Regulation of Peroxisome Proliferator-Activated Receptor-  Activity by Mammalian Target of Rapamycin and Amino Acids in Adipogenesis

BST204 is a purified ginseng dry extract that has an inhibitory effect on lipopolysaccharide-induced inflammatory responses, but its effect on muscle atrophy is yet to be investigated. In this study, C2C12 myoblasts were induced to differentiate for three days followed by the treatment of dexamethasone (DEX), a corticosteroid drug, with vehicle or BST204 for one day and subjected to immunoblotting, immunocytochemistry, qRT-PCR and biochemical analysis for mitochondrial function. BST204 alleviates the myotube atrophic effect mediated by DEX via the activation of protein kinase B/mammalian target of rapamycin (Akt/mTOR) signaling. Through this pathway, BST204 suppresses the expression of muscle-specific E3 ubiquitin ligases contributing to the enhanced myotube formation and enlarged myotube diameter in DEX-treated myotubes. In addition, BST204 treatment significantly decreases the mitochondrial reactive oxygen species production in DEX-treated myotubes. Furthermore, BST204 improves mitochondrial function by upregulating the expression of peroxisome proliferator-activated receptor-γ coactivator-1α (PGC1α) in DEX-induced myotube atrophy. This study provides a mechanistic insight into the effect of BST204 on DEX-induced myotube atrophy, suggesting that BST204 has protective effects against the toxicity of a corticosteroid drug in muscle and promising potential as a nutraceutical remedy for the treatment of muscle weakness and atrophy.

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A Tale of Two Diseases: Exploring Mechanisms Linking Diabetes Mellitus with Alzheimer’s Disease

Journal of Alzheimer s Disease ◽

10.3233/jad-210612 ◽

2021 ◽

pp. 1-17

Author(s):

Jessica Lynn ◽

Mingi Park ◽

Christiana Ogunwale ◽

George K. Acquaah-Mensah

Keyword(s):

Diabetes Mellitus ◽

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Glycogen Synthase ◽

Mammalian Target Of Rapamycin ◽

Insulin Receptors ◽

Peroxisome Proliferator ◽

Peroxisome Proliferator Activated Receptor ◽

Main Component ◽

The Impact

Dementias, including the type associated with Alzheimer’s disease (AD), are on the rise worldwide. Similarly, type 2 diabetes mellitus (T2DM) is one of the most prevalent chronic diseases globally. Although mechanisms and treatments are well-established for T2DM, there remains much to be discovered. Recent research efforts have further investigated factors involved in the etiology of AD. Previously perceived to be unrelated diseases, commonalities between T2DM and AD have more recently been observed. As a result, AD has been labeled as “type 3 diabetes”. In this review, we detail the shared processes that contribute to these two diseases. Insulin resistance, the main component of the pathogenesis of T2DM, is also present in AD, causing impaired brain glucose metabolism, neurodegeneration, and cognitive impairment. Dysregulation of insulin receptors and components of the insulin signaling pathway, including protein kinase B, glycogen synthase kinase 3β, and mammalian target of rapamycin are reported in both diseases. T2DM and AD also show evidence of inflammation, oxidative stress, mitochondrial dysfunction, advanced glycation end products, and amyloid deposition. The impact that changes in neurovascular structure and genetics have on the development of these conditions is also being examined. With the discovery of factors contributing to AD, innovative treatment approaches are being explored. Investigators are evaluating the efficacy of various T2DM medications for possible use in AD, including but not limited to glucagon-like peptide-1 receptor agonists, and peroxisome proliferator-activated receptor-gamma agonists. Furthermore, there are 136 active trials involving 121 therapeutic agents targeting novel AD biomarkers. With these efforts, we are one step closer to alleviating the ravaging impact of AD on our communities.

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TM4SF5 Knockout Protects Mice from Diet-Induced Obesity Partly by Regulating Autophagy in Adipose Tissue

10.2337/figshare.14831082.v1 ◽

2021 ◽

Author(s):

Cheoljun Choi ◽

Yeonho Son ◽

Jinyoung Kim ◽

Yoon Keun Cho ◽

Abhirup Saha ◽

...

Keyword(s):

Adipose Tissue ◽

Oxidative Metabolism ◽

Metabolic Diseases ◽

Mammalian Target Of Rapamycin ◽

Regulatory Function ◽

Peroxisome Proliferator ◽

Peroxisome Proliferator Activated Receptor ◽

Brown Adipose ◽

Mtorc1 Signaling ◽

Mitochondrial Oxidative Metabolism

Transmembrane 4 L six family member 5 (TM4SF5) functions as a sensor for lysosomal arginine levels and activates the mammalian target of rapamycin complex 1 (mTORC1). While the mTORC1 signaling pathway plays a key role in adipose tissue metabolism, the regulatory function of TM4SF5 in adipocytes remains unclear. This study aimed to establish a TM4SF5 knockout (KO) mouse model and investigated the effects of TM4SF5 KO on mTORC1 signaling-mediated autophagy and mitochondrial metabolism in adipose tissue. TM4SF5 expression was higher in inguinal white adipose tissue (iWAT) than in brown adipose tissue and significantly upregulated by a high-fat diet (HFD). TM4SF5 KO reduced mTORC1 activation and enhanced autophagy and lipolysis in adipocytes. RNA-seq analysis of TM4SF5 KO mouse iWAT showed that the expression of genes involved in peroxisome proliferator-activated receptor alpha signaling pathways and mitochondrial oxidative metabolism was upregulated. Consequently, TM4SF5 KO reduced adiposity and increased energy expenditure and mitochondrial oxidative metabolism. TM4SF5 KO prevented HFD-induced glucose intolerance and inflammation in adipose tissue. Collectively, our study demonstrated that TM4SF5 regulates autophagy and lipid catabolism in adipose tissue and suggested that TM4SF5 could be therapeutically targeted for the treatment of obesity-related metabolic diseases.

