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Vinitha T, Sharika R, Balamurugan K. Oleoylethanolamine precursor triggers lipolysis during Time-Restricted Intermittent Fasting and promotes longevity and healthy aging of Caenorhabditis elegans. J Physiol Biochem 2025:10.1007/s13105-025-01087-6. [PMID: 40332671 DOI: 10.1007/s13105-025-01087-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2025] [Accepted: 04/26/2025] [Indexed: 05/08/2025]
Abstract
Intermittent fasting (IF), Time-Restricted Intermittent Fasting (TRIF), and fasting-mimicking diets have gained popularity among weight loss programs. The body efficiently utilizes its energy reserves to activate metabolic processes in response to food intake. Modifying food regimens can alter/extend life span and promote healthy aging by activating specific metabolic processes. However, changes in general lipid metabolism, especially the alteration in N-acylethanolamide (NAE) regulation and their role in promoting lipolysis and extending life span during TRIF, are still inadequately explored. To bridge the knowledge gap, this study focuses on enhancing Oleoylethanolamine (OEA), a precursor molecule that instigates satiety, promotes lipolysis and extends the life span of model system, Caenorhabditis elegans. TRIF regimen in C. elegans induces OEA, which in turn lead to satiety followed by lipolysis and ATP synthesis. Lipolysis is stimulated by the increase in Adipose Tissue Triglyceride Lipase-1 (ATGL-1) activity that results from the enrichment in OEA precursor. In addition, the TRIF regimen induces oxidative stress resistance in C. elegans. Subsequently, this promotes longevity and slow aging in C. elegans by altering the insulin/ insulin-like growth factor signaling (IIS) pathway. The present study suggested the beneficial effects of time-restricted fasting in the eukaryotic model nematodes through the activation of lipid metabolism that involves enhanced production of OEA precursors which promotes lipolysis. In addition, the data revealed that the increased ATP production resulted in oxidative stress tolerance that promoted longevity and slow aging processes.
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Affiliation(s)
- Thondimuthu Vinitha
- Department of Biotechnology, Alagappa University, Science Campus, Karaikudi, Tamil Nadu, 630003, India
| | - Rajasekharan Sharika
- Department of Biotechnology, Alagappa University, Science Campus, Karaikudi, Tamil Nadu, 630003, India
| | - Krishnaswamy Balamurugan
- Department of Biotechnology, Alagappa University, Science Campus, Karaikudi, Tamil Nadu, 630003, India.
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2
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Chen S, Su X, Zhu J, Xiao L, Cong Y, Yang L, Du Z, Huang X. Metabolic plasticity sustains the robustness of Caenorhabditis elegans embryogenesis. EMBO Rep 2023; 24:e57440. [PMID: 37885348 PMCID: PMC10702823 DOI: 10.15252/embr.202357440] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2023] [Revised: 09/22/2023] [Accepted: 10/11/2023] [Indexed: 10/28/2023] Open
Abstract
Embryogenesis is highly dependent on maternally loaded materials, particularly those used for energy production. Different environmental conditions and genetic backgrounds shape embryogenesis. The robustness of embryogenesis in response to extrinsic and intrinsic changes remains incompletely understood. By analyzing the levels of two major nutrients, glycogen and neutral lipids, we discovered stage-dependent usage of these two nutrients along with mitochondrial morphology changes during Caenorhabditis elegans embryogenesis. ATGL, the rate-limiting lipase in cellular lipolysis, is expressed and required in the hypodermis to regulate mitochondrial function and support embryogenesis. The embryonic lethality of atgl-1 mutants can be suppressed by reducing sinh-1/age-1-akt signaling, likely through modulating glucose metabolism to maintain sustainable glucose consumption. The embryonic lethality of atgl-1(xd314) is also affected by parental nutrition. Parental glucose and oleic acid supplements promote glycogen storage in atgl-1(xd314) embryos to compensate for the impaired lipolysis. The rescue by parental vitamin B12 supplement is likely through enhancing mitochondrial function in atgl-1 mutants. These findings reveal that metabolic plasticity contributes to the robustness of C. elegans embryogenesis.
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Affiliation(s)
- Siyu Chen
- State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental BiologyChinese Academy of SciencesBeijingChina
- University of Chinese Academy of SciencesBeijingChina
| | - Xing Su
- State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental BiologyChinese Academy of SciencesBeijingChina
- University of Chinese Academy of SciencesBeijingChina
| | - Jinglin Zhu
- State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental BiologyChinese Academy of SciencesBeijingChina
- University of Chinese Academy of SciencesBeijingChina
| | - Long Xiao
- State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental BiologyChinese Academy of SciencesBeijingChina
- University of Chinese Academy of SciencesBeijingChina
| | - Yulin Cong
- State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental BiologyChinese Academy of SciencesBeijingChina
- University of Chinese Academy of SciencesBeijingChina
| | - Leilei Yang
- State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental BiologyChinese Academy of SciencesBeijingChina
- University of Chinese Academy of SciencesBeijingChina
| | - Zhuo Du
- State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental BiologyChinese Academy of SciencesBeijingChina
- University of Chinese Academy of SciencesBeijingChina
| | - Xun Huang
- State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental BiologyChinese Academy of SciencesBeijingChina
- University of Chinese Academy of SciencesBeijingChina
- Tianjian Laboratory of Advanced Biomedical SciencesZhengzhouChina
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3
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Application of Caenorhabditis elegans in Lipid Metabolism Research. Int J Mol Sci 2023; 24:ijms24021173. [PMID: 36674689 PMCID: PMC9860639 DOI: 10.3390/ijms24021173] [Citation(s) in RCA: 23] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2022] [Revised: 01/01/2023] [Accepted: 01/05/2023] [Indexed: 01/11/2023] Open
Abstract
Over the last decade, the development and prevalence of obesity have posed a serious public health risk, which has prompted studies on the regulation of adiposity. With the ease of genetic manipulation, the diversity of the methods for characterizing body fat levels, and the observability of feeding behavior, Caenorhabditis elegans (C. elegans) is considered an excellent model for exploring energy homeostasis and the regulation of the cellular fat storage. In addition, the homology with mammals in the genes related to the lipid metabolism allows many aspects of lipid modulation by the regulators of the central nervous system to be conserved in this ideal model organism. In recent years, as the complex network of genes that maintain an energy balance has been gradually expanded and refined, the regulatory mechanisms of lipid storage have become clearer. Furthermore, the development of methods and devices to assess the lipid levels has become a powerful tool for studies in lipid droplet biology and the regulation of the nematode lipid metabolism. Herein, based on the rapid progress of C. elegans lipid metabolism-related studies, this review outlined the lipid metabolic processes, the major signaling pathways of fat storage regulation, and the primary experimental methods to assess the lipid content in nematodes. Therefore, this model system holds great promise for facilitating the understanding, management, and therapies of human obesity and other metabolism-related diseases.
