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1
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Ray E, Mohan K, Ahmad S, Wolf MTF. Physiology of a Forgotten Electrolyte-Magnesium Disorders. ADVANCES IN KIDNEY DISEASE AND HEALTH 2023; 30:148-163. [PMID: 36868730 DOI: 10.1053/j.akdh.2022.12.001] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/17/2022] [Revised: 11/26/2022] [Accepted: 12/06/2022] [Indexed: 03/05/2023]
Abstract
Magnesium (Mg2+) is the second most common intracellular cation and the fourth most abundant element on earth. However, Mg2+ is a frequently overlooked electrolyte and often not measured in patients. While hypomagnesemia is common in 15% of the general population, hypermagnesemia is typically only found in preeclamptic women after Mg2+ therapy and in patients with ESRD. Mild to moderate hypomagnesemia has been associated with hypertension, metabolic syndrome, type 2 diabetes mellitus, CKD, and cancer. Nutritional Mg2+ intake and enteral Mg2+ absorption are important for Mg2+ homeostasis, but the kidneys are the key regulators of Mg2+ homeostasis by limiting urinary excretion to less than 4% while the gastrointestinal tract loses over 50% of the Mg2+ intake in the feces. Here, we review the physiological relevance of Mg2+, the current knowledge of Mg2+ absorption in the kidneys and the gut, the different causes of hypomagnesemia, and a diagnostic approach on how to assess Mg2+ status. We highlight the latest discoveries of monogenetic conditions causing hypomagnesemia, which have enhanced our understanding of tubular Mg2+ absorption. We will also discuss external and iatrogenic causes of hypomagnesemia and advances in the treatment of hypomagnesemia.
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Affiliation(s)
- Evan Ray
- Renal-Electrolyte Division, Department of Internal Medicine, University of Pittsburgh, PA
| | - Krithika Mohan
- Department of Nephrology, Hosmat Hospital, HBR Layout, Bangalore, India
| | - Syeda Ahmad
- Renal-Electrolyte Division, Department of Internal Medicine, University of Pittsburgh, PA
| | - Matthias T F Wolf
- Pediatric Nephrology, Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX.
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2
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Ramírez-Plascencia OD, Saderi N, Cárdenas-Romero S, García-García F, Peña-Escudero C, Flores-Sandoval O, Azuara-Álvarez L, Báez-Ruiz A, Salgado-Delgado R. Leptin and adiponectin regulate the activity of nuclei involved in sleep-wake cycle in male rats. Front Neurosci 2022; 16:907508. [PMID: 35937866 PMCID: PMC9355486 DOI: 10.3389/fnins.2022.907508] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2022] [Accepted: 07/04/2022] [Indexed: 11/13/2022] Open
Abstract
Epidemiological and experimental evidence recognize a relationship between sleep-wake cycles and adiposity levels, but the mechanisms that link both are not entirely understood. Adipose tissue secretes adiponectin and leptin hormones, mainly involved as indicators of adiposity levels and recently associated to sleep. To understand how two of the main adipose tissue hormones could influence sleep-wake regulation, we evaluated in male rats, the effect of direct administration of adiponectin or leptin in the ventrolateral preoptic nuclei (VLPO), a major area for sleep promotion. The presence of adiponectin (AdipoR1 and AdipoR2) and leptin receptors in VLPO were confirmed by immunohistochemistry. Adiponectin administration increased wakefulness during the rest phase, reduced delta power, and activated wake-promoting neurons, such as the locus coeruleus (LC), tuberomammillary nucleus (TMN) and hypocretin/orexin neurons (OX) within the lateral hypothalamus (LH) and perifornical area (PeF). Conversely, leptin promoted REM and NREM sleep, including increase of delta power during NREM sleep, and induced c-Fos expression in VLPO and melanin concentrating hormone expressing neurons (MCH). In addition, a reduction in wake-promoting neurons activity was found in the TMN, lateral hypothalamus (LH) and perifornical area (PeF), including in the OX neurons. Moreover, leptin administration reduced tyrosine hydroxylase (TH) immunoreactivity in the LC. Our data suggest that adiponectin and leptin act as hormonal mediators between the status of body energy and the regulation of the sleep-wake cycle.
