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      Obesity and Aging in the Drosophila Model

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          Abstract

          Being overweight increases the risk of many metabolic disorders, but how it affects lifespan is not completely clear. Not all obese people become ill, and the exact mechanism that turns excessive fat storage into a health-threatening state remains unknown. Drosophila melanogaster has served as an excellent model for many diseases, including obesity, diabetes, and hyperglycemia-associated disorders, such as cardiomyopathy or nephropathy. Here, we review the connections between fat storage and aging in different types of fly obesity. Whereas obesity induced by high-fat or high-sugar diet is associated with hyperglycemia, cardiomyopathy, and in some cases, shortening of lifespan, there are also examples in which obesity correlates with longevity. Transgenic lines with downregulations of the insulin/insulin-like growth factor (IIS) and target of rapamycin (TOR) signaling pathways, flies reared under dietary restriction, and even certain longevity selection lines are obese, yet long-lived. The mechanisms that underlie the differential lifespans in distinct types of obesity remain to be elucidated, but fat turnover, inflammatory pathways, and dysregulations of glucose metabolism may play key roles. Altogether, Drosophila is an excellent model to study the physiology of adiposity in both health and disease.

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          Most cited references145

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          Pathophysiology and treatment of type 2 diabetes: perspectives on the past, present, and future.

          Glucose metabolism is normally regulated by a feedback loop including islet β cells and insulin-sensitive tissues, in which tissue sensitivity to insulin affects magnitude of β-cell response. If insulin resistance is present, β cells maintain normal glucose tolerance by increasing insulin output. Only when β cells cannot release sufficient insulin in the presence of insulin resistance do glucose concentrations rise. Although β-cell dysfunction has a clear genetic component, environmental changes play an essential part. Modern research approaches have helped to establish the important role that hexoses, aminoacids, and fatty acids have in insulin resistance and β-cell dysfunction, and the potential role of changes in the microbiome. Several new approaches for treatment have been developed, but more effective therapies to slow progressive loss of β-cell function are needed. Recent findings from clinical trials provide important information about methods to prevent and treat type 2 diabetes and some of the adverse effects of these interventions. However, additional long-term studies of drugs and bariatric surgery are needed to identify new ways to prevent and treat type 2 diabetes and thereby reduce the harmful effects of this disease. Copyright © 2014 Elsevier Ltd. All rights reserved.
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            Regulation of lifespan in Drosophila by modulation of genes in the TOR signaling pathway.

            In many species, reducing nutrient intake without causing malnutrition extends lifespan. Like DR (dietary restriction), modulation of genes in the insulin-signaling pathway, known to alter nutrient sensing, has been shown to extend lifespan in various species. In Drosophila, the target of rapamycin (TOR) and the insulin pathways have emerged as major regulators of growth and size. Hence we examined the role of TOR pathway genes in regulating lifespan by using Drosophila. We show that inhibition of TOR signaling pathway by alteration of the expression of genes in this nutrient-sensing pathway, which is conserved from yeast to human, extends lifespan in a manner that may overlap with known effects of dietary restriction on longevity. In Drosophila, TSC1 and TSC2 (tuberous sclerosis complex genes 1 and 2) act together to inhibit TOR (target of rapamycin), which mediates a signaling pathway that couples amino acid availability to S6 kinase, translation initiation, and growth. We find that overexpression of dTsc1, dTsc2, or dominant-negative forms of dTOR or dS6K all cause lifespan extension. Modulation of expression in the fat is sufficient for the lifespan-extension effects. The lifespan extensions are dependent on nutritional condition, suggesting a possible link between the TOR pathway and dietary restriction.
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              Diabetes mellitus: a "thrifty" genotype rendered detrimental by "progress"?

              J V Neel (1962)
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                Author and article information

                Journal
                Int J Mol Sci
                Int J Mol Sci
                ijms
                International Journal of Molecular Sciences
                MDPI
                1422-0067
                27 June 2018
                July 2018
                : 19
                : 7
                : 1896
                Affiliations
                [1 ]Department of Zoology, Stockholm University, Svante Arrhenius väg 18B, S-106 91 Stockholm, Sweden
                [2 ]Institute of Zoology, Slovak Academy of Sciences, Dúbravská cesta 9, 845 06 Bratislava, Slovakia
                Author notes
                [* ]Correspondence: martina.galikova@ 123456zoologi.su.se (M.G.); peter.klepsatel@ 123456gmail.com (P.K.); Tel.: +49-152-1471-6362 (M.G.); +49-152-1812-3314 (P.K.)
                Author information
                https://orcid.org/0000-0001-8934-0236
                Article
                ijms-19-01896
                10.3390/ijms19071896
                6073435
                29954158
                e76cd377-2c75-414b-ba57-c1436f6cb528
                © 2018 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 19 May 2018
                : 25 June 2018
                Categories
                Review

                Molecular biology
                drosophila,obesity,energy metabolism,lifespan,high-sugar diet,high-fat diet,dietary restriction,obesity paradox,akh,iis

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