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4
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Beaudoin-Chabot C, Wang L, Celik C, Abdul Khalid ATF, Thalappilly S, Xu S, Koh JH, Lim VWX, Low AD, Thibault G. The unfolded protein response reverses the effects of glucose on lifespan in chemically-sterilized C. elegans. Nat Commun 2022; 13:5889. [PMID: 36261415 PMCID: PMC9582010 DOI: 10.1038/s41467-022-33630-0] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2018] [Accepted: 09/27/2022] [Indexed: 12/02/2022] Open
Abstract
Metabolic diseases often share common traits, including accumulation of unfolded proteins in the endoplasmic reticulum (ER). Upon ER stress, the unfolded protein response (UPR) is activated to limit cellular damage which weakens with age. Here, we show that Caenorhabditis elegans fed a bacterial diet supplemented high glucose at day 5 of adulthood (HGD-5) extends their lifespan, whereas exposed at day 1 (HGD-1) experience shortened longevity. We observed a metabolic shift only in HGD-1, while glucose and infertility synergistically prolonged the lifespan of HGD-5, independently of DAF-16. Notably, we identified that UPR stress sensors ATF-6 and PEK-1 contributed to the longevity of HGD-5 worms, while ire-1 ablation drastically increased HGD-1 lifespan. Together, we postulate that HGD activates the otherwise quiescent UPR in aged worms to overcome ageing-related stress and restore ER homeostasis. In contrast, young animals subjected to HGD provokes unresolved ER stress, conversely leading to a detrimental stress response.
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Affiliation(s)
| | - Lei Wang
- School of Biological Sciences, Nanyang Technological University, Singapore, 637551, Singapore
- Department Physiology and Biophysics, University of Miami Miller School of Medicine, Miami, FL, 33136, USA
| | - Cenk Celik
- School of Biological Sciences, Nanyang Technological University, Singapore, 637551, Singapore
| | | | - Subhash Thalappilly
- School of Biological Sciences, Nanyang Technological University, Singapore, 637551, Singapore
| | - Shiyi Xu
- School of Biological Sciences, Nanyang Technological University, Singapore, 637551, Singapore
| | - Jhee Hong Koh
- School of Biological Sciences, Nanyang Technological University, Singapore, 637551, Singapore
| | - Venus Wen Xuan Lim
- School of Biological Sciences, Nanyang Technological University, Singapore, 637551, Singapore
| | - Ann Don Low
- School of Biological Sciences, Nanyang Technological University, Singapore, 637551, Singapore
| | - Guillaume Thibault
- School of Biological Sciences, Nanyang Technological University, Singapore, 637551, Singapore.
- Mechanobiology Institute, National University of Singapore, Singapore, 117411, Singapore.
- Institute of Molecular and Cell Biology, A*STAR, Singapore, 138673, Singapore.
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5
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Zečić A, Dhondt I, Braeckman BP. Accumulation of Glycogen and Upregulation of LEA-1 in C. elegans daf-2(e1370) Support Stress Resistance, Not Longevity. Cells 2022; 11:245. [PMID: 35053361 PMCID: PMC8773926 DOI: 10.3390/cells11020245] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2021] [Revised: 12/26/2021] [Accepted: 01/07/2022] [Indexed: 02/04/2023] Open
Abstract
DAF-16-dependent activation of a dauer-associated genetic program in the C. elegans insulin/IGF-1 daf-2(e1370) mutant leads to accumulation of large amounts of glycogen with concomitant upregulation of glycogen synthase, GSY-1. Glycogen is a major storage sugar in C. elegans that can be used as a short-term energy source for survival, and possibly as a reservoir for synthesis of a chemical chaperone trehalose. Its role in mitigating anoxia, osmotic and oxidative stress has been demonstrated previously. Furthermore, daf-2 mutants show increased abundance of the group 3 late embryogenesis abundant protein LEA-1, which has been found to act in synergy with trehalose to exert its protective role against desiccation and heat stress in vitro, and to be essential for desiccation tolerance in C. elegans dauer larvae. Here we demonstrate that accumulated glycogen is not required for daf-2 longevity, but specifically protects against hyperosmotic stress, and serves as an important energy source during starvation. Similarly, lea-1 does not act to support daf-2 longevity. Instead, it contributes to increased resistance of daf-2 mutants to heat, osmotic, and UV stress. In summary, our experimental results suggest that longevity and stress resistance can be uncoupled in IIS longevity mutants.
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Affiliation(s)
| | | | - Bart P. Braeckman
- Laboratory of Aging Physiology and Molecular Evolution, Department of Biology, Ghent University, K. L. Ledeganckstraat 35, B-9000 Ghent, Belgium; (A.Z.); (I.D.)
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6
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Bai J, Li J, Pan R, Zhu Y, Xiao X, Li Y, Li C. Polysaccharides from Volvariella volvacea inhibit fat accumulation in C. elegans dependent on the aak-2/nhr-49-mediated pathway. J Food Biochem 2021; 45:e13912. [PMID: 34561881 DOI: 10.1111/jfbc.13912] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2021] [Revised: 08/02/2021] [Accepted: 08/09/2021] [Indexed: 12/28/2022]
Abstract
Volvariella volvacea has bioactivities in improving immunity, anti-oxidation, and alleviating obesity, which is an excellent functional food. Polysaccharide from Volvariella volvacea (VPS), one of the main bioactive components, exerts a potential fat-lowering effect, but its exact mechanism remains unclear. In this study, the effects and molecular pathways of VPS regulate the fat deposition of Caenorhabditis elegans. Results showed that VPS at low (250 μg/ml), medium (500 μg/ml) and high (750 μg/ml) concentrations all reduced the overall fat, without inhibitory effects on the growth and movement abilities of nematode. VPS at 500 μg/ml could dramatically decrease the triglyceride (TG) level of wild-type nematode, while no significant changes in TG content were observed in mutants deficient in aak-2 (energy receptor), nhr-49 (nuclear transcription factor), fat-5, and fat-7 genes. VPS declines fat storage of C. elegans, largely through the aak-2/nhr-49-mediated fatty acid synthesis pathway, and partially the acs-2-mediated fatty acid oxidation pathway. PRACTICAL APPLICATIONS: A model illustrates the mechanism of polysaccharide from Volvariella volvacea (VPS) inhibiting fat accumulation in Caenorhabditis elegans. VPS may directly or indirectly activate the energy sensor aak-2, which governs lipid metabolism. Results demonstrate that VPS regulates fat metabolism including fatty acid oxidation (FAO) and fatty acid synthesis (FAS), rather than lipolysis. In the FAO, VPS promotes FAO by up-regulating the mRNA and protein levels of acs-2. In FAS, VPS significantly down-regulated the transcriptional regulator nhr-49 and the downstream targets fat-5, fat-6, and fat-7, thereby declining the overall fat deposition. In conclusion, VPS inhibits the fat accumulation of C. elegans largely dependent on an aak-2/nhr-49-mediated FAS pathway.
