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Maniyadath B, Zhang Q, Gupta RK, Mandrup S. Adipose tissue at single-cell resolution. Cell Metab 2023; 35:386-413. [PMID: 36889280 PMCID: PMC10027403 DOI: 10.1016/j.cmet.2023.02.002] [Citation(s) in RCA: 76] [Impact Index Per Article: 38.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/26/2022] [Revised: 01/22/2023] [Accepted: 02/03/2023] [Indexed: 03/09/2023]
Abstract
Adipose tissue exhibits remarkable plasticity with capacity to change in size and cellular composition under physiological and pathophysiological conditions. The emergence of single-cell transcriptomics has rapidly transformed our understanding of the diverse array of cell types and cell states residing in adipose tissues and has provided insight into how transcriptional changes in individual cell types contribute to tissue plasticity. Here, we present a comprehensive overview of the cellular atlas of adipose tissues focusing on the biological insight gained from single-cell and single-nuclei transcriptomics of murine and human adipose tissues. We also offer our perspective on the exciting opportunities for mapping cellular transitions and crosstalk, which have been made possible by single-cell technologies.
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Affiliation(s)
- Babukrishna Maniyadath
- Center for Functional Genomics and Tissue Plasticity, Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense M, Denmark
| | - Qianbin Zhang
- Department of Internal Medicine, Touchstone Diabetes Center, UT Southwestern Medical Center, Dallas, TX, USA
| | - Rana K Gupta
- Department of Internal Medicine, Touchstone Diabetes Center, UT Southwestern Medical Center, Dallas, TX, USA.
| | - Susanne Mandrup
- Center for Functional Genomics and Tissue Plasticity, Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense M, Denmark.
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2
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Fang H, Stone KP, Wanders D, Forney LA, Gettys TW. The Origins, Evolution, and Future of Dietary Methionine Restriction. Annu Rev Nutr 2022; 42:201-226. [PMID: 35588443 PMCID: PMC9936953 DOI: 10.1146/annurev-nutr-062320-111849] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
The original description of dietary methionine restriction (MR) used semipurified diets to limit methionine intake to 20% of normal levels, and this reduction in dietary methionine increased longevity by ∼30% in rats. The MR diet also produces paradoxical increases in energy intake and expenditure and limits fat deposition while reducing tissue and circulating lipids and enhancing overall insulin sensitivity. In the years following the original 1993 report, a comprehensive effort has been made to understand the nutrient sensing and signaling systems linking reduced dietary methionine to the behavioral, physiological, biochemical, and transcriptional components of the response. Recent work has shown that transcriptional activation of hepatic fibroblast growth factor 21 (FGF21) is a key event linking the MR diet to many but not all components of its metabolic phenotype. These findings raise the interesting possibility of developing therapeutic, MR-based diets that produce the beneficial effects of FGF21 by nutritionally modulating its transcription and release.
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Affiliation(s)
- Han Fang
- Laboratory of Nutrient Sensing and Adipocyte Signaling, Pennington Biomedical Research Center, Baton Rouge, Louisiana, USA;
| | - Kirsten P Stone
- Laboratory of Nutrient Sensing and Adipocyte Signaling, Pennington Biomedical Research Center, Baton Rouge, Louisiana, USA;
| | - Desiree Wanders
- Department of Nutrition, Georgia State University, Atlanta, Georgia, USA
| | - Laura A Forney
- Department of Kinesiology, Houston Baptist University, Houston, Texas, USA
| | - Thomas W Gettys
- Laboratory of Nutrient Sensing and Adipocyte Signaling, Pennington Biomedical Research Center, Baton Rouge, Louisiana, USA;
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3
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Accumulation of γδ T cells in visceral fat with aging promotes chronic inflammation. GeroScience 2022; 44:1761-1778. [PMID: 35477832 PMCID: PMC9213615 DOI: 10.1007/s11357-022-00572-w] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2021] [Accepted: 04/12/2022] [Indexed: 11/25/2022] Open
Abstract
Adipose tissue dysfunction is strongly linked to the development of chronic inflammation and cardiometabolic disorders in aging. While much attention has been given to the role of resident adipose tissue immune cells in the disruption of homeostasis in obesity, age-specific effects remain understudied. Here, we identified and characterized a population of γδ T cells, which show unique age-dependent accumulation in the visceral adipose tissue (VAT) of both mice and humans. Diet-induced obesity likewise increased γδ T cell numbers; however, the effect was greater in the aged where the increase was independent of fat mass. γδ T cells in VAT express a tissue-resident memory T cell phenotype (CD44hiCD62LlowCD69+) and are predominantly IL-17A-producing cells. Transcriptome analyses of immunomagnetically purified γδ T cells identified significant age-associated differences in expression of genes related to inflammation, immune cell composition, and adipocyte differentiation, suggesting age-dependent qualitative changes in addition to the quantitative increase. Genetic deficiency of γδ T cells in old age improved the metabolic phenotype, characterized by increased respiratory exchange ratio, and lowered levels of IL-6 both systemically and locally in VAT. Decreased IL-6 was predominantly due to reduced production by non-immune stromal cells, primarily preadipocytes, and adipose-derived stem cells. Collectively, these findings suggest that an age-dependent increase of tissue-resident γδ T cells in VAT contributes to local and systemic chronic inflammation and metabolic dysfunction in aging.
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De Luca M, Mandala M, Rose G. Towards an understanding of the mechanoreciprocity process in adipocytes and its perturbation with aging. Mech Ageing Dev 2021; 197:111522. [PMID: 34147549 DOI: 10.1016/j.mad.2021.111522] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2021] [Revised: 05/29/2021] [Accepted: 06/15/2021] [Indexed: 12/25/2022]
Abstract
Adipose tissue (AT) is a complex organ, with multiple functions that are essential for maintaining metabolic health. A feature of AT is its capability to expand in response to physiological challenges, such as pregnancy and aging, and during chronic states of positive energy balance occurring throughout life. AT grows through adipogenesis and/or an increase in the size of existing adipocytes. One process that is required for healthy AT growth is the remodeling of the extracellular matrix (ECM), which is a necessary step to restore mechanical homeostasis and maintain tissue integrity and functionality. While the relationship between mechanobiology and adipogenesis is now well recognized, less is known about the role of adipocyte mechanosignaling pathways in AT growth. In this review article, we first summarize evidence linking ECM remodelling to AT expansion and how its perturbation is associated to a metabolically unhealthy phenotype. Subsequently, we highlight findings suggesting that molecules involved in the dynamic, bidirectional process (mechanoreciprocity) enabling adipocytes to sense changes in the mechanical properties of the ECM are interconnected to pathways regulating lipid metabolism. Finally, we discuss processes through which aging may influence the ability of adipocytes to appropriately respond to alterations in ECM composition.
