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      LKB1 deletion with the RIP2.Cre transgene modifies pancreatic β-cell morphology and enhances insulin secretion in vivo

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          Abstract

          The tumor suppressor liver kinase B1 (LKB1), also called STK11, is a protein kinase mutated in Peutz-Jeghers syndrome. LKB1 phosphorylates AMP-activated protein kinase (AMPK) and several related protein kinases. Whereas deletion of both catalytic isoforms of AMPK from the pancreatic β-cell and hypothalamic neurons using the rat insulin promoter (RIP2). Cre transgene (βAMPKdKO) diminishes insulin secretion in vivo, deletion of LKB1 in the β-cell with an inducible Pdx-1.CreER transgene enhances insulin secretion in mice. To determine whether the differences between these models reflect genuinely distinct roles for the two kinases in the β-cell or simply differences in the timing and site(s) of deletion, we have therefore created mice deleted for LKB1 with the RIP2.Cre transgene. In marked contrast to βAMPKdKO mice, βLKB1KO mice showed diminished food intake and weight gain, enhanced insulin secretion, unchanged insulin sensitivity, and improved glucose tolerance. In line with the phenotype of Pdx1- CreER mice, total β-cell mass and the size of individual islets and β-cells were increased and islet architecture was markedly altered in βLKB1KO islets. Signaling by mammalian target of rapamycin (mTOR) to eIF4-binding protein-1 and ribosomal S6 kinase was also enhanced. In contrast to Pdx1- CreER-mediated deletion, the expression of Glut2, glucose-induced changes in membrane potential and intracellular Ca 2+ were sharply reduced in βLKB1KO mouse islets and the stimulation of insulin secretion was modestly inhibited. We conclude that LKB1 and AMPK play distinct roles in the control of insulin secretion and that the timing of LKB1 deletion, and/or its loss from extrapancreatic sites, influences the final impact on β-cell function.

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          Most cited references38

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          Calmodulin-dependent protein kinase kinase-beta is an alternative upstream kinase for AMP-activated protein kinase.

          The AMP-activated protein kinase (AMPK) is a critical regulator of energy balance at both the cellular and whole-body levels. Two upstream kinases have been reported to activate AMPK in cell-free assays, i.e., the tumor suppressor LKB1 and calmodulin-dependent protein kinase kinase. However, evidence that this is physiologically relevant currently only exists for LKB1. We now report that there is a significant basal activity and phosphorylation of AMPK in LKB1-deficient cells that can be stimulated by Ca2+ ionophores, and studies using the CaMKK inhibitor STO-609 and isoform-specific siRNAs show that CaMKKbeta is required for this effect. CaMKKbeta also activates AMPK much more rapidly than CaMKKalpha in cell-free assays. K(+)-induced depolarization in rat cerebrocortical slices, which increases intracellular Ca2+ without disturbing cellular adenine nucleotide levels, activates AMPK, and this is blocked by STO-609. Our results suggest a potential Ca(2+)-dependent neuroprotective pathway involving phosphorylation and activation of AMPK by CaMKKbeta.
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            LKB1-dependent signaling pathways.

            This review focuses on remarkable recent findings concerning the mechanism by which the LKB1 protein kinase that is mutated in Peutz-Jeghers cancer syndrome operates as a tumor suppressor. We discuss evidence that the cellular localization and activity of LKB1 is controlled through its interaction with a catalytically inactive protein resembling a protein kinase, termed STRAD, and an armadillo repeat-containing protein, named mouse protein 25 (MO25). The data suggest that LKB1 functions as a tumor suppressor by not only inhibiting proliferation, but also by exerting profound effects on cell polarity and, most unexpectedly, on the ability of a cell to detect and respond to low cellular energy levels. Genetic and biochemical findings indicate that LKB1 exerts its effects by phosphorylating and activating 14 protein kinases, all related to the AMP-activated protein kinase. The work described in this review shows how a study of an obscure cancer syndrome can uncover new and important regulatory pathways, relevant to the understanding of multiple human diseases.
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              Diabetes, obesity, and the brain.

              Recent evidence suggests a key role for the brain in the control of both body fat content and glucose metabolism. Neuronal systems that regulate energy intake, energy expenditure, and endogenous glucose production sense and respond to input from hormonal and nutrient-related signals that convey information regarding both body energy stores and current energy availability. In response to this input, adaptive changes occur that promote energy homeostasis and the maintenance of blood glucose levels in the normal range. Defects in this control system are implicated in the link between obesity and type 2 diabetes.
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                Author and article information

                Journal
                Am J Physiol Endocrinol Metab
                ajpendo
                ajpendo
                AJPENDO
                American Journal of Physiology - Endocrinology and Metabolism
                American Physiological Society (Bethesda, MD )
                0193-1849
                1522-1555
                June 2010
                30 March 2010
                1 June 2011
                : 298
                : 6
                : E1261-E1273
                Affiliations
                [1] 1Section of Cell Biology, Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, and
                [2] 2Photonics Group, Department of Physics, Imperial College London, London, United Kingdom
                Author notes
                Address for reprint requests and other correspondence: G. A. Rutter, Section of Cell Biology, Division of Diabetes, Endocrinology and Metabolism, Dept. of Medicine, Imperial College London, London, UK (e-mail: g.rutter@ 123456imperial.ac.uk ).
                Article
                E-00100-2010
                10.1152/ajpendo.00100.2010
                2886523
                20354156
                c7e2eacf-4313-4e7d-9ac1-9652786ad990
                Copyright © 2010 the American Physiological Society

                This document may be redistributed and reused, subject to www.the-aps.org/publications/journals/funding_addendum_policy.htm.

                History
                : 11 February 2010
                : 29 March 2010
                Categories
                Articles

                Endocrinology & Diabetes
                amp-activated protein kinase,pancreas,insulin secretion,β-cell,liver kinase b1,food intake

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