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Affiliation(s)
- Juan Bai
- Engineering Research Center of Edible and Medicinal Fungi, Ministry of Education, Jilin Agricultural University, Changchun, China.,School of Food and Biological Engineering, Jiangsu University, Zhenjiang, China.,Jiangsu Jiangnan Biotechnology Co., Ltd., Zhenjiang, China
| | - Jie Li
- School of Food and Biological Engineering, Jiangsu University, Zhenjiang, China
| | - Ruirong Pan
- Department of Endocrinology, Affiliated Hospital of Jiangsu University, Zhenjiang, China
| | - Ying Zhu
- School of Food and Biological Engineering, Jiangsu University, Zhenjiang, China
| | - Xiang Xiao
- School of Food and Biological Engineering, Jiangsu University, Zhenjiang, China
| | - Yu Li
- Engineering Research Center of Edible and Medicinal Fungi, Ministry of Education, Jilin Agricultural University, Changchun, China
| | - Changtian Li
- Engineering Research Center of Edible and Medicinal Fungi, Ministry of Education, Jilin Agricultural University, Changchun, China
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7
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Yang L, Liang J, Lam SM, Yavuz A, Shui G, Ding M, Huang X. Neuronal lipolysis participates in PUFA-mediated neural function and neurodegeneration. EMBO Rep 2020; 21:e50214. [PMID: 33034119 PMCID: PMC7645260 DOI: 10.15252/embr.202050214] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2020] [Revised: 08/26/2020] [Accepted: 09/08/2020] [Indexed: 01/22/2023] Open
Abstract
Lipid droplets (LDs) are dynamic cytoplasmic organelles present in most eukaryotic cells. The appearance of LDs in neurons is not usually observed under physiological conditions, but is associated with neural diseases. It remains unclear how LD dynamics is regulated in neurons and how the appearance of LDs affects neuronal functions. We discovered that mutations of two key lipolysis genes atgl-1 and lid-1 lead to LD appearance in neurons of Caenorhabditis elegans. This neuronal lipid accumulation protects neurons from hyperactivation-triggered neurodegeneration, with a mild decrease in touch sensation. We also discovered that reduced biosynthesis of polyunsaturated fatty acids (PUFAs) causes similar effects and synergizes with decreased lipolysis. Furthermore, we demonstrated that these changes in lipolysis and PUFA biosynthesis increase PUFA partitioning toward triacylglycerol, and reduced incorporation of PUFAs into phospholipids increases neuronal protection. Together, these results suggest the crucial role of neuronal lipolysis in cell-autonomous regulation of neural functions and neurodegeneration.
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Affiliation(s)
- Leilei Yang
- State Key Laboratory of Molecular Developmental BiologyInstitute of Genetics and Developmental BiologyChinese Academy of SciencesBeijingChina,University of Chinese Academy of SciencesBeijingChina,Present address:
Vector CoreChinese Institute for Brain ResearchBeijingChina
| | - Jingjing Liang
- State Key Laboratory of Molecular Developmental BiologyInstitute of Genetics and Developmental BiologyChinese Academy of SciencesBeijingChina
| | - Sin Man Lam
- LipidAll Technologies Co., Ltd.ChangzhouChina
| | - Ahmet Yavuz
- Department of Molecular and Human GeneticsHuffington Center on AgingHoward Hughes Medical InstituteBaylor College of MedicineHoustonTXUSA
| | - Guanghou Shui
- State Key Laboratory of Molecular Developmental BiologyInstitute of Genetics and Developmental BiologyChinese Academy of SciencesBeijingChina,University of Chinese Academy of SciencesBeijingChina
| | - Mei Ding
- State Key Laboratory of Molecular Developmental BiologyInstitute of Genetics and Developmental BiologyChinese Academy of SciencesBeijingChina,University of Chinese Academy of SciencesBeijingChina
| | - Xun Huang
- State Key Laboratory of Molecular Developmental BiologyInstitute of Genetics and Developmental BiologyChinese Academy of SciencesBeijingChina,University of Chinese Academy of SciencesBeijingChina
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8
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Saiki P, Kawano Y, Ogi T, Klungsupya P, Muangman T, Phantanaprates W, Kongchinda P, Pinnak N, Miyazaki K. Purified Gymnemic Acids from Gymnema inodorum Tea Inhibit 3T3-L1 Cell Differentiation into Adipocytes. Nutrients 2020; 12:nu12092851. [PMID: 32957631 PMCID: PMC7551785 DOI: 10.3390/nu12092851] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2020] [Revised: 09/14/2020] [Accepted: 09/15/2020] [Indexed: 11/16/2022] Open
Abstract
Gymnema inodorum (GI) is an indigenous medicinal plant and functional food in Thailand that has recently helped to reduce plasma glucose levels in healthy humans. It is renowned for the medicinal properties of gymnemic acid and its ability to suppress glucose absorption. However, the effects of gymnemic acids on adipogenesis that contribute to the accumulation of adipose tissues associated with obesity remain unknown. The present study aimed to determine the effects of gymnemic acids derived from GI tea on adipogenesis. We purified and identified GiA-7 and stephanosides C and B from GI tea that inhibited adipocyte differentiation in 3T3-L1 cells. These compounds also suppressed the expression of peroxisome proliferator-activated receptor gamma (Pparγ)-dependent genes, indicating that they inhibit lipid accumulation and the early stage of 3T3-L1 preadipocyte differentiation. Only GiA-7 induced the expression of uncoupling protein 1 (Ucp1) and pparγ coactivator 1 alpha (Pgc1α), suggesting that GiA-7 induces mitochondrial activity and beige-like adipocytes. This is the first finding of stephanosides C and B in Gymnema inodorum. Our results suggested that GiA-7 and stephanosides C and B from GI tea could help to prevent obesity.
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Affiliation(s)
- Papawee Saiki
- Cellular and Molecular Biotechnology Research Institute, National Institute of Advance Industrial Science and Technology (AIST), Tsukuba, Ibaraki 305-8566, Japan; (Y.K.); (K.M.)
