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      KSR2 Mutations Are Associated with Obesity, Insulin Resistance, and Impaired Cellular Fuel Oxidation

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          Summary

          Kinase suppressor of Ras 2 (KSR2) is an intracellular scaffolding protein involved in multiple signaling pathways. Targeted deletion of Ksr2 leads to obesity in mice, suggesting a role in energy homeostasis. We explored the role of KSR2 in humans by sequencing 2,101 individuals with severe early-onset obesity and 1,536 controls. We identified multiple rare variants in KSR2 that disrupt signaling through the Raf-MEK-ERK pathway and impair cellular fatty acid oxidation and glucose oxidation in transfected cells; effects that can be ameliorated by the commonly prescribed antidiabetic drug, metformin. Mutation carriers exhibit hyperphagia in childhood, low heart rate, reduced basal metabolic rate and severe insulin resistance. These data establish KSR2 as an important regulator of energy intake, energy expenditure, and substrate utilization in humans. Modulation of KSR2-mediated effects may represent a novel therapeutic strategy for obesity and type 2 diabetes.

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          Highlights

          • Mutations in KSR2 are associated with obesity in humans

          • Mutations affect ERK signaling and impair the oxidation of glucose and fatty acids

          • Patients display hyperphagia, insulin resistance, and a reduced basal metabolic rate

          • KSR2 is an important regulator of energy intake and expenditure in humans

          Abstract

          Mutations in KSR2, a scaffolding protein involved in multiple signaling pathways, lead to severe metabolic alterations that cause early onset obesity in humans.

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          Most cited references46

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          Acta Crystallographica Section D Biological Crystallography, 60(12), 2126-2132
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            AMPK: a nutrient and energy sensor that maintains energy homeostasis.

            AMP-activated protein kinase (AMPK) is a crucial cellular energy sensor. Once activated by falling energy status, it promotes ATP production by increasing the activity or expression of proteins involved in catabolism while conserving ATP by switching off biosynthetic pathways. AMPK also regulates metabolic energy balance at the whole-body level. For example, it mediates the effects of agents acting on the hypothalamus that promote feeding and entrains circadian rhythms of metabolism and feeding behaviour. Finally, recent studies reveal that AMPK conserves ATP levels through the regulation of processes other than metabolism, such as the cell cycle and neuronal membrane excitability.
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              Cellular and molecular mechanisms of metformin: an overview.

              Considerable efforts have been made since the 1950s to better understand the cellular and molecular mechanisms of action of metformin, a potent antihyperglycaemic agent now recommended as the first-line oral therapy for T2D (Type 2 diabetes). The main effect of this drug from the biguanide family is to acutely decrease hepatic glucose production, mostly through a mild and transient inhibition of the mitochondrial respiratory chain complex I. In addition, the resulting decrease in hepatic energy status activates AMPK (AMP-activated protein kinase), a cellular metabolic sensor, providing a generally accepted mechanism for the action of metformin on hepatic gluconeogenesis. The demonstration that respiratory chain complex I, but not AMPK, is the primary target of metformin was recently strengthened by showing that the metabolic effect of the drug is preserved in liver-specific AMPK-deficient mice. Beyond its effect on glucose metabolism, metformin has been reported to restore ovarian function in PCOS (polycystic ovary syndrome), reduce fatty liver, and to lower microvascular and macrovascular complications associated with T2D. Its use has also recently been suggested as an adjuvant treatment for cancer or gestational diabetes and for the prevention in pre-diabetic populations. These emerging new therapeutic areas for metformin will be reviewed together with recent findings from pharmacogenetic studies linking genetic variations to drug response, a promising new step towards personalized medicine in the treatment of T2D.
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                Author and article information

                Contributors
                Journal
                Cell
                Cell
                Cell
                Cell Press
                0092-8674
                1097-4172
                07 November 2013
                07 November 2013
                : 155
                : 4
                : 765-777
                Affiliations
                [1 ]University of Cambridge Metabolic Research Laboratories and NIHR Cambridge Biomedical Research Centre, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke’s Hospital, Cambridge CB2 0QQ, UK
                [2 ]Wellcome Trust Sanger Institute, Cambridge, CB10 1SA, UK
                [3 ]Lexicon Pharmaceuticals, The Woodlands, TX 77381, USA
                [4 ]Institute of Child Health, University College London, London WC1E 6BT, UK
                [5 ]University of Bristol and Bristol Royal Hospital for Children, Bristol BS2 8BJ, UK
                [6 ]Institute of Cancer Research, Chester Beatty Laboratories, London SW3 6JB, UK
                [7 ]MRC Epidemiology Unit, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke’s Hospital, Cambridge CB2 0QQ, UK
                [8 ]MRC Mitochondrial Biology Unit, Wellcome Trust/MRC Building, Hills Road, Cambridge CB2 0XY, UK
                Author notes
                []Corresponding author isf20@ 123456cam.ac.uk
                [9]

                These authors contributed equally to this work

                Article
                S0092-8674(13)01276-2
                10.1016/j.cell.2013.09.058
                3898740
                24209692
                fc77b598-b38c-47be-ba39-1e0d536023e9
                © 2013 The Authors

                This document may be redistributed and reused, subject to certain conditions.

                History
                : 18 July 2013
                : 31 July 2013
                : 20 September 2013
                Categories
                Article

                Cell biology
                Cell biology

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