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The role of transcriptional regulators in central control of appetite and body weight

Nature Reviews Endocrinology volume 5, pages 160–166 (2009)Cite this article

Abstract

Individuals who live in industrialized countries often eat a calorie-rich diet and perform little physical activity. These habits are thought to be critical contributors to the rapidly rising incidence of obesity, a condition that affects hundreds of millions of people worldwide. High-calorie intake alters metabolic-sensing pathways in central nervous system neurons, and these changes have pathogenic roles in the development of obesity. This review aims to summarize our current knowledge about the neuronal populations (the central melanocortin system in particular) and transcriptional regulators, including STAT3 and FOXO1, that are involved in the maintenance of normal body weight. We describe the interactions between these transcriptional factors and their target genes, which encode the main appetite-regulating neuropeptides (agouti-related peptide and α-melanocyte-stimulating hormone). We discuss the transcriptional co-activator PGC-1-α and the supposed metabolic-sensor protein SIRT1, and their potential roles as targets for novel antiobesity medications.

Key Points

  • High-calorie intake alters metabolic-sensing pathways in central nervous system neurons; these alterations contribute to the development of obesity

  • A key center of the neural control of energy balance is the melanocortin system

  • Peripheral hormones, including insulin and leptin, function as key signals that regulate energy balance by direct effects on their cognate receptors on hypothalamic neurons

  • Hypothalamic receptors activate intracellular signaling molecules, including the transcription factors STAT3 and FOXO1, which translate hormonal signals into coordinated body-weight regulation

  • The transcriptional co-activator PGC-1-α and the supposed metabolic-sensor protein SIRT1 are potential molecular mediators of weight regulation, and might represent targets for novel antiobesity medications

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Figure 1: A proposed model of gene-expression regulation by SIRT1, PGC-1-α, and FOXO1 in central melanocortin neurons.

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Acknowledgements

This work was supported by the Department of Internal Medicine, Division of Hypothalamic Research, University of Texas Southwestern Medical Center (R Coppari) and by National Institutes of Health grants DK53301, MH61583, DK081185 to JK Elmquist.

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Authors and Affiliations

  1. all at the Department of Internal Medicine, Division of Hypothalamic Research, R Coppari is an Assistant Professor, G Ramadori is a Post-doctoral Fellow and JK Elmquist is a Professor, University of Texas Southwestern Medical Center, Dallas, TX, USA.,

    Roberto Coppari, Giorgio Ramadori & Joel K Elmquist

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Correspondence to Roberto Coppari.

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Coppari, R., Ramadori, G. & Elmquist, J. The role of transcriptional regulators in central control of appetite and body weight. Nat Rev Endocrinol 5, 160–166 (2009). https://doi.org/10.1038/ncpendmet1070

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