- Correspondence: ; Tel.: +81-29-861-4304
| | - Yasuhiro Kawano
- Cellular and Molecular Biotechnology Research Institute, National Institute of Advance Industrial Science and Technology (AIST), Tsukuba, Ibaraki 305-8566, Japan; (Y.K.); (K.M.)
| | - Takayuki Ogi
- Department of Environment and Natural Resources, Okinawa Industrial Technology Center, Okinawa 904-2234, Japan;
| | - Prapaipat Klungsupya
- Research and Development Group for Bio-Industries, Thailand Institute of Scientific and Technological Research (TISTR), Techno Polis, Khlong Luang, Pathum Thani 12120, Thailand; (P.K.); (T.M.); (W.P.); (P.K.); (N.P.)
| | - Thanchanok Muangman
- Research and Development Group for Bio-Industries, Thailand Institute of Scientific and Technological Research (TISTR), Techno Polis, Khlong Luang, Pathum Thani 12120, Thailand; (P.K.); (T.M.); (W.P.); (P.K.); (N.P.)
| | - Wimonsri Phantanaprates
- Research and Development Group for Bio-Industries, Thailand Institute of Scientific and Technological Research (TISTR), Techno Polis, Khlong Luang, Pathum Thani 12120, Thailand; (P.K.); (T.M.); (W.P.); (P.K.); (N.P.)
| | - Papitchaya Kongchinda
- Research and Development Group for Bio-Industries, Thailand Institute of Scientific and Technological Research (TISTR), Techno Polis, Khlong Luang, Pathum Thani 12120, Thailand; (P.K.); (T.M.); (W.P.); (P.K.); (N.P.)
| | - Nantaporn Pinnak
- Research and Development Group for Bio-Industries, Thailand Institute of Scientific and Technological Research (TISTR), Techno Polis, Khlong Luang, Pathum Thani 12120, Thailand; (P.K.); (T.M.); (W.P.); (P.K.); (N.P.)
| | - Koyomi Miyazaki
- Cellular and Molecular Biotechnology Research Institute, National Institute of Advance Industrial Science and Technology (AIST), Tsukuba, Ibaraki 305-8566, Japan; (Y.K.); (K.M.)
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9
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Bai J, Farias-Pereira R, Zhang Y, Jang M, Park Y, Kim KH. C. elegans ACAT regulates lipolysis and its related lifespan in fasting through modulation of the genes in lipolysis and insulin/IGF-1 signaling. Biofactors 2020; 46:754-765. [PMID: 32639091 DOI: 10.1002/biof.1666] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/17/2020] [Accepted: 06/09/2020] [Indexed: 12/25/2022]
Abstract
Overly active acyl-coenzyme A: cholesterol acyltransferases (ACATs) are known to contribute to the development of atherosclerosis, cancer cell proliferation and de novo lipogenesis. However, the role of ACAT in systemic lipid metabolism and its consequence of aging is unknown. Using avasimibe, a clinically proven ACAT inhibitor, and mboa-1 mutant strain, a homologous to mammalian ACAT, herein, we found that Ava treatment and mboa-1 mutant exhibited a decreased fat accumulation during feeding and increased lipolysis with extended lifespan of C. elegans during fasting. Our study highlights the essential role of ACAT inhibitor and mboa-1 in fat mobilization and the survival of C. elegans in fasting through the modulation of the genes involved in lipolysis and insulin/IGF-1 signaling.
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Affiliation(s)
- Juan Bai
- School of Food and Biological Engineering, Jiangsu University, Zhenjiang, China
- Department of Food Science, Purdue University, West Lafayette, Indiana, USA
| | | | - Yuan Zhang
- Department of Food Science, Purdue University, West Lafayette, Indiana, USA
- College of Food Science, Southwest University, Chongqing, China
| | - Miran Jang
- Department of Food Science, Purdue University, West Lafayette, Indiana, USA
| | - Yeonhwa Park
- Department of Food Science, University of Massachusetts, Amherst, Massachusetts, USA
| | - Kee-Hong Kim
- Department of Food Science, Purdue University, West Lafayette, Indiana, USA
- Center for Cancer Research, Purdue University, West Lafayette, Indiana, USA
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10
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Kim JH, Lee S, Cho EJ. Flavonoids from Acer okamotoanum Inhibit Adipocyte Differentiation and Promote Lipolysis in the 3T3-L1 Cells. Molecules 2020; 25:molecules25081920. [PMID: 32326254 PMCID: PMC7222000 DOI: 10.3390/molecules25081920] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2020] [Revised: 04/16/2020] [Accepted: 04/20/2020] [Indexed: 12/25/2022] Open
Abstract
Flavonoids, quercitrin, isoquercitrin (IQ), and afzelin, were isolated from ethyl acetate fraction of Acer okamotoanum. We investigated anti-obesity effects and mechanisms of three flavonoids from A. okamotoanum in the differentiated 3T3-L1 cells. The differentiated 3T3-L1 cells increased triglyceride (TG) contents, compared with non-differentiated normal group. However, treatments of three flavonoids from A. okamotoanum decreased TG contents without cytotoxicity. In addition, they showed significant down-regulation of several adipogenic transcription factors, such as γ-cytidine-cytidine-adenosine-adenosine-thymidine/enhancer binding protein -α, -β, and peroxisome proliferator-activated receptor-γ, compared with non-treated control group. Furthermore, treatment of the flavonoids inhibited expressions of lipogenesis-related proteins including fatty acid synthase, adipocyte protein 2, and glucose transporter 4. Moreover, IQ-treated group showed significant up-regulation of lipolysis-related proteins such as adipose triglyceride lipase and hormone-sensitive lipase. In addition, flavonoids significantly activated 5′-adenosine monophosphate-activated protein kinase (AMPK) compared to control group. In particular, IQ showed higher inhibition of TG accumulation by regulation of pathways related with both adipogenesis and lipolysis, than other flavonoids. The present results indicated that three flavonoids of A. okamotoanum showed anti-obesity activity by regulation of adipocyte differentiation, lipolysis, and AMPK signaling, suggesting as an anti-obesity functional agents.