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Affiliation(s)
- Maria De Luca
- Department of Nutrition Sciences, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
| | - Maurizio Mandala
- Department of Biology, Ecology and Earth Science, University of Calabria, Rende, 87036, Italy
| | - Giuseppina Rose
- Department of Biology, Ecology and Earth Science, University of Calabria, Rende, 87036, Italy
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Mau T, O’Brien M, Ghosh AK, Miller RA, Yung R. Life-span Extension Drug Interventions Affect Adipose Tissue Inflammation in Aging. J Gerontol A Biol Sci Med Sci 2020; 75:89-98. [PMID: 31353414 PMCID: PMC6909899 DOI: 10.1093/gerona/glz177] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2019] [Indexed: 02/02/2023] Open
Abstract
The National Institute on Aging (NIA)-sponsored Interventions Testing Program (ITP) has identified a number of dietary drug interventions that significantly extend life span, including rapamycin, acarbose, and 17-α estradiol. However, these drugs have diverse downstream targets, and their effects on age-associated organ-specific changes are unclear (Nadon NL, Strong R, Miller RA, Harrison DE. NIA Interventions Testing Program: investigating putative aging intervention agents in a genetically heterogeneous mouse model. EBioMedicine. 2017;21:3-4. doi:10.1016/j.ebiom.2016.11.038). Potential mechanisms by which these drugs extend life could be through their effect on inflammatory processes often noted in tissues of aging mice and humans. Our study focuses on the effects of three drugs in the ITP on inflammation in gonadal white adipose tissue (gWAT) of HET3 mice-including adiposity, adipose tissue macrophage (ATM) M1/M2 polarization, markers of cellular senescence, and endoplasmic reticulum stress. We found that rapamycin led to a 56% increase of CD45+ leukocytes in gWAT, where the majority of these are ATMs. Interestingly, rapamycin led to a 217% and 106% increase of M1 (CD45+CD64+CD206-) ATMs in females and males, respectively. Our data suggest rapamycin may achieve life-span extension in part through adipose tissue inflammation. Additionally, HET3 mice exhibit a spectrum of age-associated changes in the gWAT, but acarbose and 17-α estradiol do not strongly alter these phenotypes-suggesting that acarbose and 17- α estradiol may not influence life span through mechanisms involving adipose tissue inflammation.
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Affiliation(s)
- Theresa Mau
- Division of Geriatric and Palliative Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor
- Graduate Program in Immunology, Program in Biomedical Sciences (PIBS), University of Michigan, Ann Arbor
| | - Martin O’Brien
- Division of Geriatric and Palliative Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor
| | - Amiya K Ghosh
- Division of Geriatric and Palliative Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor
| | - Richard A Miller
- Department of Pathology and Glenn Center for Biology of Aging Research, University of Michigan, Ann Arbor
| | - Raymond Yung
- Division of Geriatric and Palliative Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor
- Graduate Program in Immunology, Program in Biomedical Sciences (PIBS), University of Michigan, Ann Arbor
- Department of Pathology and Glenn Center for Biology of Aging Research, University of Michigan, Ann Arbor
- Geriatric Research, Education, and Clinical Care Center (GRECC), VA Ann Arbor Health System, Michigan
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Salvestrini V, Sell C, Lorenzini A. Obesity May Accelerate the Aging Process. Front Endocrinol (Lausanne) 2019; 10:266. [PMID: 31130916 PMCID: PMC6509231 DOI: 10.3389/fendo.2019.00266] [Citation(s) in RCA: 146] [Impact Index Per Article: 24.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/09/2018] [Accepted: 04/10/2019] [Indexed: 12/27/2022] Open
Abstract
Lines of evidence from several studies have shown that increases in life expectancy are now accompanied by increased disability rate. The expanded lifespan of the aging population imposes a challenge on the continuous increase of chronic disease. The prevalence of overweight and obesity is increasing at an alarming rate in many parts of the world. Further to increasing the onset of metabolic imbalances, obesity leads to reduced life span and affects cellular and molecular processes in a fashion resembling aging. Nine key hallmarks of the aging process have been proposed. In this review, we will review these hallmarks and discuss pathophysiological changes that occur with obesity, that are similar to or contribute to those that occur during aging. We present and discuss the idea that obesity, in addition to having disease-specific effects, may accelerate the rate of aging affecting all aspects of physiology and thus shortening life span and health span.
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Affiliation(s)
- Valentina Salvestrini
- Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, Italy
| | - Christian Sell
- Department of Pathology, Drexel University College of Medicine, Philadelphia, PA, United States
| | - Antonello Lorenzini
- Department of Biomedical and Neuromotor Sciences, Biochemistry Unit, University of Bologna, Bologna, Italy
- *Correspondence: Antonello Lorenzini
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Chen G, Li Q, Luo Y, Liu T, Zhou S, Pan E, Peng L. Effect of Notoginsenoside R1 on autologous adipose graft in rats. Mol Med Rep 2018; 17:5928-5933. [PMID: 29436657 DOI: 10.3892/mmr.2018.8596] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2016] [Accepted: 04/04/2017] [Indexed: 11/06/2022] Open
Abstract
Autologous fat particle transplantation has been widely used by surgeons. The present study evaluated the effect of Notoginsenoside R1 (NR1) treatment on rat autologous fat graft, along with the quality and retention rates. Male Sprague‑Dawley rats (n=60) received fat particle auto‑transplantation from the left abdominal cavity into lateral dorsum. A total of 14 days after surgery, NR1 in different doses (50, 100 and 200 mg/kg/day) was injected into rats, following which blood and fat graft samples were harvested at days 7, 14 and 28. Assessments were carried out by hematoxylin and eosin staining, western blotting, ELISA and immunohistochemistry (IHC). The survival rate of fat grafts was increased in three experimental groups, as detected by weight measurement. Histological scoring demonstrated that there were significant differences in tissue integrity between the 100 mg/kg/day group and the other 3 groups. hepatocyte growth factor, vascular endothelial growth factor, fibroblast growth factor, angiotensin and S100 levels in the 100 mg/kg/day NR1 group was increased compared with the other 2 treatment groups; however, all 3 treatment groups demonstrated increased expression of these proteins compared with the control group. Additionally, cluster of differentiation (CD)68 exhibited negative expression and CD31 showed weakly positive expression in all three experiments, as assessed by IHC. In conclusion, 100 mg/kg/day NR1 may potentially promote the retention rate and enhance the quality of autologous fat grafts via increasing vascularity in the recipient site. These results implicate NR1 as a therapeutic strategy for the improvement of outcome following fat graft surgery.
