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      Activation of AMP-Activated Protein Kinase-Sirtuin 1 Pathway Contributes to Salvianolic Acid A-Induced Browning of White Adipose Tissue in High-Fat Diet Fed Male Mice

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          Abstract

          Background: Salvianolic acid A (Sal A), a natural polyphenolic compound extracted from Radix Salvia miltiorrhiza (Danshen), exhibits exceptional pharmacological activities against cardiovascular diseases. While a few studies have reported anti-obesity properties of Sal A, the underlying mechanisms are largely unknown. Given the prevalence of obesity and promising potential of browning of white adipose tissue to combat obesity, recent research has focused on herbal ingredients that may promote browning and increase energy expenditure.

          Purpose: The present study was designed to investigate the protective antiobesity mechanisms of Sal A, in part through white adipose browning.

          Methods: Both high-fat diet (HFD)-induced obese (DIO) male mice model and fully differentiated C3H10T1/2 adipocytes from mouse embryo fibroblasts were employed in this study. Sal A (20 and 40 mg/kg) was administrated to DIO mice by intraperitoneal injection for 13-weeks. Molecular mechanisms mediating effects of Sal A were evaluated.

          Resluts: Sal A treatment significantly attenuated HFD-induced weight gain and lipid accumulation in epididymal fat pad. Uncoupling protein 1 (UCP-1), a specialized thermogenic protein and marker for white adipocyte browning, was significantly induced by Sal A treatment in both white adipose tissues and cultured adipocytes. Further mechanistic investigations revealed that Sal A robustly reversed HFD-decreased AMP-activated protein kinase (AMPK) phosphorylation and sirtuin 1 (SIRT1) expression in mice. Genetically silencing either AMPK or SIRT1 using siRNA abolished UCP-1 upregulation by Sal A. AMPK silencing significantly blocked Sal A-increased SIRT1 expression, while SIRT1 silencing did not affect Sal A-upregulated phosphorylated-AMPK. These findings indicate that AMPK was involved in Sal A-increased SIRT1.

          Conclusion: Sal A increases white adipose tissue browning in HFD-fed male mice and in cultured adipocytes. Thus, Sal is a potential natural therapeutic compound for treating and/or preventing obesity.

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          Most cited references55

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          Brown and beige fat: development, function and therapeutic potential.

          Adipose tissue, best known for its role in fat storage, can also suppress weight gain and metabolic disease through the action of specialized, heat-producing adipocytes. Brown adipocytes are located in dedicated depots and express constitutively high levels of thermogenic genes, whereas inducible 'brown-like' adipocytes, also known as beige cells, develop in white fat in response to various activators. The activities of brown and beige fat cells reduce metabolic disease, including obesity, in mice and correlate with leanness in humans. Many genes and pathways that regulate brown and beige adipocyte biology have now been identified, providing a variety of promising therapeutic targets for metabolic disease.
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            AMPK: Sensing Glucose as well as Cellular Energy Status.

            Mammalian AMPK is known to be activated by falling cellular energy status, signaled by rising AMP/ATP and ADP/ATP ratios. We review recent information about how this occurs but also discuss new studies suggesting that AMPK is able to sense glucose availability independently of changes in adenine nucleotides. The glycolytic intermediate fructose-1,6-bisphosphate (FBP) is sensed by aldolase, which binds to the v-ATPase on the lysosomal surface. In the absence of FBP, interactions between aldolase and the v-ATPase are altered, allowing formation of an AXIN-based AMPK-activation complex containing the v-ATPase, Ragulator, AXIN, LKB1, and AMPK, causing increased Thr172 phosphorylation and AMPK activation. This nutrient-sensing mechanism activates AMPK but also primes it for further activation if cellular energy status subsequently falls. Glucose sensing at the lysosome, in which AMPK and other components of the activation complex act antagonistically with another key nutrient sensor, mTORC1, may have been one of the ancestral roles of AMPK.
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              Brown remodeling of white adipose tissue by SirT1-dependent deacetylation of Pparγ.

              Brown adipose tissue (BAT) can disperse stored energy as heat. Promoting BAT-like features in white adipose (WAT) is an attractive, if elusive, therapeutic approach to staunch the current obesity epidemic. Here we report that gain of function of the NAD-dependent deacetylase SirT1 or loss of function of its endogenous inhibitor Deleted in breast cancer-1 (Dbc1) promote "browning" of WAT by deacetylating peroxisome proliferator-activated receptor (Ppar)-γ on Lys268 and Lys293. SirT1-dependent deacetylation of Lys268 and Lys293 is required to recruit the BAT program coactivator Prdm16 to Pparγ, leading to selective induction of BAT genes and repression of visceral WAT genes associated with insulin resistance. An acetylation-defective Pparγ mutant induces a brown phenotype in white adipocytes, whereas an acetylated mimetic fails to induce "brown" genes but retains the ability to activate "white" genes. We propose that SirT1-dependent Pparγ deacetylation is a form of selective Pparγ modulation of potential therapeutic import. Copyright © 2012 Elsevier Inc. All rights reserved.
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                Author and article information

                Contributors
                Journal
                Front Pharmacol
                Front Pharmacol
                Front. Pharmacol.
                Frontiers in Pharmacology
                Frontiers Media S.A.
                1663-9812
                28 May 2021
                2021
                : 12
                : 614406
                Affiliations
                [ 1 ]School of Public Health, Zhejiang Chinese Medical University, Hangzhou, China
                [ 2 ]School of Life Science, Zhejiang Chinese Medical University, Hangzhou, China
                [ 3 ]Molecular Medicine Institute, Zhejiang Chinese Medical University, Hangzhou, China
                [ 4 ]College of Animal Science, Zhejiang University, Hangzhou, China
                [ 5 ]Department of Kinesiology and Nutrition, University of Illinois at Chicago, Chicago, IL, United States
                Author notes
                *Correspondence: Xiaobing Dou, xbdou77@ 123456gmail.com ; Songtao Li, lisongtao@ 123456zcmu.edu.cn

                Edited by: Jinyong Peng, Dalian Medical University, China

                Reviewed by: Haiyan Song, Shanghai University of Traditional Chinese Medicine, China

                Baolin Liu, China Pharmaceutical University, China

                Xingwei Liang, Guangxi University, China

                This article was submitted to Gastrointestinal and Hepatic Pharmacology, a section of the journal Frontiers in Pharmacology

                [†]

                These authors have contributed equally to this work

                Article
                614406
                10.3389/fphar.2021.614406
                8193940
                34122060
                b1863763-c082-44cc-a903-c4419205aa3b
                Copyright © 2021 Lai, Qian, Ding, Zhou, Fu, Du, Wang, Song, Li and Dou.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 06 October 2020
                : 18 May 2021
                Funding
                Funded by: National Natural Science Foundation of China 10.13039/501100001809
                Award ID: 81973041 81773981
                Funded by: Natural Science Foundation of Zhejiang Province 10.13039/501100004731
                Award ID: LR20H260001
                Categories
                Pharmacology
                Original Research

                Pharmacology & Pharmaceutical medicine
                salvianolic acid a,ampk,sirt1,adipocyte browning,obesity
                Pharmacology & Pharmaceutical medicine
                salvianolic acid a, ampk, sirt1, adipocyte browning, obesity

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