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Affiliation(s)
- Ji Hyun Kim
- Department of Food Science and Nutrition & Kimchi Research Institute, Pusan National University, Busan 46241, Korea;
| | - Sanghyun Lee
- Department of Plant Science and Technology, Chung-Ang University, Anseong 17546, Korea;
| | - Eun Ju Cho
- Department of Food Science and Nutrition & Kimchi Research Institute, Pusan National University, Busan 46241, Korea;
- Correspondence: ; Tel.: +82-51-510-2837
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11
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Penkov S, Raghuraman BK, Erkut C, Oertel J, Galli R, Ackerman EJM, Vorkel D, Verbavatz JM, Koch E, Fahmy K, Shevchenko A, Kurzchalia TV. A metabolic switch regulates the transition between growth and diapause in C. elegans. BMC Biol 2020; 18:31. [PMID: 32188449 PMCID: PMC7081555 DOI: 10.1186/s12915-020-0760-3] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2019] [Accepted: 02/27/2020] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Metabolic activity alternates between high and low states during different stages of an organism's life cycle. During the transition from growth to quiescence, a major metabolic shift often occurs from oxidative phosphorylation to glycolysis and gluconeogenesis. We use the entry of Caenorhabditis elegans into the dauer larval stage, a developmentally arrested stage formed in response to harsh environmental conditions, as a model to study the global metabolic changes and underlying molecular mechanisms associated with growth to quiescence transition. RESULTS Here, we show that the metabolic switch involves the concerted activity of several regulatory pathways. Whereas the steroid hormone receptor DAF-12 controls dauer morphogenesis, the insulin pathway maintains low energy expenditure through DAF-16/FoxO, which also requires AAK-2/AMPKα. DAF-12 and AAK-2 separately promote a shift in the molar ratios between competing enzymes at two key branch points within the central carbon metabolic pathway diverting carbon atoms from the TCA cycle and directing them to gluconeogenesis. When both AAK-2 and DAF-12 are suppressed, the TCA cycle is active and the developmental arrest is bypassed. CONCLUSIONS The metabolic status of each developmental stage is defined by stoichiometric ratios within the constellation of metabolic enzymes driving metabolic flux and controls the transition between growth and quiescence.
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Affiliation(s)
- Sider Penkov
- Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany. .,Paul Langerhans Institute Dresden of the Helmholtz Zentrum München at the University Hospital and Faculty of Medicine Carl Gustav Carus of TU Dresden, Dresden, Germany. .,Institute for Clinical Chemistry and Laboratory Medicine, University Clinic and Medical Faculty, TU Dresden, Dresden, Germany.
| | | | - Cihan Erkut
- Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany.,Present address: German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Jana Oertel
- Institute of Resource Ecology at the Helmholtz-Zentrum Dresden-Rossendorf, Dresden, Germany
| | - Roberta Galli
- Faculty of Medicine Carl Gustav Carus, Department of Anesthesiology and Intensive Care Medicine, Clinical Sensoring and Monitoring, TU Dresden, Dresden, Germany
| | | | - Daniela Vorkel
- Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany
| | - Jean-Marc Verbavatz
- Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany.,Institut Jacques Monod, Université de Paris/CNRS, Paris, France
| | - Edmund Koch
- Faculty of Medicine Carl Gustav Carus, Department of Anesthesiology and Intensive Care Medicine, Clinical Sensoring and Monitoring, TU Dresden, Dresden, Germany
| | - Karim Fahmy
- Institute of Resource Ecology at the Helmholtz-Zentrum Dresden-Rossendorf, Dresden, Germany
| | - Andrej Shevchenko
- Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany
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DAF-16/FoxO in Caenorhabditis elegans and Its Role in Metabolic Remodeling. Cells 2020; 9:cells9010109. [PMID: 31906434 PMCID: PMC7017163 DOI: 10.3390/cells9010109] [Citation(s) in RCA: 122] [Impact Index Per Article: 24.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2019] [Revised: 12/30/2019] [Accepted: 12/31/2019] [Indexed: 12/31/2022] Open
Abstract
DAF-16, the only forkhead box transcription factors class O (FoxO) homolog in Caenorhabditis elegans, integrates signals from upstream pathways to elicit transcriptional changes in many genes involved in aging, development, stress, metabolism, and immunity. The major regulator of DAF-16 activity is the insulin/insulin-like growth factor 1 (IGF-1) signaling (IIS) pathway, reduction of which leads to lifespan extension in worms, flies, mice, and humans. In C. elegans daf-2 mutants, reduced IIS leads to a heterochronic activation of a dauer survival program during adulthood. This program includes elevated antioxidant defense and a metabolic shift toward accumulation of carbohydrates (i.e., trehalose and glycogen) and triglycerides, and activation of the glyoxylate shunt, which could allow fat-to-carbohydrate conversion. The longevity of daf-2 mutants seems to be partially supported by endogenous trehalose, a nonreducing disaccharide that mammals cannot synthesize, which points toward considerable differences in downstream mechanisms by which IIS regulates aging in distinct groups.
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Dakik P, Medkour Y, Mohammad K, Titorenko VI. Mechanisms Through Which Some Mitochondria-Generated Metabolites Act as Second Messengers That Are Essential Contributors to the Aging Process in Eukaryotes Across Phyla. Front Physiol 2019; 10:461. [PMID: 31057428 PMCID: PMC6482166 DOI: 10.3389/fphys.2019.00461] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2019] [Accepted: 04/02/2019] [Indexed: 12/21/2022] Open
Abstract
Recent studies have revealed that some low-molecular weight molecules produced in mitochondria are essential contributing factors to aging and aging-associated pathologies in evolutionarily distant eukaryotes. These molecules are intermediates or products of certain metabolic reactions that are activated in mitochondria in response to specific changes in the nutrient, stress, proliferation, or age status of the cell. After being released from mitochondria, these metabolites directly or indirectly change activities of a distinct set of protein sensors that reside in various cellular locations outside of mitochondria. Because these protein sensors control the efficiencies of some pro- or anti-aging cellular processes, such changes in their activities allow to create a pro- or anti-aging cellular pattern. Thus, mitochondria can function as signaling platforms that respond to certain changes in cell stress and physiology by remodeling their metabolism and releasing a specific set of metabolites known as "mitobolites." These mitobolites then define the pace of cellular and organismal aging because they regulate some longevity-defining processes taking place outside of mitochondria. In this review, we discuss recent progress in understanding mechanisms underlying the ability of mitochondria to function as such signaling platforms in aging and aging-associated diseases.
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14
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Firouzi S, Malekahmadi M, Ghayour-Mobarhan M, Ferns G, Rahimi HR. Barberry in the treatment of obesity and metabolic syndrome: possible mechanisms of action. Diabetes Metab Syndr Obes 2018; 11:699-705. [PMID: 30519065 PMCID: PMC6233907 DOI: 10.2147/dmso.s181572] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/05/2023] Open
Abstract
Obesity is a consequence of an imbalance between energy intake and energy expenditure. It affects people of both genders and all age groups, ethnicity and socioeconomic groups, and in developed and developing countries. Obesity is often accompanied by the metabolic syndrome (MetS). MetS is characterized by a clustering of cardiovascular risk factors, including high blood pressure, adiposity, dyslipidemia and glucose intolerance, which together increase the risk of atherosclerotic cardiovascular disease, type 2 diabetes mellitus and other causes of mortality. Nowadays, there is a growing interest in the use of plant-based agents instead of synthetic drugs to manage chronic diseases such as MetS; one such example is Berberis vulgaris. B. vulgaris contains isoquinonline alkaloids such as berberine, berberrubine and berbamine. Recent studies have proved that berberine exhibits pharmacological activities and positive effects on the risk factors of obesity and MetS. We have reviewed original articles related to the possible molecular mechanisms of action of berberine on obesity and MetS. Berberine suppresses adipocyte differentiation and decreases obesity. It also regulates glucose metabolism via decreasing insulin resistance and increasing insulin secretion. Other effects of berberine include antihyperlipidemic and antihypertensive activities and endothelial protection.