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Affiliation(s)
- Guizong Chen
- Department of Plastic Surgery, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China
| | - Qin Li
- Department of Plastic Surgery, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China
| | - Yanping Luo
- Department of Plastic Surgery, Guangzhou Mylike Aesthetic Surgery Hospital, Guangzhou, Guangdong 510000, P.R. China
| | - Tao Liu
- Department of Plastic Surgery, Guangzhou Mylike Aesthetic Surgery Hospital, Guangzhou, Guangdong 510000, P.R. China
| | - Shaolong Zhou
- Department of Plastic Surgery, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China
| | - Er Pan
- Department of Plastic Surgery, General Hospital of Guangzhou Military Command of PLA, Guangzhou, Guangdong 510000, P.R. China
| | - Lixia Peng
- Department of Plastic Surgery, General Hospital of Guangzhou Military Command of PLA, Guangzhou, Guangdong 510000, P.R. China
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Loap S, Lathe R. Mechanism Underlying Tissue Cryotherapy to Combat Obesity/Overweight: Triggering Thermogenesis. J Obes 2018; 2018:5789647. [PMID: 29854439 PMCID: PMC5954866 DOI: 10.1155/2018/5789647] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/28/2017] [Revised: 03/26/2018] [Accepted: 04/04/2018] [Indexed: 01/05/2023] Open
Abstract
BACKGROUND Local adipose tissue (AT) cooling is used to manage obesity and overweight, but the mechanism is unclear. The current view is that acute local cooling of AT induces adipocyte cell disruption and inflammation ("cryolipolysis") that lead to adipocyte cell death, with loss of subcutaneous fat being recorded over a prolonged period of weeks/months. A contrasting view is that AT loss via targeted cryotherapy might be mediated by thermogenic fat metabolism without cell disruption. METHODS In this retrospective study of individuals presenting for cryotherapy to the Clinic BioEsthetic, Paris, France, we recorded waist circumference, body weight, and body mass index (BMI) by direct measurement and by whole-body dual-energy X-ray absorptiometric scanning. In select individuals, blood analysis of markers of inflammation and fat mobilization was performed before and after the procedure. RESULTS We report that (i) single sessions of tissue cryotherapy lead to significant loss of tissue volume in the time frame of hours and (ii) multiple daily procedures lead to a cumulative decline in AT, as assessed by waist circumference, body weight, and BMI, confirmed by whole-body dual-energy X-ray absorptiometric scanning. In addition, (iii) blood analysis following tissue cryotherapy found no significant changes in biochemical parameters including markers of inflammation. Moreover, (iv) calculations of heat extracted and of compensatory weight loss taking place through thermogenesis are substantially consistent with the observed loss of AT. CONCLUSIONS These findings argue that cold-induced thermogenesis ("cryothermogenesis") rather than adipocyte disruption underlies the reduction in AT volume, raising the prospect that more intensive cryotherapy may be a viable option for combating obesity and overweight.
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Affiliation(s)
| | - Richard Lathe
- Division of Infection and Pathway Medicine, University of Edinburgh, Little France, Edinburgh, UK
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9
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Ejaz A, Mitterberger MC, Lu Z, Mattesich M, Zwierzina ME, Hörl S, Kaiser A, Viertler HP, Rostek U, Meryk A, Khalid S, Pierer G, Bast RC, Zwerschke W. Weight Loss Upregulates the Small GTPase DIRAS3 in Human White Adipose Progenitor Cells, Which Negatively Regulates Adipogenesis and Activates Autophagy via Akt-mTOR Inhibition. EBioMedicine 2016; 6:149-161. [PMID: 27211557 PMCID: PMC4856797 DOI: 10.1016/j.ebiom.2016.03.030] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2015] [Revised: 02/26/2016] [Accepted: 03/03/2016] [Indexed: 01/14/2023] Open
Abstract
Long-term weight-loss (WL) interventions reduce insulin serum levels, protect from obesity, and postpone age-associated diseases. The impact of long-term WL on adipose-derived stromal/progenitor cells (ASCs) is unknown. We identified DIRAS3 and IGF-1 as long-term WL target genes up-regulated in ASCs in subcutaneous white adipose tissue of formerly obese donors (WLDs). We show that DIRAS3 negatively regulates Akt, mTOR and ERK1/2 signaling in ASCs undergoing adipogenesis and acts as a negative regulator of this pathway and an activator of autophagy. Studying the IGF-1–DIRAS3 interaction in ASCs of WLDs, we demonstrate that IGF-1, although strongly up-regulated in these cells, hardly activates Akt, while ERK1/2 and S6K1 phosphorylation is activated by IGF-1. Overexpression of DIRAS3 in WLD ASCs completely inhibits Akt phosphorylation also in the presence of IGF-1. Phosphorylation of ERK1/2 and S6K1 is lesser reduced under these conditions. In conclusion, our key findings are that DIRAS3 down-regulates Akt–mTOR signaling in ASCs of WLDs. Moreover, DIRAS3 inhibits adipogenesis and activates autophagy in these cells.
Long-term weight loss (WL) induces DIRAS3 and IGF-1 in ASCs of sWAT in formerly obese humans. DIRAS3 selectively down-regulates IGF-1R-Akt–mTOR signaling in ASCs and channels the IGF-1 stimulus to the ERK1/2 branch. DIRAS3 inhibits adipogenesis and activates autophagy in ASCs. Long-term weight loss (WL) interventions reduce insulin serum levels, protect from obesity and postpone age-associated diseases. The impact of WL on adipose-derived stromal/progenitor cells (ASCs), stem cell-like cells in human subcutaneous white adipose tissue (sWAT), is not understood. We found that WL induced GTP-binding RAS-like 3 (DIRAS3) and insulin-like growth factor 1 (IGF-1), regulators of the IGF-1–mTOR signal transduction pathway, in ASCs in sWAT of formerly obese humans. We demonstrate that DIRAS3 selectively down-regulates IGF-1R–Akt–mTOR signaling in ASCs upon WL even in the presence of high IGF-1 level and that DIRAS3 inhibits adipogenesis and activates autophagy in these cells.
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Affiliation(s)
- Asim Ejaz
- Division of Cell Metabolism and Differentiation Research, Institute for Biomedical Aging Research, University of Innsbruck, 6020 Innsbruck, Austria
| | - Maria C Mitterberger
- Division of Cell Metabolism and Differentiation Research, Institute for Biomedical Aging Research, University of Innsbruck, 6020 Innsbruck, Austria
| | - Zhen Lu
- Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Monika Mattesich
- Department of Plastic and Reconstructive Surgery, Innsbruck Medical University, 6020 Innsbruck, Austria
| | - Marit E Zwierzina
- Department of Anatomy, Histology and Embryology, Innsbruck Medical University, 6020 Innsbruck, Austria
| | - Susanne Hörl
- Division of Cell Metabolism and Differentiation Research, Institute for Biomedical Aging Research, University of Innsbruck, 6020 Innsbruck, Austria
| | - Andreas Kaiser
- Division of Cell Metabolism and Differentiation Research, Institute for Biomedical Aging Research, University of Innsbruck, 6020 Innsbruck, Austria
| | - Hans-Peter Viertler
- Division of Cell Metabolism and Differentiation Research, Institute for Biomedical Aging Research, University of Innsbruck, 6020 Innsbruck, Austria
| | - Ursula Rostek
- Division of Cell Metabolism and Differentiation Research, Institute for Biomedical Aging Research, University of Innsbruck, 6020 Innsbruck, Austria
| | - Andreas Meryk
- Division of Cell Metabolism and Differentiation Research, Institute for Biomedical Aging Research, University of Innsbruck, 6020 Innsbruck, Austria
| | - Sana Khalid
- Daniel Swarovski Research Laboratory, Department of Visceral, Transplant and Thoracic Surgery, Innsbruck Medical University, 6020 Innsbruck, Austria
| | - Gerhard Pierer
- Department of Plastic and Reconstructive Surgery, Innsbruck Medical University, 6020 Innsbruck, Austria
| | - Robert C Bast
- Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Werner Zwerschke
- Division of Cell Metabolism and Differentiation Research, Institute for Biomedical Aging Research, University of Innsbruck, 6020 Innsbruck, Austria.
