Rep. 2016;6: 38586. doi 10.1038/srep38586Mayer A.L., Higgins C.B., Heitmeier M.R., Kraft T.E., Qian X., Crowley J.R., Hyrc K.L., Beatty W.L., Yarasheski K.E., Hruz P.W., DeBosch B.J. SLC2A8 (GLUT8) is a mammalian trehalose transporter required for trehalose-induced autophagy. Sci Rep. 2016;6: 38586. doi 10.1038/srep38586Mizote A., Yamada M., Yoshizane C., Arai N., Maruta K., Arai S., Endo S., Ogawa R., Mitsuzumi H., Ariyasu T., Fukuda S. Daily intake of trehalose is effective in the prevention of lifestyle-related diseases in individuals with risk factors for metabolic syndrome. J Nutr Sci Vitaminol (Tokyo). 2016;62(6):380-387. doi 10.3177/jnsv. 62.380Mizote A., Yamada M., Yoshizane C., Arai N., Maruta K., Arai S., Endo S., Ogawa R., Mitsuzumi H., Ariyasu T., Fukuda S. Daily intake of trehalose is effective in the prevention of lifestyle-related diseases in individuals with risk factors for metabolic syndrome. J Nutr Sci Vitaminol (Tokyo). 2016;62(6):380-387. doi 10.3177/jnsv. 62.380Parafati M., Lascala A., Morittu V.M., Trimboli F., Rizzuto A., Brunelli E., Coscarelli F., Costa N., Britti D., Ehrlich J., Isidoro C., Mollace V., Janda E. Bergamot polyphenol fraction prevents nonalcoholic fatty liver disease via stimulation of lipophagy in cafeteria diet-induced rat model of metabolic syndrome. J Nutr Biochem. 2015;26(9):938-948. doi 10.1016/j.jnutbio.2015.03.008Parafati M., Lascala A., Morittu V.M., Trimboli F., Rizzuto A., Brunelli E., Coscarelli F., Costa N., Britti D., Ehrlich J., Isidoro C., Mollace V., Janda E. Bergamot polyphenol fraction prevents nonalcoholic fatty liver disease via stimulation of lipophagy in cafeteria diet-induced rat model of metabolic syndrome. J Nutr Biochem. 2015;26(9):938-948. doi 10.1016/j.jnutbio.2015.03.008Pelletier R.M., Layeghkhavidaki H., Vitale M.L. Glucose, insulin, insulin receptor subunits α and β in normal and spontaneously diabetic and obese ob/ob and db/db infertile mouse testis and hypophysis. Reprod Biol Endocrinol. 2020;18(1):25. doi 10.1186/s12958-020-00583-2Pelletier R.M., Layeghkhavidaki H., Vitale M.L. Glucose, insulin, insulin receptor subunits α and β in normal and spontaneously diabetic and obese ob/ob and db/db infertile mouse testis and hypophysis. Reprod Biol Endocrinol. 2020;18(1):25. doi 10.1186/s12958-020-00583-2Pugazhenthi S., Qin L., Reddy P.H. Common neurodegenerative pathways in obesity, diabetes, and Alzheimer’s disease. Biochim Biophys Acta Mol Basis Dis. 2017;1863(5):1037-1045. doi 10.1016/j.bbadis. 2016.04.017Pugazhenthi S., Qin L., Reddy P.H. Common neurodegenerative pathways in obesity, diabetes, and Alzheimer’s disease. Biochim Biophys Acta Mol Basis Dis. 2017;1863(5):1037-1045. doi 10.1016/j.bbadis. 2016.04.017Pupyshev A.B., Belichenko V.M., Tenditnik M.V., Bashirzade A.A., Dubrovina N.I., Ovsyukova M.V., Akopyan A.A., Fedoseeva L.A., Korolenko T.A., Amstislavskaya T.G., Tikhonova M.A. Combined induction of mTOR-dependent and mTOR-independent pathways of autophagy activation as an experimental therapy for Alzheimer’s disease-like pathology in a mouse model. Pharmacol Biochem Behav. 2022a;217:173406. doi 10.1016/j.pbb.2022.173406Pupyshev A.B., Belichenko V.M., Tenditnik M.V., Bashirzade A.A., Dubrovina N.I., Ovsyukova M.V., Akopyan A.A., Fedoseeva L.A., Korolenko T.A., Amstislavskaya T.G., Tikhonova M.A. Combined induction of mTOR-dependent and mTOR-independent pathways of autophagy activation as an experimental therapy for Alzheimer’s disease-like pathology in a mouse model. Pharmacol Biochem Behav. 