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Affiliation(s)
- Safieh Firouzi
- Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran, ,
- Student Research Committee, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mahsa Malekahmadi
- Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran, ,
- Student Research Committee, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Majid Ghayour-Mobarhan
- Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran, ,
- Department of Modern Sciences and Technology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran, , ,
| | - Gordon Ferns
- Department of Medical Education, Brighton and Sussex Medical School, University of Brighton Falmer Campus, Brighton, UK
| | - Hamid Reza Rahimi
- Department of Modern Sciences and Technology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran, , ,
- Neurogenic Inflammation Research Center, Mashhad University of Medical Sciences, Mashhad, Iran,
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15
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Auclair N, Melbouci L, St-Pierre D, Levy E. Gastrointestinal factors regulating lipid droplet formation in the intestine. Exp Cell Res 2018; 363:1-14. [PMID: 29305172 DOI: 10.1016/j.yexcr.2017.12.031] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2017] [Revised: 12/28/2017] [Accepted: 12/29/2017] [Indexed: 12/22/2022]
Abstract
Cytoplasmic lipid droplets (CLD) are considered as neutral lipid reservoirs, which protect cells from lipotoxicity. It became clear that these fascinating dynamic organelles play a role not only in energy storage and metabolism, but also in cellular lipid and protein handling, inter-organelle communication, and signaling among diverse functions. Their dysregulation is associated with multiple disorders, including obesity, liver steatosis and cardiovascular diseases. The central aim of this review is to highlight the link between intra-enterocyte CLD dynamics and the formation of chylomicrons, the main intestinal dietary lipid vehicle, after overviewing the morphology, molecular composition, biogenesis and functions of CLD.
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Affiliation(s)
- N Auclair
- Research Centre, CHU Sainte-Justine and Department of Montreal, Quebec, Canada H3T 1C5; Nutrition, Université de Montréal, Montreal, Quebec, Canada H3T 1C5
| | - L Melbouci
- Research Centre, CHU Sainte-Justine and Department of Montreal, Quebec, Canada H3T 1C5; Department of Sciences and Physical Activities, UQAM, Quebec, Canada H2X 1Y4
| | - D St-Pierre
- Research Centre, CHU Sainte-Justine and Department of Montreal, Quebec, Canada H3T 1C5; Department of Sciences and Physical Activities, UQAM, Quebec, Canada H2X 1Y4
| | - E Levy
- Research Centre, CHU Sainte-Justine and Department of Montreal, Quebec, Canada H3T 1C5; Nutrition, Université de Montréal, Montreal, Quebec, Canada H3T 1C5; Institute of Nutrition and Functional Foods (INAF), Université Laval, Quebec, Quebec, Canada G1V 0A6.
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16
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Watts JL, Ristow M. Lipid and Carbohydrate Metabolism in Caenorhabditis elegans. Genetics 2017; 207:413-446. [PMID: 28978773 PMCID: PMC5629314 DOI: 10.1534/genetics.117.300106] [Citation(s) in RCA: 110] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2017] [Accepted: 08/02/2017] [Indexed: 12/14/2022] Open
Abstract
Lipid and carbohydrate metabolism are highly conserved processes that affect nearly all aspects of organismal biology. Caenorhabditis elegans eat bacteria, which consist of lipids, carbohydrates, and proteins that are broken down during digestion into fatty acids, simple sugars, and amino acid precursors. With these nutrients, C. elegans synthesizes a wide range of metabolites that are required for development and behavior. In this review, we outline lipid and carbohydrate structures as well as biosynthesis and breakdown pathways that have been characterized in C. elegans We bring attention to functional studies using mutant strains that reveal physiological roles for specific lipids and carbohydrates during development, aging, and adaptation to changing environmental conditions.
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Affiliation(s)
- Jennifer L Watts
- School of Molecular Biosciences and Center for Reproductive Biology, Washington State University, Pullman, Washington 99164
| | - Michael Ristow
- Energy Metabolism Laboratory, Institute of Translational Medicine, Department of Health Sciences and Technology, Swiss Federal Institute of Technology Zurich, 8603 Schwerzenbach-Zurich, Switzerland
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17
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Schubert KM, Qiu J, Blodow S, Wiedenmann M, Lubomirov LT, Pfitzer G, Pohl U, Schneider H. The AMP-Related Kinase (AMPK) Induces Ca
2+
-Independent Dilation of Resistance Arteries by Interfering With Actin Filament Formation. Circ Res 2017; 121:149-161. [DOI: 10.1161/circresaha.116.309962] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/12/2016] [Revised: 05/23/2017] [Accepted: 06/06/2017] [Indexed: 12/13/2022]
Abstract
Rationale:
Decreasing Ca
2+
sensitivity of vascular smooth muscle (VSM) allows for vasodilation without lowering of cytosolic Ca
2+
. This may be particularly important in states requiring maintained dilation, such as hypoxia. AMP-related kinase (AMPK) is an important cellular energy sensor in VSM. Regulation of Ca
2+
sensitivity usually is attributed to myosin light chain phosphatase activity, but findings in non-VSM identified changes in the actin cytoskeleton. The potential role of AMPK in this setting is widely unknown.
Objective:
To assess the influence of AMPK on the actin cytoskeleton in VSM of resistance arteries with regard to potential Ca
2+
desensitization of VSM contractile apparatus.
Methods and Results:
AMPK induced a slowly developing dilation at unchanged cytosolic Ca
2+
levels in potassium chloride–constricted intact arteries isolated from mouse mesenteric tissue. This dilation was not associated with changes in phosphorylation of myosin light chain or of myosin light chain phosphatase regulatory subunit. Using ultracentrifugation and confocal microscopy, we found that AMPK induced depolymerization of F-actin (filamentous actin). Imaging of arteries from LifeAct mice showed F-actin rarefaction in the midcellular portion of VSM. Immunoblotting revealed that this was associated with activation of the actin severing factor cofilin. Coimmunoprecipitation experiments indicated that AMPK leads to the liberation of cofilin from 14-3-3 protein.
Conclusions:
AMPK induces actin depolymerization, which reduces vascular tone and the response to vasoconstrictors. Our findings demonstrate a new role of AMPK in the control of actin cytoskeletal dynamics, potentially allowing for long-term dilation of microvessels without substantial changes in cytosolic Ca
2+
.
