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      Is Open Access

      GDF15 Provides an Endocrine Signal of Nutritional Stress in Mice and Humans

      1 , 12 , 1 , 12 , 1 , 12 , 1 , 1 , 1 , 1 , 3 , 1 , 1 , 1 , 6 , 6 , 7 , 7 , 4 , 5 , 5 , 11 , 8 , 9 , 1 , 2 , 1 , 2 , 1 , 1 , 1 , 5 , 1 , 3 , 6 , 10 , 4 , 4 , 4 , 1 , 13 , 1 , 13 , 14 , , 1 , 13 , ∗∗

      Cell Metabolism

      Cell Press

      GDF15, GFRAL, integrated stress response, overnutrion, conditioned taste aversion

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          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Summary

          GDF15 is an established biomarker of cellular stress. The fact that it signals via a specific hindbrain receptor, GFRAL, and that mice lacking GDF15 manifest diet-induced obesity suggest that GDF15 may play a physiological role in energy balance. We performed experiments in humans, mice, and cells to determine if and how nutritional perturbations modify GDF15 expression. Circulating GDF15 levels manifest very modest changes in response to moderate caloric surpluses or deficits in mice or humans, differentiating it from classical intestinally derived satiety hormones and leptin. However, GDF15 levels do increase following sustained high-fat feeding or dietary amino acid imbalance in mice. We demonstrate that GDF15 expression is regulated by the integrated stress response and is induced in selected tissues in mice in these settings. Finally, we show that pharmacological GDF15 administration to mice can trigger conditioned taste aversion, suggesting that GDF15 may induce an aversive response to nutritional stress.

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          Highlights

          • Dietary changes influencing adipose/gut-derived hormones do not alter GDF15 levels
          • Chronic high-fat or acute lysine-deficient diet exposure increases GDF15 levels
          • GDF15 administration triggers conditioned taste aversion in mice
          • GDF15 is a stress-induced hormone that may mediate an aversive dietary response

          Abstract

          Patel et al. show that whereas short-term overfeeding or fasting does not change GDF15 levels substantially, prolonged high-fat feeding and lysine-deficient diets activate the integrated stress response and increase GDF15 levels. GDF15 administration triggers conditioned taste aversion in mice, suggesting that GDF15 might induce an aversive response to nutritional stress.

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          Most cited references 76

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          Regulated translation initiation controls stress-induced gene expression in mammalian cells.

           H Zeng,  R Wek,  Isabel Novoa (2001)
          Protein kinases that phosphorylate the alpha subunit of eukaryotic initiation factor 2 (eIF2alpha) are activated in stressed cells and negatively regulate protein synthesis. Phenotypic analysis of targeted mutations in murine cells reveals a novel role for eIF2alpha kinases in regulating gene expression in the unfolded protein response (UPR) and in amino acid starved cells. When activated by their cognate upstream stress signals, the mammalian eIF2 kinases PERK and GCN2 repress translation of most mRNAs but selectively increase translation of Activating Transcription Factor 4 (ATF4), resulting in the induction of the downstream gene CHOP (GADD153). This is the first example of a mammalian signaling pathway homologous to the well studied yeast general control response in which eIF2alpha phosphorylation activates genes involved in amino acid biosynthesis. Mammalian cells thus utilize an ancient pathway to regulate gene expression in response to diverse stress signals.
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            An integrated stress response regulates amino acid metabolism and resistance to oxidative stress.

            Eukaryotic cells respond to unfolded proteins in their endoplasmic reticulum (ER stress), amino acid starvation, or oxidants by phosphorylating the alpha subunit of translation initiation factor 2 (eIF2alpha). This adaptation inhibits general protein synthesis while promoting translation and expression of the transcription factor ATF4. Atf4(-/-) cells are impaired in expressing genes involved in amino acid import, glutathione biosynthesis, and resistance to oxidative stress. Perk(-/-) cells, lacking an upstream ER stress-activated eIF2alpha kinase that activates Atf4, accumulate endogenous peroxides during ER stress, whereas interference with the ER oxidase ERO1 abrogates such accumulation. A signaling pathway initiated by eIF2alpha phosphorylation protects cells against metabolic consequences of ER oxidation by promoting the linked processes of amino acid sufficiency and resistance to oxidative stress.
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              Adipocyte death defines macrophage localization and function in adipose tissue of obese mice and humans.