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Böhm A, Weigert C, Staiger H, Häring HU. Exercise and diabetes: relevance and causes for response variability. Endocrine 2016; 51:390-401. [PMID: 26643313 PMCID: PMC4762932 DOI: 10.1007/s12020-015-0792-6] [Citation(s) in RCA: 46] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/10/2015] [Accepted: 10/28/2015] [Indexed: 12/31/2022]
Abstract
Exercise as a key prevention strategy for diabetes and obesity is commonly accepted and recommended throughout the world. Unfortunately, not all individuals profit to the same extent, some exhibit exercise resistance. This phenomenon of non-response to exercise is found for several endpoints, including glucose tolerance and insulin sensitivity. Since these non-responders are of notable quantity, there is the need to understand the underlying mechanisms and to identify predictors of response. This displays the basis to develop personalized training intervention regimes. In this review, we summarize the current knowledge on response variability, with focus on human studies and improvement of glucose homeostasis as outcome.
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Affiliation(s)
- Anja Böhm
- Department of Internal Medicine IV, Division of Endocrinology, Diabetology, Angiology, Nephrology, and Clinical Chemistry, University Hospital Tübingen, Eberhard Karls University Tübingen, 72076, Tübingen, Germany
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the Eberhard Karls University Tübingen, Tübingen, Germany
- German Center for Diabetes Research (DZD), 85764, München-Neuherberg, Germany
| | - Cora Weigert
- Department of Internal Medicine IV, Division of Endocrinology, Diabetology, Angiology, Nephrology, and Clinical Chemistry, University Hospital Tübingen, Eberhard Karls University Tübingen, 72076, Tübingen, Germany
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the Eberhard Karls University Tübingen, Tübingen, Germany
- German Center for Diabetes Research (DZD), 85764, München-Neuherberg, Germany
| | - Harald Staiger
- Department of Internal Medicine IV, Division of Endocrinology, Diabetology, Angiology, Nephrology, and Clinical Chemistry, University Hospital Tübingen, Eberhard Karls University Tübingen, 72076, Tübingen, Germany
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the Eberhard Karls University Tübingen, Tübingen, Germany
- German Center for Diabetes Research (DZD), 85764, München-Neuherberg, Germany
| | - Hans-Ulrich Häring
- Department of Internal Medicine IV, Division of Endocrinology, Diabetology, Angiology, Nephrology, and Clinical Chemistry, University Hospital Tübingen, Eberhard Karls University Tübingen, 72076, Tübingen, Germany.
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the Eberhard Karls University Tübingen, Tübingen, Germany.
- German Center for Diabetes Research (DZD), 85764, München-Neuherberg, Germany.
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11
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Aging and adipose tissue: potential interventions for diabetes and regenerative medicine. Exp Gerontol 2016; 86:97-105. [PMID: 26924669 DOI: 10.1016/j.exger.2016.02.013] [Citation(s) in RCA: 225] [Impact Index Per Article: 25.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2016] [Revised: 02/22/2016] [Accepted: 02/24/2016] [Indexed: 12/15/2022]
Abstract
Adipose tissue dysfunction occurs with aging and has systemic effects, including peripheral insulin resistance, ectopic lipid deposition, and inflammation. Fundamental aging mechanisms, including cellular senescence and progenitor cell dysfunction, occur in adipose tissue with aging and may serve as potential therapeutic targets in age-related disease. In this review, we examine the role of adipose tissue in healthy individuals and explore how aging leads to adipose tissue dysfunction, redistribution, and changes in gene regulation. Adipose tissue plays a central role in longevity, and interventions restricted to adipose tissue may impact lifespan. Conversely, obesity may represent a state of accelerated aging. We discuss the potential therapeutic potential of targeting basic aging mechanisms, including cellular senescence, in adipose tissue, using type II diabetes and regenerative medicine as examples. We make the case that aging should not be neglected in the study of adipose-derived stem cells for regenerative medicine strategies, as elderly patients make up a large portion of individuals in need of such therapies.
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12
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Liu R, Pulliam DA, Liu Y, Salmon AB. Dynamic differences in oxidative stress and the regulation of metabolism with age in visceral versus subcutaneous adipose. Redox Biol 2015; 6:401-408. [PMID: 26355396 PMCID: PMC4572386 DOI: 10.1016/j.redox.2015.07.014] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2015] [Revised: 07/22/2015] [Accepted: 07/24/2015] [Indexed: 12/25/2022] Open
Abstract
Once thought only as storage for excess nutrients, adipose tissue has been shown to be a dynamic organ implicated in the regulation of many physiological processes. There is emerging evidence supporting differential roles for visceral and subcutaneous white adipose tissue in maintaining health, although how these roles are modulated by the aging process is not clear. However, the proposed beneficial effects of subcutaneous fat suggest that targeting maintenance of this tissue could lead to healthier aging. In this study, we tested whether alterations in adipose function with age might be associated with changes in oxidative stress. Using visceral and subcutaneous adipose from C57BL/6 mice, we discovered effects of both age and depot location on markers of lipolysis and adipogenesis. Conversely, accumulation of oxidative damage and changes in enzymatic antioxidant expression with age were largely similar between these two depots. The activation of each of the stress signaling pathways JNK and MAPK/ERK was relatively suppressed in subcutaneous adipose tissue suggesting reduced sensitivity to oxidative stress. Similarly, pre-adipocytes from subcutaneous adipose were significantly more resistant than visceral-derived cells to cell death caused by oxidative stress. Cellular respiration in visceral-derived cells was dramatically higher than in cells derived from subcutaneous adipose despite little evidence for differences in mitochondrial density. Together, our data identify molecular mechanisms by which visceral and subcutaneous adipose differ with age and suggest potential targetable means to preserve healthy adipose aging.
Aging alters metabolism differently in C57BL/6 visceral and subcutaneous fat. Oxidative stress and antioxidants show little difference between these fat depots. Age-induced activation of JNK and ERK/MAPK is elevated in visceral fat. Preadipocytes from visceral fat have relatively higher metabolic rate.
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Affiliation(s)
- Roy Liu
- The Sam and Ann Barshop Institute for Longevity and Aging Studies, The University of Texas Health Science Center at San Antonio, San Antonio, TX, USA
| | - Daniel A Pulliam
- The Sam and Ann Barshop Institute for Longevity and Aging Studies, The University of Texas Health Science Center at San Antonio, San Antonio, TX, USA; Departments of Cellular & Structural Biology, The University of Texas Health Science Center at San Antonio, San Antonio, TX, USA
| | - Yuhong Liu
- The Sam and Ann Barshop Institute for Longevity and Aging Studies, The University of Texas Health Science Center at San Antonio, San Antonio, TX, USA
| | - Adam B Salmon
- The Sam and Ann Barshop Institute for Longevity and Aging Studies, The University of Texas Health Science Center at San Antonio, San Antonio, TX, USA; Molecular Medicine, The University of Texas Health Science Center at San Antonio, San Antonio, TX, USA; Geriatric Research, Education and Clinical Center, South Texas Veterans Health Care System, San Antonio, TX, USA.