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Affiliation(s)
- Kai Michael Schubert
- From the Walter Brendel Centre of Experimental Medicine, Biomedical Center of LMU, Ludwig Maximilian University of Munich, Germany (K.M.S., J.Q., S.B., M.W., U.P., H.S.); Munich Cluster for Systems Neurology (SyNergy), Germany (K.M.S., S.B., U.P., H.S.); Deutsches Zentrum für Herz- Kreislauf-Forschung (German Center for Cardiovascular Research), Partner Site Munich Heart Alliance, Munich, Germany (K.M.S., S.B., U.P., H.S.); and Institute of Vegetative Physiology, University of Cologne, Germany (L.T
| | - Jiehua Qiu
- From the Walter Brendel Centre of Experimental Medicine, Biomedical Center of LMU, Ludwig Maximilian University of Munich, Germany (K.M.S., J.Q., S.B., M.W., U.P., H.S.); Munich Cluster for Systems Neurology (SyNergy), Germany (K.M.S., S.B., U.P., H.S.); Deutsches Zentrum für Herz- Kreislauf-Forschung (German Center for Cardiovascular Research), Partner Site Munich Heart Alliance, Munich, Germany (K.M.S., S.B., U.P., H.S.); and Institute of Vegetative Physiology, University of Cologne, Germany (L.T
| | - Stephanie Blodow
- From the Walter Brendel Centre of Experimental Medicine, Biomedical Center of LMU, Ludwig Maximilian University of Munich, Germany (K.M.S., J.Q., S.B., M.W., U.P., H.S.); Munich Cluster for Systems Neurology (SyNergy), Germany (K.M.S., S.B., U.P., H.S.); Deutsches Zentrum für Herz- Kreislauf-Forschung (German Center for Cardiovascular Research), Partner Site Munich Heart Alliance, Munich, Germany (K.M.S., S.B., U.P., H.S.); and Institute of Vegetative Physiology, University of Cologne, Germany (L.T
| | - Margarethe Wiedenmann
- From the Walter Brendel Centre of Experimental Medicine, Biomedical Center of LMU, Ludwig Maximilian University of Munich, Germany (K.M.S., J.Q., S.B., M.W., U.P., H.S.); Munich Cluster for Systems Neurology (SyNergy), Germany (K.M.S., S.B., U.P., H.S.); Deutsches Zentrum für Herz- Kreislauf-Forschung (German Center for Cardiovascular Research), Partner Site Munich Heart Alliance, Munich, Germany (K.M.S., S.B., U.P., H.S.); and Institute of Vegetative Physiology, University of Cologne, Germany (L.T
| | - Lubomir T. Lubomirov
- From the Walter Brendel Centre of Experimental Medicine, Biomedical Center of LMU, Ludwig Maximilian University of Munich, Germany (K.M.S., J.Q., S.B., M.W., U.P., H.S.); Munich Cluster for Systems Neurology (SyNergy), Germany (K.M.S., S.B., U.P., H.S.); Deutsches Zentrum für Herz- Kreislauf-Forschung (German Center for Cardiovascular Research), Partner Site Munich Heart Alliance, Munich, Germany (K.M.S., S.B., U.P., H.S.); and Institute of Vegetative Physiology, University of Cologne, Germany (L.T
| | - Gabriele Pfitzer
- From the Walter Brendel Centre of Experimental Medicine, Biomedical Center of LMU, Ludwig Maximilian University of Munich, Germany (K.M.S., J.Q., S.B., M.W., U.P., H.S.); Munich Cluster for Systems Neurology (SyNergy), Germany (K.M.S., S.B., U.P., H.S.); Deutsches Zentrum für Herz- Kreislauf-Forschung (German Center for Cardiovascular Research), Partner Site Munich Heart Alliance, Munich, Germany (K.M.S., S.B., U.P., H.S.); and Institute of Vegetative Physiology, University of Cologne, Germany (L.T
| | - Ulrich Pohl
- From the Walter Brendel Centre of Experimental Medicine, Biomedical Center of LMU, Ludwig Maximilian University of Munich, Germany (K.M.S., J.Q., S.B., M.W., U.P., H.S.); Munich Cluster for Systems Neurology (SyNergy), Germany (K.M.S., S.B., U.P., H.S.); Deutsches Zentrum für Herz- Kreislauf-Forschung (German Center for Cardiovascular Research), Partner Site Munich Heart Alliance, Munich, Germany (K.M.S., S.B., U.P., H.S.); and Institute of Vegetative Physiology, University of Cologne, Germany (L.T
| | - Holger Schneider
- From the Walter Brendel Centre of Experimental Medicine, Biomedical Center of LMU, Ludwig Maximilian University of Munich, Germany (K.M.S., J.Q., S.B., M.W., U.P., H.S.); Munich Cluster for Systems Neurology (SyNergy), Germany (K.M.S., S.B., U.P., H.S.); Deutsches Zentrum für Herz- Kreislauf-Forschung (German Center for Cardiovascular Research), Partner Site Munich Heart Alliance, Munich, Germany (K.M.S., S.B., U.P., H.S.); and Institute of Vegetative Physiology, University of Cologne, Germany (L.T
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Lipid Droplet-Associated Hydrolase Promotes Lipid Droplet Fusion and Enhances ATGL Degradation and Triglyceride Accumulation. Sci Rep 2017; 7:2743. [PMID: 28578400 PMCID: PMC5457427 DOI: 10.1038/s41598-017-02963-y] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2016] [Accepted: 04/20/2017] [Indexed: 01/09/2023] Open
Abstract
Lipid droplet (LD)-associated hydrolase (LDAH) is a newly identified LD protein abundantly expressed in tissues that predominantly store triacylglycerol (TAG). However, how LDAH regulates TAG metabolism remains unknown. We found that upon oleic acid loading LDAH translocalizes from the ER to newly formed LDs, and induces LD coalescence in a tubulin-dependent manner. LDAH overexpression and downregulation in HEK293 cells increase and decrease, respectively, TAG levels. Pulse and chase experiments show that LDAH enhances TAG biogenesis, but also decreases TAG turnover and fatty acid release from cells. Mutations in predicted catalytic and acyltransferase motifs do not influence TAG levels, suggesting that the effect is independent of LDAH’s enzymatic activity. However, a LDAH alternative-splicing variant missing 90 amino acids at C-terminus does not promote LD fusion or TAG accumulation, while it still localizes to LDs. Interestingly, LDAH enhances polyubiquitination and proteasomal degradation of adipose triglyceride lipase (ATGL), a rate limiting enzyme of TAG hydrolysis. Co-expression of ATGL reverses the changes in LD phenotype induced by LDAH, and both proteins counterbalance their effects on TAG stores. Together, these studies support that under conditions of TAG storage in LDs LDAH plays a primarily lipogenic role, inducing LD growth and enhancing degradation of ATGL.