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Affiliation(s)
- Oscar Daniel Ramírez-Plascencia
- Departamento de Fisiología Celular, Facultad de Ciencias, Universidad Autónoma de San Luis Potosí, San Luis Potosí, Mexico
- Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United States
| | - Nadia Saderi
- Departamento de Fisiología Celular, Facultad de Ciencias, Universidad Autónoma de San Luis Potosí, San Luis Potosí, Mexico
| | - Skarleth Cárdenas-Romero
- Departamento de Fisiología Celular, Facultad de Ciencias, Universidad Autónoma de San Luis Potosí, San Luis Potosí, Mexico
| | - Fabio García-García
- Departamento de Biomedicina, Instituto de Ciencias de la Salud, Universidad Veracruzana, Veracruz, Mexico
| | - Carolina Peña-Escudero
- Departamento de Biomedicina, Instituto de Ciencias de la Salud, Universidad Veracruzana, Veracruz, Mexico
| | - Omar Flores-Sandoval
- Departamento de Fisiología Celular, Facultad de Ciencias, Universidad Autónoma de San Luis Potosí, San Luis Potosí, Mexico
| | - Lucia Azuara-Álvarez
- Departamento de Fisiología Celular, Facultad de Ciencias, Universidad Autónoma de San Luis Potosí, San Luis Potosí, Mexico
| | - Adrián Báez-Ruiz
- Departamento de Fisiología Celular, Facultad de Ciencias, Universidad Autónoma de San Luis Potosí, San Luis Potosí, Mexico
| | - Roberto Salgado-Delgado
- Departamento de Fisiología Celular, Facultad de Ciencias, Universidad Autónoma de San Luis Potosí, San Luis Potosí, Mexico
- *Correspondence: Roberto Salgado-Delgado,
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Jeong JK, Dow SA, Young CN. Sensory Circumventricular Organs, Neuroendocrine Control, and Metabolic Regulation. Metabolites 2021; 11:metabo11080494. [PMID: 34436435 PMCID: PMC8402088 DOI: 10.3390/metabo11080494] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2021] [Revised: 07/13/2021] [Accepted: 07/27/2021] [Indexed: 11/16/2022] Open
Abstract
The central nervous system is critical in metabolic regulation, and accumulating evidence points to a distributed network of brain regions involved in energy homeostasis. This is accomplished, in part, by integrating peripheral and central metabolic information and subsequently modulating neuroendocrine outputs through the paraventricular and supraoptic nucleus of the hypothalamus. However, these hypothalamic nuclei are generally protected by a blood-brain-barrier limiting their ability to directly sense circulating metabolic signals—pointing to possible involvement of upstream brain nuclei. In this regard, sensory circumventricular organs (CVOs), brain sites traditionally recognized in thirst/fluid and cardiovascular regulation, are emerging as potential sites through which circulating metabolic substances influence neuroendocrine control. The sensory CVOs, including the subfornical organ, organum vasculosum of the lamina terminalis, and area postrema, are located outside the blood-brain-barrier, possess cellular machinery to sense the metabolic interior milieu, and establish complex neural networks to hypothalamic neuroendocrine nuclei. Here, evidence for a potential role of sensory CVO-hypothalamic neuroendocrine networks in energy homeostasis is presented.
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Affiliation(s)
| | | | - Colin N. Young
- Correspondence: ; Tel.: +1-202-994-9575; Fax: +1-202-994-287
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Peyser D, Scolnick B, Hildebrandt T, Taylor JA. Heart rate variability as a biomarker for anorexia nervosa: A review. EUROPEAN EATING DISORDERS REVIEW 2020; 29:20-31. [PMID: 32975349 DOI: 10.1002/erv.2791] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2020] [Revised: 07/17/2020] [Accepted: 08/19/2020] [Indexed: 01/13/2023]
Abstract
OBJECTIVE Anorexia nervosa (AN) typically begins in early adolescence and other than weight status has few reliable biomarkers. Early diagnosis is a critical prognostic factor, but this can be clinically challenging. Heart rate variability (HRV), the beat-by-beat variance in heart rate (HR), may provide a unique assessment for the presence of AN because it has clinical utility as a biomarker of cardiac autonomic control in various populations (e.g., athletes, the aged, those with cardiovascular diseases, etc.). We present a review of the literature examining HRV in those with AN. METHOD Relevant publications were selected from PubMed using the search terms 'anorexia nervosa AND (HR OR HRV)'. Twenty papers were selected and reviewed. RESULTS The majority of studies suggest that those with AN have markedly and consistently elevated HRV compared to controls, even greater than among young athletes. However, no studies have explored HRV as a biomarker for AN. DISCUSSION Future studies on HRV should elucidate its role as a diagnostic biomarker for AN as well as its responsiveness with serial measurement to track response rates and predict relapse.
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Affiliation(s)
- Deena Peyser
- Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Barbara Scolnick
- Department of Psychology, Boston University, Boston, Massachusetts, USA
| | - Tom Hildebrandt
- Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - J Andrew Taylor
- Spaulding Research Institute and Department of Physical Medicine and Rehabilitation, Harvard Medical School, Boston, Massachusetts, USA
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5
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Abstract
PURPOSE OF REVIEW The central nervous system plays a pivotal role in the regulation of extracellular fluid volume and consequently arterial blood pressure. Key hypothalamic regions sense and integrate neurohumoral signals to subsequently alter intake (thirst and salt appetite) and output (renal excretion via neuroendocrine and autonomic function). Here, we review recent findings that provide new insight into such mechanisms that may represent new therapeutic targets. RECENT FINDINGS Implementation of cutting edge neuroscience approaches such as opto- and chemogenetics highlight pivotal roles of circumventricular organs to impact body fluid homeostasis. Key signaling mechanisms within these areas include the N-terminal variant of transient receptor potential vannilloid type-1, NaX, epithelial sodium channel, brain electroneutral transporters, and non-classical actions of vasopressin. Despite the identification of several new mechanisms, future studies need to better define the neurochemical phenotype and molecular profiles of neurons within circumventricular organs for future therapeutic potential.