2022a;217:173406. doi 10.1016/j.pbb.2022.173406Pupyshev A.B., Klyushnik T.P., Akopyan A.A., Singh S.K., Tikhonova M.A. Disaccharide trehalose in experimental therapies for neurodegenerative disorders: molecular targets and translational potential. Pharmacol Res. 2022b;183:106373. doi 10.1016/j.phrs.2022. 106373Pupyshev A.B., Klyushnik T.P., Akopyan A.A., Singh S.K., Tikhonova M.A. Disaccharide trehalose in experimental therapies for neurodegenerative disorders: molecular targets and translational potential. Pharmacol Res. 2022b;183:106373. doi 10.1016/j.phrs.2022. 106373Pupyshev A.B., Akopyan A.A., Tenditnik M.V., Ovsyukova M.V., Dubrovina N.I., Belichenko V.M., Korolenko T.A., Zozulya S.A., Klyushnik T.P., Tikhonova M.A. Alimentary treatment with trehalose in a pharmacological model of Alzheimer’s disease in mice: effects of different dosages and treatment regimens. Pharmaceutics. 2024;16(6):813. doi 10.3390/pharmaceutics16060813Pupyshev A.B., Akopyan A.A., Tenditnik M.V., Ovsyukova M.V., Dubrovina N.I., Belichenko V.M., Korolenko T.A., Zozulya S.A., Klyushnik T.P., Tikhonova M.A. Alimentary treatment with trehalose in a pharmacological model of Alzheimer’s disease in mice: effects of different dosages and treatment regimens. Pharmaceutics. 2024;16(6):813. doi 10.3390/pharmaceutics16060813Ren H., Wang D., Zhang L., Kang X., Li Y., Zhou X., Yuan G. Catalpol induces autophagy and attenuates liver steatosis in ob/ob and highfat diet-induced obese mice. Aging (Albany NY ). 2019;11(21):9461- 9477. doi 10.18632/aging.102396Ren H., Wang D., Zhang L., Kang X., Li Y., Zhou X., Yuan G. Catalpol induces autophagy and attenuates liver steatosis in ob/ob and highfat diet-induced obese mice. Aging (Albany NY ). 2019;11(21):9461- 9477. doi 10.18632/aging.102396Rusmini P., Cortese K., Crippa V., Cristofani R., Cicardi M.E., Ferrari V., Vezzoli G., … Galbiati M., Garrè M., Morelli E., Vaccari T., Poletti A. Trehalose induces autophagy via lysosomal-mediated TFEB activation in models of motoneuron degeneration. Autophagy. 2019; 15(4):631-651. doi 10.1080/15548627.2018.1535292Rusmini P., Cortese K., Crippa V., Cristofani R., Cicardi M.E., Ferrari V., Vezzoli G., … Galbiati M., Garrè M., Morelli E., Vaccari T., Poletti A. Trehalose induces autophagy via lysosomal-mediated TFEB activation in models of motoneuron degeneration. Autophagy. 2019; 15(4):631-651. doi 10.1080/15548627.2018.1535292Sahebkar A., Hatamipour M., Tabatabaei S.A. Trehalose administration attenuates atherosclerosis in rabbits fed a high-fat diet. J Cell Biochem. 2019;120(6):9455-9459. doi 10.1002/jcb.28221Sahebkar A., Hatamipour M., Tabatabaei S.A. Trehalose administration attenuates atherosclerosis in rabbits fed a high-fat diet. J Cell Biochem. 2019;120(6):9455-9459. doi 10.1002/jcb.28221Sarkar S. Regulation of autophagy by mTOR-dependent and mTORindependent pathways: autophagy dysfunction in neurodegenerative diseases and therapeutic application of autophagy enhancers. Biochem Soc Trans. 2013;41(5):1103-1130. doi 10.1042/BST20130134Sarkar S. Regulation of autophagy by mTOR-dependent and mTORindependent pathways: autophagy dysfunction in neurodegenerative diseases and therapeutic application of autophagy enhancers. Biochem Soc Trans. 2013;41(5):1103-1130. doi 10.1042/BST20130134Sato S., Okamoto K., Minami R., Kohri H., Yamamoto S. Trehalose can be used as a parenteral saccharide source in rabbits. J Nutrition. 1999;129(1):158-164. doi 10.1093/jn/129.1.158Sato S., Okamoto K., Minami R., Kohri H., Yamamoto S. Trehalose can be used as a parenteral saccharide source in rabbits. J Nutrition. 