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19
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Berberine increases adipose triglyceride lipase in 3T3-L1 adipocytes through the AMPK pathway. Lipids Health Dis 2016; 15:214. [PMID: 27938388 PMCID: PMC5148888 DOI: 10.1186/s12944-016-0383-4] [Citation(s) in RCA: 49] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2016] [Accepted: 11/30/2016] [Indexed: 11/16/2022] Open
Abstract
Background Obesity is closely related to the metabolism of triacylglycerol (TG) in adipocytes. Adipose triglyceride lipase (ATGL) and hormone-sensitive lipase (HSL) are rate-limiting enzymes that control the hydrolysis of TG. Effects on ATGL and HSL to increase lipolysis may counteract obesity. Berberine (BBR) is a compound derived from the Chinese medicine plant Coptis chinensis. In the present study we show the effects of BBR on ATGL and HSL and explore the potential underlying mechanisms of these effects. Methods The TG content in cells was measured using a colorimetric assay. The expressions of HSL, ATGL and GPAT3 were evaluated by Western-blotting. The expression of ATGL was also evaluated by real-time PCR and radioimmunoassay. Compound C, an inhibitor of AMP-activated protein kinase (AMPK), was used to explore the possible pathway that involved in the effect of BBR on ATGL. Results TG content of differentiated 3T3-L1 cells was significantly decreased by more than 10% after treated with BBR. In differentiated 3T3-L1 adipocytes, BBR increased the expression of p-HSL and ATGL, and these effects were time-depended (p <0.01). The effect of BBR on ATGL expression could be abolished by Compound C which suggested that AMPK pathway was involved in the effects of BBR on p-HSL and ATGL. Conclusions BBR could increase the expression of ATGL and therefore stimulate basal lipolysis in mature adipocytes through the associated mechanisms related to the AMPK pathway.
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20
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Lim GE, Johnson JD. 14-3-3ζ: A numbers game in adipocyte function? Adipocyte 2016; 5:232-7. [PMID: 27386155 PMCID: PMC4916895 DOI: 10.1080/21623945.2015.1120913] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/06/2015] [Revised: 11/05/2015] [Accepted: 11/10/2015] [Indexed: 12/22/2022] Open
Abstract
Molecular scaffolds are often viewed as passive signaling molecules that facilitate protein-protein interactions. However, new evidence gained from the use of loss-of-function or gain-of-function models is dispelling this notion. Our own recent discovery of 14-3-3ζ as an essential regulator of adipogenesis highlights the complex roles of this member of the 14-3-3 protein family. Depletion of the 14-3-3ζ isoform affected parallel pathways that drive adipocyte development, including pathways controlling the stability of key adipogenic transcription factors and cell cycle progression. Going beyond adipocyte differentiation, this study opens new avenues of research in the context of metabolism, as 14-3-3ζ binds to a variety of well-established metabolic proteins that harbor its canonical phosphorylation binding motifs. This suggests that 14-3-3ζ may contribute to key metabolic signaling pathways, such as those that facilitate glucose uptake and fatty acid metabolism. Herein, we discuss these novel areas of research, which will undoubtedly shed light onto novel roles of 14-3-3ζ, and perhaps its related family members, on glucose homeostasis.
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Affiliation(s)
- Gareth E. Lim
- Department of Cellular and Physiological Sciences, University of British Columbia, Vancouver, British Columbia, Canada
| | - James D. Johnson
- Department of Cellular and Physiological Sciences, University of British Columbia, Vancouver, British Columbia, Canada
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21
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McCarthy AD, Cortizo AM, Sedlinsky C. Metformin revisited: Does this regulator of AMP-activated protein kinase secondarily affect bone metabolism and prevent diabetic osteopathy. World J Diabetes 2016; 7:122-133. [PMID: 27022443 PMCID: PMC4807302 DOI: 10.4239/wjd.v7.i6.122] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/27/2015] [Revised: 12/24/2015] [Accepted: 01/31/2016] [Indexed: 02/05/2023] Open
Abstract
Patients with long-term type 1 and type 2 diabetes mellitus (DM) can develop skeletal complications or “diabetic osteopathy”. These include osteopenia, osteoporosis and an increased incidence of low-stress fractures. In this context, it is important to evaluate whether current anti-diabetic treatments can secondarily affect bone metabolism. Adenosine monophosphate-activated protein kinase (AMPK) modulates multiple metabolic pathways and acts as a sensor of the cellular energy status; recent evidence suggests a critical role for AMPK in bone homeostasis. In addition, AMPK activation is believed to mediate most clinical effects of the insulin-sensitizer metformin. Over the past decade, several research groups have investigated the effects of metformin on bone, providing a considerable body of pre-clinical (in vitro, ex vivo and in vivo) as well as clinical evidence for an anabolic action of metformin on bone. However, two caveats should be kept in mind when considering metformin treatment for a patient with type 2 DM at risk for diabetic osteopathy. In the first place, metformin should probably not be considered an anti-osteoporotic drug; it is an insulin sensitizer with proven macrovascular benefits that can secondarily improve bone metabolism in the context of DM. Secondly, we are still awaiting the results of randomized placebo-controlled studies in humans that evaluate the effects of metformin on bone metabolism as a primary endpoint.
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22
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Ahmadi M, Roy R. 5'-AMP-Activated Protein Kinase Signaling in Caenorhabditis elegans. EXPERIENTIA SUPPLEMENTUM (2012) 2016; 107:375-388. [PMID: 27812988 DOI: 10.1007/978-3-319-43589-3_15] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
AMP-activated protein kinase (AMPK) is one of the central regulators of cellular and organismal metabolism in eukaryotes. Once activated by decreased energy levels, it induces ATP production by promoting catabolic pathways while conserving ATP by inhibiting anabolic pathways. AMPK plays a crucial role in various aspects of cellular function such as regulating growth, reprogramming metabolism, autophagy, and cell polarity. In this chapter, we focus on how recent breakthroughs made using the model organism Caenorhabditis elegans have contributed to our understanding of AMPK function and how it can be utilized in the future to elucidate hitherto unknown aspects of AMPK signaling.
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Affiliation(s)
- Moloud Ahmadi
- Department of Biology, McGill University, 1205 Avenue Docteur Penfield, Montreal, QC, Canada, H3A 1B1
| | - Richard Roy
- Department of Biology, McGill University, 1205 Avenue Docteur Penfield, Montreal, QC, Canada, H3A 1B1.
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