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13
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Storage capacity of subcutaneous fat in Japanese adults. Eur J Clin Nutr 2015; 69:933-8. [PMID: 25649236 DOI: 10.1038/ejcn.2014.292] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2014] [Revised: 11/14/2014] [Accepted: 12/13/2014] [Indexed: 11/08/2022]
Abstract
BACKGROUND On the basis of our previous study, which examined the nonlinear relationship between visceral fat area (VFA) and percent regional fat mass in the trunk, we hypothesise the presence of some storage capacity of subcutaneous fat. This study aimed to examine the storage capacity of subcutaneous fat on the basis of subcutaneous fat area (SFA) and VFA in 791 Japanese adult males and 563 females. METHODS Regression analyses by using SFA as a dependent variable and VFA as an independent variable were performed for each group classified by visceral fat obesity (VO): VO (VFA ⩾ 100 cm(2)) and the no-VO (NVO) groups. To statistically identify an optimal critical point for subcutaneous fat accumulation, we changed the cutoff point for the VO group from 50-150 cm(2) in 10-cm(2) increments and confirmed the significance of the correlation between SFA and VFA for each obesity group, the statistical difference in correlations between NVO and VO groups, and the goodness of fit for the two regression lines using the standard error of estimation values. These analyses were conducted for each sex and age (<65 and ⩾ 65 years) group. RESULTS The critical point for subcutaneous fat accumulation appears at the following cutoff points of VFA: 130 cm(2) in <65-year-old males, 110 cm(2) in ⩾ 65-year-old males and 100 cm(2) in both female groups. CONCLUSIONS These results suggest the presence of some storage capacity of subcutaneous fat. As a further application, these findings may serve to improve the risk assessment of obesity-related diseases.
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14
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Zhang Y, Fischer KE, Soto V, Liu Y, Sosnowska D, Richardson A, Salmon AB. Obesity-induced oxidative stress, accelerated functional decline with age and increased mortality in mice. Arch Biochem Biophys 2015; 576:39-48. [PMID: 25558793 DOI: 10.1016/j.abb.2014.12.018] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2014] [Revised: 12/05/2014] [Accepted: 12/20/2014] [Indexed: 12/22/2022]
Abstract
Obesity is a serious chronic disease that increases the risk of numerous co-morbidities including metabolic syndrome, cardiovascular disease and cancer as well as increases risk of mortality, leading some to suggest this condition represents accelerated aging. Obesity is associated with significant increases in oxidative stress in vivo and, despite the well-explored relationship between oxidative stress and aging, the role this plays in the increased mortality of obese subjects remains an unanswered question. Here, we addressed this by undertaking a comprehensive, longitudinal study of a group of high fat-fed obese mice and assessed both their changes in oxidative stress and in their performance in physiological assays known to decline with aging. In female C57BL/6J mice fed a high-fat diet starting in adulthood, mortality was significantly increased as was oxidative damage in vivo. High fat-feeding significantly accelerated the decline in performance in several assays, including activity, gait, and rotarod. However, we also found that obesity had little effect on other markers of function and actually improved performance in grip strength, a marker of muscular function. Together, this first comprehensive assessment of longitudinal, functional changes in high fat-fed mice suggests that obesity may induce segmental acceleration of some of the aging process.
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Affiliation(s)
- Yiqiang Zhang
- The Sam and Ann Barshop Institute for Longevity and Aging Studies, The University of Texas Health Science Center at San Antonio, San Antonio, TX, USA; Department of Physiology, The University of Texas Health Science Center at San Antonio, San Antonio, TX, USA
| | - Kathleen E Fischer
- Department of Biology, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Vanessa Soto
- The Sam and Ann Barshop Institute for Longevity and Aging Studies, The University of Texas Health Science Center at San Antonio, San Antonio, TX, USA
| | - Yuhong Liu
- The Sam and Ann Barshop Institute for Longevity and Aging Studies, The University of Texas Health Science Center at San Antonio, San Antonio, TX, USA
| | - Danuta Sosnowska
- Reynolds Oklahoma Center on Aging, University of Oklahoma Health Sciences Center and Oklahoma City VA Medical Center, Oklahoma, OK, USA
| | - Arlan Richardson
- Reynolds Oklahoma Center on Aging, University of Oklahoma Health Sciences Center and Oklahoma City VA Medical Center, Oklahoma, OK, USA
| | - Adam B Salmon
- The Sam and Ann Barshop Institute for Longevity and Aging Studies, The University of Texas Health Science Center at San Antonio, San Antonio, TX, USA; Department of Molecular Medicine, The University of Texas Health Science Center at San Antonio, San Antonio, TX, USA; Geriatric Research, Education and Clinical Center, South Texas Veterans Health Care System, San Antonio, TX, USA.
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15
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How calorie-focused thinking about obesity and related diseases may mislead and harm public health. An alternative. Public Health Nutr 2014; 18:571-81. [DOI: 10.1017/s1368980014002559] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Abstract
AbstractPrevailing thinking about obesity and related diseases holds that quantifying calories should be a principal concern and target for intervention. Part of this thinking is that consumed calories – regardless of their sources – are equivalent; i.e. ‘a calorie is a calorie’. The present commentary discusses various problems with the idea that ‘a calorie is a calorie’ and with a primarily quantitative focus on food calories. Instead, the authors argue for a greater qualitative focus on the sources of calories consumed (i.e. a greater focus on types of foods) and on the metabolic changes that result from consuming foods of different types. In particular, the authors consider how calorie-focused thinking is inherently biased against high-fat foods, many of which may be protective against obesity and related diseases, and supportive of starchy and sugary replacements, which are likely detrimental. Shifting the focus to qualitative food distinctions, a central argument of the paper is that obesity and related diseases are problems due largely to food-induced physiology (e.g. neurohormonal pathways) not addressable through arithmetic dieting (i.e. calorie counting). The paper considers potential harms of public health initiatives framed around calorie balance sheets – targeting ‘calories in’ and/or ‘calories out’ – that reinforce messages of overeating and inactivity as underlying causes, rather than intermediate effects, of obesity. Finally, the paper concludes that public health should work primarily to support the consumption of whole foods that help protect against obesity-promoting energy imbalance and metabolic dysfunction and not continue to promote calorie-directed messages that may create and blame victims and possibly exacerbate epidemics of obesity and related diseases.
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16
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Zhang H, Xue Y, Wang H, Huang Y, Du M, Yang Q, Zhu MJ. Mast cell deficiency exacerbates inflammatory bowel symptoms in interleukin-10-deficient mice. World J Gastroenterol 2014; 20:9106-9115. [PMID: 25083083 PMCID: PMC4112873 DOI: 10.3748/wjg.v20.i27.9106] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/06/2013] [Revised: 01/07/2014] [Accepted: 03/05/2014] [Indexed: 02/06/2023] Open
Abstract
AIM: To test the role of mast cells in gut inflammation and colitis using interleukin (IL)-10-deficient mice as an experimental model.