1999;129(1):158-164. doi 10.1093/jn/129.1.158Stachowicz A., Wiśniewska A., Kuś K., Kiepura A., Gębska A., Gaj­ da M., Białas M., Totoń-Żurańska J., Stachyra K., Suski M., Jawień J., Korbut R., Olszanecki R. The influence of trehalose on atherosclerosis and hepatic steatosis in apolipoprotein E knockout mice. Int J Mol Sci. 2019;20(7):1552. doi 10.3390/ijms20071552Stachowicz A., Wiśniewska A., Kuś K., Kiepura A., Gębska A., Gaj­ da M., Białas M., Totoń-Żurańska J., Stachyra K., Suski M., Jawień J., Korbut R., Olszanecki R. The influence of trehalose on atherosclerosis and hepatic steatosis in apolipoprotein E knockout mice. Int J Mol Sci. 2019;20(7):1552. doi 10.3390/ijms20071552Su S., Liu X., Zhu M., Liu W., Liu J., Yuan Y., Fu F., Rao Z., Liu J., Lu Y., Chen Y. Trehalose ameliorates nonalcoholic fatty liver disease by regulating IRE1α-TFEB signaling pathway. J Agric Food Chem. 2025;73(1):521-540. doi 10.1021/acs.jafc.4c08669Su S., Liu X., Zhu M., Liu W., Liu J., Yuan Y., Fu F., Rao Z., Liu J., Lu Y., Chen Y. Trehalose ameliorates nonalcoholic fatty liver disease by regulating IRE1α-TFEB signaling pathway. J Agric Food Chem. 2025;73(1):521-540. doi 10.1021/acs.jafc.4c08669Tamargo-Gómez I., Mariño G. AMPK: regulation of metabolic dynamics in the context of autophagy. Int J Mol Sci. 2018;19(12):3812. doi 10.3390/ijms19123812Tamargo-Gómez I., Mariño G. AMPK: regulation of metabolic dynamics in the context of autophagy. Int J Mol Sci. 2018;19(12):3812. doi 10.3390/ijms19123812Yaribeygi H., Yaribeygi A., Sathyapalan T., Sahebkar A. Molecular mechanisms of trehalose in modulating glucose homeostasis in diabetes. Diabetes Metab Syndr. 2019;13(3):2214-2218. doi 10.1016/j.dsx.2019.05.023Yaribeygi H., Yaribeygi A., Sathyapalan T., Sahebkar A. Molecular mechanisms of trehalose in modulating glucose homeostasis in diabetes. Diabetes Metab Syndr. 2019;13(3):2214-2218. doi 10.1016/j.dsx.2019.05.023Yoshizane C., Mizote A., Yamada M., Arai N., Arai S., Maruta K., Mitsuzumi H., Ariyasu T., Ushio S., Fukuda S. Glycemic, insulinemic and incretin responses after oral trehalose ingestion in healthy subjects. Nutr J. 2017;16(1):9. doi 10.1186/s12937-017-0233-xYoshizane C., Mizote A., Yamada M., Arai N., Arai S., Maruta K., Mitsuzumi H., Ariyasu T., Ushio S., Fukuda S. Glycemic, insulinemic and incretin responses after oral trehalose ingestion in healthy subjects. Nutr J. 2017;16(1):9. doi 10.1186/s12937-017-0233-xZhang Y., DeBosch B.J. Using trehalose to prevent and treat metabolic function: effectiveness and mechanisms. Curr Opin Clin Nutr Metab Care. 2019;22(4):303-310. doi 10.1097/MCO.0000000000000568Zhang Y., DeBosch B.J. Using trehalose to prevent and treat metabolic function: effectiveness and mechanisms. Curr Opin Clin Nutr Metab Care. 2019;22(4):303-310. doi 10.1097/MCO.0000000000000568Zhang Y., Sowers J.R., Ren J. Targeting autophagy in obesity: from pathophysiology to management. Nat Rev Endocrinol. 2018;14(6): 356-376. doi 10.1038/s41574-018-0009-1Zhang Y., Sowers J.R., Ren J. Targeting autophagy in obesity: from pathophysiology to management. Nat Rev Endocrinol. 2018;14(6): 356-376. doi 10.1038/s41574-018-0009-1Zhang Y., Higgins C.B., Fortune H.M., Chen P., Stothard A.I., Mayer A.L., Swarts B.M., DeBosch B.J. Hepatic arginase 2 (Arg2) is sufficient to convey the therapeutic metabolic effects of fasting. Nat Commun. 2019;10(1):1587. doi 10.1038/s41467-019-09642-8Zhang Y., Higgins C.B., Fortune H.M., Chen P., Stothard A.I., Mayer A.L., Swarts B.M., DeBosch B.J. Hepatic arginase 2 (Arg2) is sufficient to convey the therapeutic metabolic effects of fasting. Nat Commun. 2019;10(1):1587. doi 10.1038/s41467-019-09642-8

The authors declare that there are no conflicts of interest present.