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      Hypothalamic KLF4 mediates leptin's effects on food intake via AgRP

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          Abstract

          Krüppel-like factor 4 (KLF4) is a zinc-finger-type transcription factor expressed in a range of tissues that plays multiple functions. We report that hypothalamic KLF4 represents a new transcription factor specifically modulating agouti-related protein (AgRP) expression in vivo. Hypothalamic KLF4 colocalizes with AgRP neurons and is modulated by nutritional status and leptin. Over-expression of KLF4 in the hypothalamic arcuate nucleus (ARC) induces food intake and increases body weight through the specific stimulation of AgRP, as well as blunting leptin sensitivity in lean rats independent of forkhead box protein 01 (FoxO1). Down-regulation of KLF4 in the ARC inhibits fasting-induced food intake in both lean and diet-induced obese (DIO) rats. Silencing KLF4, however, does not, on its own, enhance peripheral leptin sensitivity in DIO rats.

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          Anatomy and regulation of the central melanocortin system.

          Roger Cone (2005)
          The central melanocortin system is perhaps the best-characterized neuronal pathway involved in the regulation of energy homeostasis. This collection of circuits is unique in having the capability of sensing signals from a staggering array of hormones, nutrients and afferent neural inputs. It is likely to be involved in integrating long-term adipostatic signals from leptin and insulin, primarily received by the hypothalamus, with acute signals regulating hunger and satiety, primarily received by the brainstem. The system is also unique from a regulatory point of view in that it is composed of fibers expressing both agonists and antagonists of melanocortin receptors. Given that the central melanocortin system is an active target for development of drugs for the treatment of obesity, diabetes and cachexia, it is important to understand the system in its full complexity, including the likelihood that the system also regulates the cardiovascular and reproductive systems.
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            Sp1 and krüppel-like factor family of transcription factors in cell growth regulation and cancer.

            A R Black, J D Black, J. Azizkhan-Clifford (2001)
            The Sp/KLF family contains at least twenty identified members which include Sp1-4 and numerous krüppel-like factors. Members of the family bind with varying affinities to sequences designated as 'Sp1 sites' (e.g., GC-boxes, CACCC-boxes, and basic transcription elements). Family members have different transcriptional properties and can modulate each other's activity by a variety of mechanisms. Since cells can express multiple family members, Sp/KLF factors are likely to make up a transcriptional network through which gene expression can be fine-tuned. 'Sp1 site'-dependent transcription can be growth-regulated, and the activity, expression, and/or post-translational modification of multiple family members is altered with cell growth. Furthermore, Sp/KLF factors are involved in many growth-related signal transduction pathways and their overexpression can have positive or negative effects on proliferation. In addition to growth control, Sp/KLF factors have been implicated in apoptosis and angiogenesis; thus, the family is involved in several aspects of tumorigenesis. Consistent with a role in cancer, Sp/KLF factors interact with oncogenes and tumor suppressors, they can be oncogenic themselves, and altered expression of family members has been detected in tumors. Effects of changes in Sp/KLF factors are context-dependent and can appear contradictory. Since these factors act within a network, this diversity of effects may arise from differences in the expression profile of family members in various cells. Thus, it is likely that the properties of the overall network of Sp/KLF factors play a determining role in regulation of cell growth and tumor progression. Copyright 2001 Wiley-Liss, Inc.
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              KLF family members regulate intrinsic axon regeneration ability.

              Darcie L Moore, Murray G Blackmore, Ying Hu … (2009)
              Neurons in the central nervous system (CNS) lose their ability to regenerate early in development, but the underlying mechanisms are unknown. By screening genes developmentally regulated in retinal ganglion cells (RGCs), we identified Krüppel-like factor-4 (KLF4) as a transcriptional repressor of axon growth in RGCs and other CNS neurons. RGCs lacking KLF4 showed increased axon growth both in vitro and after optic nerve injury in vivo. Related KLF family members suppressed or enhanced axon growth to differing extents, and several growth-suppressive KLFs were up-regulated postnatally, whereas growth-enhancing KLFs were down-regulated. Thus, coordinated activities of different KLFs regulate the regenerative capacity of CNS neurons.
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                Author and article information

                Contributors
                Carlos Dieguez
                Ruben Nogueiras
                Journal
                Journal ID (nlm-ta): Mol Metab
                Journal ID (iso-abbrev): Mol Metab
                Title: Molecular Metabolism
                Publisher: Elsevier
                ISSN (Electronic): 2212-8778
                Publication date PMC-release: 15 April 2014
                Publication date (Electronic): 15 April 2014
                Publication date Collection: July 2014
                Volume: 3
                Issue: 4
                Pages: 441-451
                Affiliations
                [1 ]Department of Physiology, CIMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria, Santiago de Compostela 15782, Spain
                [2 ]CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), 15706, Spain
                [3 ]Department of Morphological Sciences, School of Medicine, University of Santiago de Compostela-Instituto de Investigación Sanitaria, Santiago de Compostela 15782, Spain
                Author notes
                [∗ ]Corresponding authors. Department of Physiology, Centro de Investigaciones Medicas de la Universidad de Santiago (CIMUS), University of Santiago de Compostela & CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Avenida de Barcelona s/n, 15782 Santiago de Compostela, A Coruña, Spain. Tel.: +34 881815437. carlos.dieguez@ 123456usc.es ruben.nogueiras@ 123456usc.es
                Article
                Publisher ID: S2212-8778(14)00079-9
                DOI: 10.1016/j.molmet.2014.04.001
                PMC ID: 4060210
                PubMed ID: 24944903
                SO-VID: a57e1de9-5b7b-4b80-b9c4-5e7f1056e01f
                Copyright © © 2014 The Authors
                License:

                This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/3.0/).

                History
                Date received : 28 February 2014
                Date revision received : 1 April 2014
                Date accepted : 2 April 2014
                Categories
                Subject: Original Article

                Keywords: agrp,food intake,leptin
                Data availability:
                Keywords: agrp, food intake, leptin

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