METHODS: Mast cell-deficient (KitW-sh/W-sh) mice were crossbred with IL-10-deficient mice to obtain double knockout (DKO) mice. The growth, mucosal damage and colitis status of DKO mice were compared with their IL-10-deficient littermates.
RESULTS: DKO mice exhibited exacerbated colitis compared with their IL-10-deficient littermates, as shown by increased pathological score, higher myeloperoxidase content, enhanced Th1 type pro-inflammatory cytokines and inflammatory signaling, elevated oxidative stress, as well as pronounced goblet cell loss. In addition, deficiency in mast cells resulted in enhanced mucosal damage, increased gut permeability, and impaired epithelial tight junctions. Mast cell deficiency was also linked to systemic inflammation, as demonstrated by higher serum levels of tumor necrosis factor α and interferon γ in DKO mice than that in IL-10-deficient mice.
CONCLUSION: Mast cell deficiency in IL-10-deficient mice resulted in systematic and gut inflammation, impaired gut barrier function, and severer Th1-mediated colitis when compared to mice with only IL-10-deficiency. Inflammation and impaired gut epithelial barrier function likely form a vicious cycle to worsen colitis in the DKO mice.
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17
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Escudero B, Lucas D, Albo C, Dhup S, Bacher JW, Sánchez-Muñoz A, Fernández M, Rivera-Torres J, Carmona RM, Fuster E, Carreiro C, Bernad R, González MA, Andrés V, Blanco L, Roche E, Fabregat I, Samper E, Bernad A. Polμ deficiency increases resistance to oxidative damage and delays liver aging. PLoS One 2014; 9:e93074. [PMID: 24691161 PMCID: PMC3972199 DOI: 10.1371/journal.pone.0093074] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2013] [Accepted: 02/28/2014] [Indexed: 01/02/2023] Open
Abstract
Polμ is an error-prone PolX polymerase that contributes to classical NHEJ DNA repair. Mice lacking Polμ (Polμ−/−) show altered hematopoiesis homeostasis and DSB repair and a more pronounced nucleolytic resection of some V(D)J junctions. We previously showed that Polμ−/− mice have increased learning capacity at old ages, suggesting delayed brain aging. Here we investigated the effect of Polμ−/− deficiency on liver aging. We found that old Polμ−/− mice (>20 month) have greater liver regenerative capacity compared with wt animals. Old Polμ−/− liver showed reduced genomic instability and increased apoptosis resistance. However, Polμ−/− mice did not show an extended life span and other organs (e.g., heart) aged normally. Our results suggest that Polμ deficiency activates transcriptional networks that reduce constitutive apoptosis, leading to enhanced liver repair at old age.
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Affiliation(s)
- Beatriz Escudero
- Departamento de Cardiología Regenerativa, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain
- Departamento de Inmunología y Oncología, Centro Nacional de Biotecnología/CSIC, Campus Universidad Autónoma de Madrid, Madrid, Spain
| | - Daniel Lucas
- Departamento de Inmunología y Oncología, Centro Nacional de Biotecnología/CSIC, Campus Universidad Autónoma de Madrid, Madrid, Spain
| | - Carmen Albo
- Departamento de Cardiología Regenerativa, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain
| | - Suveera Dhup
- Departamento de Cardiología Regenerativa, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain
| | - Jeff W. Bacher
- Genetic Analysis Group, Promega Corporation, Madison,Wisconsin, United States of America
| | - Aránzazu Sánchez-Muñoz
- Departamento de Bioquímica y Biología Molecular II, Universidad Complutense, Madrid, Spain
| | - Margarita Fernández
- Departamento de Bioquímica y Biología Molecular II, Universidad Complutense, Madrid, Spain
| | - José Rivera-Torres
- Departamento de Epidemiología, Aterotrombosis e Imagen, Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain
| | - Rosa M. Carmona
- Departamento de Cardiología Regenerativa, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain
- Departamento de Inmunología y Oncología, Centro Nacional de Biotecnología/CSIC, Campus Universidad Autónoma de Madrid, Madrid, Spain
| | - Encarnación Fuster
- Institute of Bioengineering, Miguel Hernandez University, Elche (Alicante), Spain
| | - Candelas Carreiro
- Departamento de Cardiología Regenerativa, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain
| | - Raquel Bernad
- Departamento de Inmunología y Oncología, Centro Nacional de Biotecnología/CSIC, Campus Universidad Autónoma de Madrid, Madrid, Spain
| | - Manuel A. González
- Departamento de Cardiología Regenerativa, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain
- Departamento de Inmunología y Oncología, Centro Nacional de Biotecnología/CSIC, Campus Universidad Autónoma de Madrid, Madrid, Spain
| | - Vicente Andrés
- Departamento de Epidemiología, Aterotrombosis e Imagen, Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain
| | - Luis Blanco
- Centro de Biología Molecular Severo Ochoa/CSIC, Cantoblanco, Madrid, Spain
| | - Enrique Roche
- Institute of Bioengineering, Miguel Hernandez University, Elche (Alicante), Spain
- CIBERobn(CB12/03/30038) Instituto de Salud Carlos, Madrid, Spain
| | - Isabel Fabregat
- Bellvitge Biomedical Research Institut (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain
| | - Enrique Samper
- Departamento de Cardiología Regenerativa, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain
- Departamento de Inmunología y Oncología, Centro Nacional de Biotecnología/CSIC, Campus Universidad Autónoma de Madrid, Madrid, Spain
| | - Antonio Bernad
- Departamento de Cardiología Regenerativa, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain
- Departamento de Inmunología y Oncología, Centro Nacional de Biotecnología/CSIC, Campus Universidad Autónoma de Madrid, Madrid, Spain
- * E-mail:
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18
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Ghosh S, Wanders D, Stone KP, Van NT, Cortez CC, Gettys TW. A systems biology analysis of the unique and overlapping transcriptional responses to caloric restriction and dietary methionine restriction in rats. FASEB J 2014; 28:2577-90. [PMID: 24571921 DOI: 10.1096/fj.14-249458] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
Dietary methionine restriction (MR) and calorie restriction (CR) each improve metabolic health and extend life span. We used comprehensive transcriptome profiling and systems biology analysis to interrogate the unique and overlapping molecular responses in rats provided these dietary regimens for 20 mo after weaning. Microarray analysis was conducted on inguinal white adipose (IWAT), brown adipose tissue (BAT), liver, and skeletal muscle. Compared to controls, CR-induced transcriptomic responses (absolute fold change ≥1.5 and P≤0.05) were comparable in IWAT, BAT, and liver (~800 genes). MR-induced effects were largely restricted to IWAT and liver (~2400 genes). Pathway enrichment and gene-coexpression analyses showed that induction of fatty acid synthesis in IWAT was common to CR and MR, whereas immunity and proinflammatory signaling pathways were specifically down-regulated in MR-treated IWAT and liver (FDR≤0.07-0.3). BAT demonstrated consistent down-regulation of PPAR-signaling under CR and MR, whereas muscle was largely unaffected. Interactome analysis identified CR-specific down-regulation of cytoskeletal matrix components in IWAT and MR-specific up-regulation of ribosomal genes in liver (FDR≤0.001). Transcriptomic down-regulation of inflammation genes by MR in IWAT was consistent with upstream inhibition of STAT3. Together, these results provide an integrated picture of the breadth of transcriptional responses to MR and CR among key metabolic tissues.