              Macrophage infiltration of white adipose tissue (WAT) is implicated in the metabolic complications of obesity. The precipitating event(s) and function(s) of macrophage infiltration into WAT are unknown. We demonstrate that >90% of all macrophages in WAT of obese mice and humans are localized to dead adipocytes, where they fuse to form syncytia that sequester and scavenge the residual "free" adipocyte lipid droplet and ultimately form multinucleate giant cells, a hallmark of chronic inflammation. Adipocyte death increases in obese (db/db) mice (30-fold) and humans and exhibits ultrastructural features of necrosis (but not apoptosis). These observations identify necrotic-like adipocyte death as a pathologic hallmark of obesity and suggest that scavenging of adipocyte debris is an important function of WAT macrophages in obese individuals. The frequency of adipocyte death is positively correlated with increased adipocyte size in obese mice and humans and in hormone-sensitive lipase-deficient (HSL-/-) mice, a model of adipocyte hypertrophy without increased adipose mass. WAT of HSL-/- mice exhibited a 15-fold increase in necrotic-like adipocyte death and formation of macrophage syncytia, coincident with increased tumor necrosis factor-alpha gene expression. These results provide a novel framework for understanding macrophage recruitment, function, and persistence in WAT of obese individuals.
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                Author and article information

                Contributors
                Journal
                Cell Metab
                Cell Metab
                Cell Metabolism
                Cell Press
                1550-4131
                1932-7420
                05 March 2019
                05 March 2019
                : 29
                : 3
                : 707-718.e8
                Affiliations
                [1 ]Metabolic Research Laboratories, Wellcome Trust-Medical Research Council Institute of Metabolic Science, University of Cambridge, Cambridge CB2 0QQ, UK
                [2 ]Cambridge Institute for Medical Research, Cambridge University, Cambridge CB2 0XY, UK
                [3 ]INRA, Unité de Nutrition Humaine, Université Clermont Auvergne, 63000 Clermont-Ferrand, France
                [4 ]Internal Medicine Research Unit, Pfizer Global R&D, 1 Portland Street, Cambridge, MA, USA
                [5 ]School of Sport, Exercise and Health Sciences, Loughborough University, Loughborough, Leicestershire LE11 3TU, UK
                [6 ]Translational Research Institute for Metabolism and Diabetes, Florida Hospital, Orlando, FL, USA
                [7 ]Pennington Biomedical Research Center, Baton Rouge, LA, USA
                [8 ]Department of Clinical Medicine, Aarhus University Hospital, Aarhus University, Aarhus, Denmark
                [9 ]Section of Specialized Endocrinology, Department of Endocrinology, Oslo University Hospital, Rikshospitalet, Oslo, Norway
                [10 ]Department of Physical Performance, Norwegian School of Sport Sciences, Oslo, Norway
                Author notes
                []Corresponding author dbs23@ 123456medschl.cam.ac.uk
                [∗∗ ]Corresponding author so104@ 123456medschl.cam.ac.uk
                [11]

                Present address: Metabolic Research Group, Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford OX3 7LE, UK

                [12]

                These authors contributed equally

                [13]

                Senior author

                [14]

                Lead Contact

                Article
                S1550-4131(18)30753-8
                10.1016/j.cmet.2018.12.016
                6408327
                30639358
                © 2018 The Authors

                This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

                Categories
                Article

                Cell biology

                overnutrion, integrated stress response, gfral, gdf15, conditioned taste aversion

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