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      Neuroendocrine control of appetite and metabolism

      review-article
      , ,
      Experimental & Molecular Medicine
      Nature Publishing Group UK
      Hypothalamus, Homeostasis

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          Abstract

          Body homeostasis is predominantly controlled by hormones secreted by endocrine organs. The central nervous system contains several important endocrine structures, including the hypothalamic-pituitary axis. Conventionally, neurohormones released by the hypothalamus and the pituitary gland (hypophysis) have received much attention owing to the unique functions of the end hormones released by their target peripheral organs (e.g., glucocorticoids released by the adrenal glands). Recent advances in mouse genetics have revealed several important metabolic functions of hypothalamic neurohormone-expressing cells, many of which are not readily explained by the action of the corresponding classical downstream hormones. Notably, the newly identified functions are better explained by the action of conventional neurotransmitters (e.g., glutamate and GABA) that constitute a neuronal circuit. In this review, we discuss the regulation of appetite and metabolism by hypothalamic neurohormone-expressing cells, with a focus on the distinct contributions of neurohormones and neurotransmitters released by these neurons.

          Metabolism: Dual function for neurohormone-producing cells in the brain

          Signaling molecules produced by the brain’s hypothalamus function both as neurotransmitters (within the central nervous system) and hormones (throughout the rest of the body) to regulate appetite and metabolism. Jong-Woo Sohn and colleagues from the Korea Advanced Institute of Science and Technology in Daejeon, South Korea, summarize the well-established ways in which certain hypothalamic cells interact with parts of the pituitary gland in the brain to control the activity of hormones involved in feeding behaviors and energy balances.The same cells can also impact appetite and metabolism in non-hormonal ways. New research has shown that neurohormone-producing cells in the hypothalamus can form connections with appetite-associated neurons and communicate via neurotransmitters. A deeper understanding of this process could lead to new therapies for obesity, diabetes and other metabolic disorders.

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          Most cited references117

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          Thyroid hormone regulation of metabolism.

          Thyroid hormone (TH) is required for normal development as well as regulating metabolism in the adult. The thyroid hormone receptor (TR) isoforms, α and β, are differentially expressed in tissues and have distinct roles in TH signaling. Local activation of thyroxine (T4), to the active form, triiodothyronine (T3), by 5'-deiodinase type 2 (D2) is a key mechanism of TH regulation of metabolism. D2 is expressed in the hypothalamus, white fat, brown adipose tissue (BAT), and skeletal muscle and is required for adaptive thermogenesis. The thyroid gland is regulated by thyrotropin releasing hormone (TRH) and thyroid stimulating hormone (TSH). In addition to TRH/TSH regulation by TH feedback, there is central modulation by nutritional signals, such as leptin, as well as peptides regulating appetite. The nutrient status of the cell provides feedback on TH signaling pathways through epigentic modification of histones. Integration of TH signaling with the adrenergic nervous system occurs peripherally, in liver, white fat, and BAT, but also centrally, in the hypothalamus. TR regulates cholesterol and carbohydrate metabolism through direct actions on gene expression as well as cross-talk with other nuclear receptors, including peroxisome proliferator-activated receptor (PPAR), liver X receptor (LXR), and bile acid signaling pathways. TH modulates hepatic insulin sensitivity, especially important for the suppression of hepatic gluconeogenesis. The role of TH in regulating metabolic pathways has led to several new therapeutic targets for metabolic disorders. Understanding the mechanisms and interactions of the various TH signaling pathways in metabolism will improve our likelihood of identifying effective and selective targets.
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            The role of the hypothalamic-pituitary-adrenal axis in neuroendocrine responses to stress

            Animals respond to stress by activating a wide array of behavioral and physiological responses that are collectively referred to as the stress response. Corticotropin-releasing factor (CRF) plays a central role in the stress response by regulating the hypothalamic-pituitary-adrenal (HPA) axis. In response to stress, CRF initiates a cascade of events that culminate in the release of glucocorticoids from the adrenal cortex. As a result of the great number of physiological and behavioral effects exerted by glucocorticoids, several mechanisms have evolved to control HPA axis activation and integrate the stress response. Glucocorticoid feedback inhibition plays a prominent role in regulating the magnitude and duration of glucocorticoid release. In addition to glucocorticoid feedback, the HPA axis is regulated at the level of the hypothalamus by a diverse group of afferent projections from limbic, mid-brain, and brain stem nuclei. The stress response is also mediated in part by brain stem noradrenergic neurons, sympathetic andrenornedullary circuits, and parasympathetic systems. In summary, the aim of this review is to discuss the role of the HPA axis in the integration of adaptive responses to stress. We also identify and briefly describe the major neuronal and endocrine systems that contribute to the regulation of the HPA axis and the maintenance of homeostasis in the face of aversive stimuli.
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              The inhibitory circuit architecture of the lateral hypothalamus orchestrates feeding.

              The growing prevalence of overeating disorders is a key contributor to the worldwide obesity epidemic. Dysfunction of particular neural circuits may trigger deviations from adaptive feeding behaviors. The lateral hypothalamus (LH) is a crucial neural substrate for motivated behavior, including feeding, but the precise functional neurocircuitry that controls LH neuronal activity to engage feeding has not been defined. We observed that inhibitory synaptic inputs from the extended amygdala preferentially innervate and suppress the activity of LH glutamatergic neurons to control food intake. These findings help explain how dysregulated activity at a number of unique nodes can result in a cascading failure within a defined brain network to produce maladaptive feeding.
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                Author and article information

                Contributors
                jwsohn@kaist.ac.kr
                Journal
                Exp Mol Med
                Exp Mol Med
                Experimental & Molecular Medicine
                Nature Publishing Group UK (London )
                1226-3613
                2092-6413
                9 April 2021
                9 April 2021
                April 2021
                : 53
                : 4
                : 505-516
                Affiliations
                GRID grid.37172.30, ISNI 0000 0001 2292 0500, Department of Biological Sciences, , Korea Advanced Institute of Science and Technology, ; Daejeon, South Korea
                Author information
                http://orcid.org/0000-0002-2401-0620
                http://orcid.org/0000-0002-2840-4176
                Article
                597
                10.1038/s12276-021-00597-9
                8102538
                33837263
                12a370a0-f859-4bba-840b-0d7b212d3281
                © The Author(s) 2021

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 15 September 2020
                : 11 February 2021
                : 17 February 2021
                Funding
                Funded by: FundRef https://doi.org/10.13039/501100003725, National Research Foundation of Korea (NRF);
                Award ID: 2019R1A2C2005161
                Award ID: 2016R1C1B2006614
                Award Recipient :
                Categories
                Review Article
                Custom metadata
                © The Author(s) 2021

                Molecular medicine
                hypothalamus,homeostasis
                Molecular medicine
                hypothalamus, homeostasis

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