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Affiliation(s)
- Sujoy Ghosh
- Laboratory of Computational Biology and Laboratory of Nutrient Sensing and Adipocyte Signaling, Pennington Biomedical Research Center, Baton Rouge, Louisiana, USA; and Cardiovascular and Metabolic Disorders Research Program, Duke-National University of Singapore Graduate Medical School, Singapore
| | - Desiree Wanders
- Laboratory of Nutrient Sensing and Adipocyte Signaling, Pennington Biomedical Research Center, Baton Rouge, Louisiana, USA; and
| | - Kirsten P Stone
- Laboratory of Nutrient Sensing and Adipocyte Signaling, Pennington Biomedical Research Center, Baton Rouge, Louisiana, USA; and
| | - Nancy T Van
- Laboratory of Nutrient Sensing and Adipocyte Signaling, Pennington Biomedical Research Center, Baton Rouge, Louisiana, USA; and
| | - Cory C Cortez
- Laboratory of Nutrient Sensing and Adipocyte Signaling, Pennington Biomedical Research Center, Baton Rouge, Louisiana, USA; and
| | - Thomas W Gettys
- Laboratory of Computational Biology and Laboratory of Nutrient Sensing and Adipocyte Signaling, Pennington Biomedical Research Center, Baton Rouge, Louisiana, USA; and
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19
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Finelli C, Sommella L, Gioia S, La Sala N, Tarantino G. Should visceral fat be reduced to increase longevity? Ageing Res Rev 2013; 12:996-1004. [PMID: 23764746 DOI: 10.1016/j.arr.2013.05.007] [Citation(s) in RCA: 71] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2012] [Revised: 05/21/2013] [Accepted: 05/28/2013] [Indexed: 02/07/2023]
Abstract
Several epidemiologic studies have implicated visceral fat as a major risk factor for insulin resistance, type 2 diabetes mellitus, cardiovascular disease, stroke, metabolic syndrome and death. Utilizing novel models of visceral obesity, numerous studies have demonstrated that the relationship between visceral fat and longevity is causal while the accrual of subcutaneous fat does not appear to play an important role in the etiology of disease risk. Specific recommended intake levels vary based on a number of factors, including current weight, activity levels, and weight loss goals. It is discussed the need of reducing the visceral fat as a potential treatment strategy to prevent or delay age-related diseases and to increase longevity.
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Affiliation(s)
- Carmine Finelli
- Center of Obesity and Eating Disorders, Stella Maris Mediterraneum Foundation, Chiaromonte, Potenza, Italy.
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20
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Intapad S, Tull FL, Brown AD, Dasinger JH, Ojeda NB, Fahling JM, Alexander BT. Renal denervation abolishes the age-dependent increase in blood pressure in female intrauterine growth-restricted rats at 12 months of age. Hypertension 2013; 61:828-34. [PMID: 23424240 DOI: 10.1161/hypertensionaha.111.00645] [Citation(s) in RCA: 79] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Perinatal insults program sex differences in blood pressure, with males more susceptible than females. Aging may augment developmental programming of chronic disease, but the mechanisms involved are not clear. We previously reported that female growth-restricted offspring are normotensive after puberty. Therefore, we tested the hypothesis that age increases susceptibility to hypertension in female growth-restricted offspring. Blood pressure remained similar at 6 months of age; however, blood pressure was significantly elevated in female growth-restricted offspring relative to control by 12 months of age (137±3 vs 117±4 mm Hg; P<0.01, respectively). Body weight did not differ at 6 or 12 months of age; however, total fat mass and visceral fat were significantly increased at 12 months in female growth-restricted offspring (P<0.05 vs control). Glomerular filtration rate remained normal, yet renal vascular resistance was increased at 12 months of age in female growth-restricted offspring (P<0.05 vs control). Plasma leptin, which can increase sympathetic nerve activity, did not differ at 6 months but was increased at 12 months of age in female growth-restricted offspring (P<0.05 vs control). Because of the age-dependent increase in leptin, we hypothesized that the renal nerves may contribute to the age-dependent increase in blood pressure. Bilateral renal denervation abolished the elevated blood pressure in female growth-restricted offspring normalizing it relative to denervated female control offspring. Thus, these data indicate that age induces an increase in visceral fat and circulating leptin associated with a significant increase in blood pressure in female growth-restricted offspring, with the renal nerves serving as an underlying mechanism.
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Affiliation(s)
- Suttira Intapad
- Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS 39216, USA
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21
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Zhang L, Dasuri K, Fernandez-Kim SO, Bruce-Keller AJ, Freeman LR, Pepping JK, Beckett TL, Murphy MP, Keller JN. Prolonged diet induced obesity has minimal effects towards brain pathology in mouse model of cerebral amyloid angiopathy: implications for studying obesity-brain interactions in mice. Biochim Biophys Acta Mol Basis Dis 2013; 1832:1456-62. [PMID: 23313575 DOI: 10.1016/j.bbadis.2013.01.002] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2012] [Revised: 12/30/2012] [Accepted: 01/02/2013] [Indexed: 12/12/2022]
Abstract
Cerebral amyloid angiopathy (CAA) occurs in nearly every individual with Alzheimer's disease (AD) and Down's syndrome, and is the second largest cause of intracerebral hemorrhage. Mouse models of CAA have demonstrated evidence for increased gliosis contributing to CAA pathology. Nearly two thirds of Americans are overweight or obese, with little known about the effects of obesity on the brain, although increasingly the vasculature appears to be a principle target of obesity effects on the brain. In the current study we describe for the first time whether diet induced obesity (DIO) modulates glial reactivity, amyloid levels, and inflammatory signaling in a mouse model of CAA. In these studies we identify surprisingly that DIO does not significantly increase Aβ levels, astrocyte (GFAP) or microglial (IBA-1) gliosis in the CAA mice. However, within the hippocampal gyri a localized increase in reactive microglia were increased in the CA1 and stratum oriens relative to CAA mice on a control diet. DIO was observed to selectively increase IL-6 in CAA mice, with IL-1β and TNF-α not increased in CAA mice in response to DIO. Taken together, these data show that prolonged DIO has only modest effects towards Aβ in a mouse model of CAA, but appears to elevate some localized microglial reactivity within the hippocampal gyri and selective markers of inflammatory signaling. These data are consistent with the majority of the existing literature in other models of Aβ pathology, which surprisingly show a mixed profile of DIO effects towards pathological processes in mouse models of neurodegenerative disease. The importance for considering the potential impact of ceiling effects in pathology within mouse models of Aβ pathogenesis, and the current experimental limitations for DIO in mice to fully replicate metabolic dysfunction present in human obesity, are discussed. This article is part of a Special Issue entitled: Animal Models of Disease.