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Amino acids regulate energy utilization through mammalian target of rapamycin complex 1 and adenosine monophosphate activated protein kinase pathway in porcine enterocytes

Animal Nutrition ◽

10.1016/j.aninu.2019.12.001 ◽

2020 ◽

Vol 6 (1) ◽

pp. 98-106

Author(s):

Hao Xiao ◽

Cuifang Zha ◽

Fangyuan Shao ◽

Li Wang ◽

Bi'e Tan

Keyword(s):

Amino Acids ◽

Protein Kinase ◽

Mammalian Target Of Rapamycin ◽

Adenosine Monophosphate ◽

Energy Utilization ◽

Target Of Rapamycin ◽

Kinase Pathway

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In Rat Hepatocytes Glucagon Increases Mammalian Target of Rapamycin Phosphorylation on Serine 2448 but Antagonizes the Phosphorylation of Its Downstream Targets Induced by Insulin and Amino Acids

Journal of Biological Chemistry ◽

10.1074/jbc.m405173200 ◽

2004 ◽

Vol 279 (41) ◽

pp. 42628-42637 ◽

Cited By ~ 38

Author(s):

Isabelle Mothe-Satney ◽

Nadine Gautier ◽

Charlotte Hinault ◽

John C. Lawrence ◽

Emmanuel Van Obberghen

Keyword(s):

Amino Acids ◽

Mammalian Target Of Rapamycin ◽

Rat Hepatocytes ◽

Target Of Rapamycin ◽

Downstream Targets

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Branched-Chain Amino Acids Enhance Premature Senescence through Mammalian Target of Rapamycin Complex I-Mediated Upregulation of p21 Protein

PLoS ONE ◽

10.1371/journal.pone.0080411 ◽

2013 ◽

Vol 8 (11) ◽

pp. e80411 ◽

Cited By ~ 21

Author(s):

Masayuki Nakano ◽

Akio Nakashima ◽

Taiki Nagano ◽

Shintaro Ishikawa ◽

Ushio Kikkawa ◽

...

Keyword(s):

Amino Acids ◽

Complex I ◽

Mammalian Target Of Rapamycin ◽

Branched Chain Amino Acids ◽

Target Of Rapamycin ◽

Premature Senescence ◽

P21 Protein ◽

Branched Chain

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Peroxisomal bifunctional enzyme binds and activates the activationfunction-1 region of the peroxisome proliferator-activated receptor α

Biochemical Journal ◽

10.1042/bj3530253 ◽

2001 ◽

Vol 353 (2) ◽

pp. 253-258 ◽

Cited By ~ 11

Author(s):

Cristiana E. JUGE-AUBRY ◽

Stéphane KUENZLI ◽

Jean-Charles SANCHEZ ◽

Denis HOCHSTRASSER ◽

Christoph A. MEIER

Keyword(s):

Amino Acids ◽

Transcriptional Activity ◽

Hormone Receptors ◽

Affinity Purification ◽

Fold Increase ◽

Activation Function ◽

Bifunctional Enzyme ◽

Peroxisome Proliferator ◽

Dependent Manner ◽

Peroxisome Proliferator Activated Receptor

The transcriptional activity of peroxisome proliferator-activated receptors (PPARs), and of nuclear hormone receptors in general, is subject to modulation by cofactors. However, most currently known co-activating proteins interact in a ligand-dependent manner with the C-terminal ligand-regulated activation function (AF)-2 domain of nuclear receptors. Since PPARα exhibits a strong constitutive transactivating function contained within an N-terminal AF-1 region, it can be speculated that a different set of cofactors might interact with this region of PPARs. An affinity purification approach was used to identify the peroxisomal enoyl-CoA hydratase/3-hydroxyacyl-CoA dehydrogenase (bifunctional enzyme, BFE) as a protein which strongly and specifically interacted with the N-terminal 92 amino acids of PPARα. ProteinŐprotein interaction assays with the cloned BFE confirmed this interaction, which could be mapped to amino acids 307Ő514 of the BFE and the N-terminal 70 amino acids of PPARα. Moreover, transient transfection experiments in hepatoma cells revealed a 2.2-fold increase in the basal and ligand-stimulated transcriptional activity of PPARα in the presence of BFE. This stimulatory effect is preferentially observed for the PPARα isoform and it is significantly stronger (4.8-fold) in non-hepatic cells, which presumably express lower levels of endogenous BFE. Hence, the BFE represents the first known cofactor capable of activating the AF-1 domain of PPAR without requiring additional regions of this receptor. These data are compatible with a model whereby the PPAR-regulated BFE is able to modulate its own expression through an enhancement of the activity of PPARα, representing a novel peroxisomalŐnuclear feed-forward regulatory loop.

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