The adipose tissue of mammals represents an important energy-storing and endocrine organ, and its dysfunction is relevant to the onset of several health problems, including non-alcoholic fatty liver disease (NAFLD). H...The adipose tissue of mammals represents an important energy-storing and endocrine organ, and its dysfunction is relevant to the onset of several health problems, including non-alcoholic fatty liver disease (NAFLD). However, whether treatments targeting adipose dysfunction could alleviate NAFLD has not been well-studied. Adrenomedullin 2 (ADM2), belonging to the CGRP superfamily, is a protective peptide that has been shown to inhibit adipose dysfunction. To investigate the adipose tissue-specific effects of ADM2 on NAFLD, adipose-specific ADM2-overexpressing transgenic (aADM2-tg) mice were developed. When fed a high-fat diet, aADM2-tg mice displayed decreased hepatic triglyceride accumulation compared to wild-type mice, which was attributable to the inhibition of hepatic de novo lipogenesis. Results from lipidomics studies showed that ADM2 decreased ceramide levels in adipocytes through the upregulation of ACER2, which catalyzes ceramide catabolism. Mechanically, activation of adipocyte HIF2α was required for ADM2 to promote ACER2-dependent adipose ceramide catabolism as well as to decrease hepatic lipid accumulation. This study highlights the role of ADM2 and adipose-derived ceramide in NAFLD and suggests that its therapeutic targeting could alleviate disease symptoms.展开更多
Atherosclerosis is a chronic multifactorial cardiovascular disease.Western diets have been reported to affect atherosclerosis through regulating adipose function.In high cholesterol diet-fed ApoE^(−/−)mice,adipocyte H...Atherosclerosis is a chronic multifactorial cardiovascular disease.Western diets have been reported to affect atherosclerosis through regulating adipose function.In high cholesterol diet-fed ApoE^(−/−)mice,adipocyte HIF-1αdeficiency or direct inhibition of HIF-1αby the selective pharmacological HIF-1αinhibitor PX-478 alleviates high cholesterol diet-induced atherosclerosis by reducing adipose ceramide generation,which lowers cholesterol levels and reduces inflammatory responses,resulting in improved dyslipidemia and atherogenesis.Smpd3,the gene encoding neutral sphingomyelinase,is identified as a new target gene directly regulated by HIF-1αthat is involved in ceramide generation.Injection of lentivirus-SMPD3 in epididymal adipose tissue reverses the decrease in ceramides in adipocytes and eliminates the improvements on atherosclerosis in the adipocyte HIF-1α-deficient mice.Therefore,HIF-1αinhibition may constitute a novel approach to slow atherosclerotic progression.展开更多
基金National Key Research and Development Program of China(Nos.2020YFA0803801,2022YFA0806400,and 2018YFA0800701)National Natural Science Foundation of China(Nos.81921001 and 32200949)+1 种基金project funded by China Postdoctoral Science Foundation(BX20220021,China)Xin Du and Julian Heng(Remotely Consulting,Australia)provided professional English-language editing of this article(Certificate No.2Tv2Ry7I).
文摘The adipose tissue of mammals represents an important energy-storing and endocrine organ, and its dysfunction is relevant to the onset of several health problems, including non-alcoholic fatty liver disease (NAFLD). However, whether treatments targeting adipose dysfunction could alleviate NAFLD has not been well-studied. Adrenomedullin 2 (ADM2), belonging to the CGRP superfamily, is a protective peptide that has been shown to inhibit adipose dysfunction. To investigate the adipose tissue-specific effects of ADM2 on NAFLD, adipose-specific ADM2-overexpressing transgenic (aADM2-tg) mice were developed. When fed a high-fat diet, aADM2-tg mice displayed decreased hepatic triglyceride accumulation compared to wild-type mice, which was attributable to the inhibition of hepatic de novo lipogenesis. Results from lipidomics studies showed that ADM2 decreased ceramide levels in adipocytes through the upregulation of ACER2, which catalyzes ceramide catabolism. Mechanically, activation of adipocyte HIF2α was required for ADM2 to promote ACER2-dependent adipose ceramide catabolism as well as to decrease hepatic lipid accumulation. This study highlights the role of ADM2 and adipose-derived ceramide in NAFLD and suggests that its therapeutic targeting could alleviate disease symptoms.
基金国家自然科学基金项目(No.81773894)福建省自然科学基金杰出青年项目(No.2019J06021)资助supported by the NSFC(No.81773894)the Natural Science Funds of Fujian Province for Distinguished Young Scholar(No.2019J06021)。
基金This work was supported by the National Key Research and Development Program of China(2018YFA0800700 and 2018YFC1003900)the National Natural Science Foundation of China(Nos.91857115,31925021,82022028 and 81921001).
文摘Atherosclerosis is a chronic multifactorial cardiovascular disease.Western diets have been reported to affect atherosclerosis through regulating adipose function.In high cholesterol diet-fed ApoE^(−/−)mice,adipocyte HIF-1αdeficiency or direct inhibition of HIF-1αby the selective pharmacological HIF-1αinhibitor PX-478 alleviates high cholesterol diet-induced atherosclerosis by reducing adipose ceramide generation,which lowers cholesterol levels and reduces inflammatory responses,resulting in improved dyslipidemia and atherogenesis.Smpd3,the gene encoding neutral sphingomyelinase,is identified as a new target gene directly regulated by HIF-1αthat is involved in ceramide generation.Injection of lentivirus-SMPD3 in epididymal adipose tissue reverses the decrease in ceramides in adipocytes and eliminates the improvements on atherosclerosis in the adipocyte HIF-1α-deficient mice.Therefore,HIF-1αinhibition may constitute a novel approach to slow atherosclerotic progression.