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Affiliation(s)
- Le Zhang
- Louisiana State University, Baton Rouge, LA 70803, USA
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23
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Alzheimer's disease promotion by obesity: induced mechanisms-molecular links and perspectives. Curr Gerontol Geriatr Res 2012; 2012:986823. [PMID: 22701480 PMCID: PMC3373073 DOI: 10.1155/2012/986823] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2012] [Accepted: 04/10/2012] [Indexed: 01/08/2023] Open
Abstract
The incidence of AD is increasing in parallel with the increase in life expectancy. At the same time the prevalence of metabolic syndrome and obesity is reaching epidemic proportions in western populations. Stress is one of the major inducers of visceral fat and obesity development, underlying accelerated aging processes. Adipose tissue is at present considered as an active endocrine organ, producing important mediators involved in metabolism regulation as well as in inflammatory mechanisms. Insulin and leptin resistance has been related to the dysregulation of energy balance and to the induction of a chronic inflammatory status which have been recognized as important cofactors in cognitive impairment and AD initiation and progression. The aim of this paper is to disclose the correlation between the onset and progression of AD and the stress-induced changes in lifestyle, leading to overnutrition and reduced physical activity, ending with metabolic syndrome and obesity. The involved molecular mechanisms will be briefly discussed, and advisable guide lines for the prevention of AD through lifestyle modifications will be proposed.
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24
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Franchini A, Mandrioli M, Franceschi C, Ottaviani E. Morpho-functional changes of fat body in bacteria fed Drosophila melanogaster strains. J Mol Histol 2011; 43:243-51. [PMID: 22179854 DOI: 10.1007/s10735-011-9382-y] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2011] [Accepted: 12/04/2011] [Indexed: 01/12/2023]
Abstract
We have examined the addition of Escherichia coli to the diet at day 0 of adult life of females from two Oregon R Drosophila melanogaster strains, selected for different longevities: a short-life with an average adult life span of 10 days and a long-life standard R strain with an average adult life span of 50 days. The addition of bacteria to the diet significantly prolonged the fly longevity in both strains and affected the structure and histochemical reactivity of the fat body. The increased survival was characterized by great amount of glycogen accumulated in fat body cells from both strains. In aged control animals, fed with standard diet, lipid droplets were seen to be stored in fat body of short-lived, but not long-lived, flies. On the whole, our data indicate that exogenous bacteria are able to extend the survival of Drosophila females, and suggest that such a beneficial effect can be mediated, at least in part, by the fat body cells that likely play a role in modulating the accumulation and mobilization of reserve stores to ensure lifelong energy homeostasis.
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Affiliation(s)
- Antonella Franchini
- Department of Biology, University of Modena and Reggio Emilia, Via Campi 213/D, 41125, Modena, Italy
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25
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Dasuri K, Zhang L, Ebenezer P, Fernandez-Kim SO, Bruce-Keller AJ, Szweda LI, Keller JN. Proteasome alterations during adipose differentiation and aging: links to impaired adipocyte differentiation and development of oxidative stress. Free Radic Biol Med 2011; 51:1727-35. [PMID: 21871954 PMCID: PMC3378646 DOI: 10.1016/j.freeradbiomed.2011.08.001] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/22/2011] [Revised: 07/29/2011] [Accepted: 08/02/2011] [Indexed: 02/07/2023]
Abstract
Intracellular proteins are degraded by a number of proteases, including the ubiquitin-proteasome pathway (UPP). Impairments in the UPP occur during the aging of a variety of tissues, although little is known in regards to age-related alterations to the UPP during the aging of adipose tissue. The UPP is known to be involved in regulating the differentiation of a variety of cell types, although the potential changes in the UPP during adipose differentiation have not been fully elucidated. How the UPP is altered in aging adipose tissue and adipocyte differentiation and the effects of proteasome inhibition on adipocyte homeostasis and differentiation are critical issues to elucidate experimentally. Adipogenesis continues throughout the life of adipose tissue, with continual differentiation of preadipocytes essential to maintaining tissue function during aging, and UPP alterations in mature adipocytes are likely to directly modulate adipose function during aging. In this study we demonstrate that aging induces alterations in the activity and expression of principal components of the UPP. Additionally, we show that multiple changes in the UPP occur during the differentiation of 3T3-L1 cells into adipocytes. In vitro data link observed UPP alterations to increased levels of oxidative stress and altered adipose biology relevant to both aging and differentiation. Taken together, these data demonstrate that changes in the UPP occur in response to adipose aging and adipogenesis and strongly suggest that proteasome inhibition is sufficient to decrease adipose differentiation, as well as increasing oxidative stress in mature adipocytes, both of which probably promote deleterious effects on adipose aging.
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Affiliation(s)
- Kalavathi Dasuri
- Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge Louisiana 70808
| | - Le Zhang
- Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge Louisiana 70808
| | - Philip Ebenezer
- Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge Louisiana 70808
| | - Sun Ok Fernandez-Kim
- Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge Louisiana 70808
| | - Annadora J. Bruce-Keller
- Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge Louisiana 70808
| | - Luke I. Szweda
- Free Radical Biology and Aging Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, USA
| | - Jeffrey N. Keller
- Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge Louisiana 70808
- Address correspondence to: Dr Jeffrey N Keller, Pennington Biomedical Research Center, 6400 Perkins Road, Baton Rouge Louisiana 70808, (P) 225-763-3190 (E)
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26
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Mansilla E, Díaz Aquino V, Zambón D, Marin GH, Mártire K, Roque G, Ichim T, Riordan NH, Patel A, Sturla F, Larsen G, Spretz R, Núñez L, Soratti C, Ibar R, van Leeuwen M, Tau JM, Drago H, Maceira A. Could metabolic syndrome, lipodystrophy, and aging be mesenchymal stem cell exhaustion syndromes? Stem Cells Int 2011; 2011:943216. [PMID: 21716667 PMCID: PMC3118295 DOI: 10.4061/2011/943216] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2010] [Accepted: 03/22/2011] [Indexed: 12/15/2022] Open
Abstract
One of the most
important and complex diseases of modern society
is metabolic syndrome. This syndrome has not
been completely understood, and therefore an
effective treatment is not available yet. We
propose a possible stem cell mechanism involved
in the development of metabolic syndrome. This
way of thinking lets us consider also other
significant pathologies that could have similar
etiopathogenic pathways, like lipodystrophic
syndromes, progeria, and aging. All these
clinical situations could be the consequence of
a progressive and persistent stem cell
exhaustion syndrome (SCES). The main outcome of
this SCES would be an irreversible loss of the
effective regenerative mesenchymal stem cells
(MSCs) pools. In this way, the normal repairing
capacities of the organism could become
inefficient. Our point of view could open the
possibility for a new strategy of treatment in
metabolic syndrome, lipodystrophic syndromes,
progeria, and even aging: stem cell
therapies.
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Affiliation(s)
- Eduardo Mansilla
- Tissue Engineering, Regenerative Medicine and Cell Therapies Laboratory, CUCAIBA, Ministry of Health, Province of Buenos Aires, 1900 La Plata, Argentina
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