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6
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Abstract
Thirst motivates animals to find and consume water. More than 40 years ago, a set of interconnected brain structures known as the lamina terminalis was shown to govern thirst. However, owing to the anatomical complexity of these brain regions, the structure and dynamics of their underlying neural circuitry have remained obscure. Recently, the emergence of new tools for neural recording and manipulation has reinvigorated the study of this circuit and prompted re-examination of longstanding questions about the neural origins of thirst. Here, we review these advances, discuss what they teach us about the control of drinking behaviour and outline the key questions that remain unanswered.
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Affiliation(s)
- Christopher A Zimmerman
- Department of Physiology, the Kavli Institute for Fundamental Neuroscience and the Neuroscience Graduate Program, University of California San Francisco, San Francisco, California 94158, USA
| | - David E Leib
- Department of Physiology, the Kavli Institute for Fundamental Neuroscience and the Neuroscience Graduate Program, University of California San Francisco, San Francisco, California 94158, USA
| | - Zachary A Knight
- Department of Physiology, the Kavli Institute for Fundamental Neuroscience and the Neuroscience Graduate Program, University of California San Francisco, San Francisco, California 94158, USA
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7
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Cancelliere NM, Ferguson AV. Subfornical organ neurons integrate cardiovascular and metabolic signals. Am J Physiol Regul Integr Comp Physiol 2016; 312:R253-R262. [PMID: 28003212 DOI: 10.1152/ajpregu.00423.2016] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2016] [Revised: 12/20/2016] [Accepted: 12/20/2016] [Indexed: 12/13/2022]
Abstract
The subfornical organ (SFO) is a critical circumventricular organ involved in the control of cardiovascular and metabolic homeostasis. Despite the plethora of circulating signals continuously sensed by the SFO, studies investigating how these signals are integrated are lacking. In this study, we use patch-clamp techniques to investigate how the traditionally classified "cardiovascular" hormone ANG II, "metabolic" hormone CCK and "metabolic" signal glucose interact and are integrated in the SFO. Sequential bath application of CCK (10 nM) and ANG (10 nM) onto dissociated SFO neurons revealed that 63% of responsive SFO neurons depolarized to both CCK and ANG; 25% depolarized to ANG only; and 12% hyperpolarized to CCK only. We next investigated the effects of glucose by incubating and recording neurons in either hypoglycemic, normoglycemic, or hyperglycemic conditions and comparing the proportions of responses to ANG (n = 55) or CCK (n = 83) application in each condition. A hyperglycemic environment was associated with a larger proportion of depolarizing responses to ANG (χ2, P < 0.05), and a smaller proportion of depolarizing responses along with a larger proportion of hyperpolarizing responses to CCK (χ2, P < 0.01). Our data demonstrate that SFO neurons excited by CCK are also excited by ANG and that glucose environment affects the responsiveness of neurons to both of these hormones, highlighting the ability of SFO neurons to integrate multiple metabolic and cardiovascular signals. These findings have important implications for this structure's role in the control of various autonomic functions during hyperglycemia.
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Affiliation(s)
| | - Alastair V Ferguson
- Centre for Neuroscience Studies, Queen's University, Kingston, Ontario, Canada
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Sun J, Gao Y, Yao T, Huang Y, He Z, Kong X, Yu KJ, Wang RT, Guo H, Yan J, Chang Y, Chen H, Scherer PE, Liu T, Williams KW. Adiponectin potentiates the acute effects of leptin in arcuate Pomc neurons. Mol Metab 2016; 5:882-891. [PMID: 27689001 PMCID: PMC5034606 DOI: 10.1016/j.molmet.2016.08.007] [Citation(s) in RCA: 53] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/19/2016] [Revised: 08/08/2016] [Accepted: 08/10/2016] [Indexed: 01/06/2023] Open
Abstract
Objective Adiponectin receptors (AdipoRs) are located on neurons of the hypothalamus involved in metabolic regulation – including arcuate proopiomelanocortin (Pomc) and Neuropeptide Y/Agouti-related peptide (NPY/AgRP) neurons. AdipoRs play a critical role in regulating glucose and fatty acid metabolism by initiating several signaling cascades overlapping with Leptin receptors (LepRs). However, the mechanism by which adiponectin regulates cellular activity in the brain remains undefined. Methods In order to resolve this issue, we utilized neuron-specific transgenic mouse models to identify Pomc and NPY/AgRP neurons which express LepRs for patch-clamp electrophysiology experiments. Results We found that leptin and adiponectin synergistically activated melanocortin neurons in the arcuate nucleus. Conversely, NPY/AgRP neurons were inhibited in response to adiponectin. The adiponectin-induced depolarization of arcuate Pomc neurons occurred via activation of Phosphoinositide-3-kinase (PI3K) signaling, independent of 5′ AMP-activated protein kinase (AMPK) activity. Adiponectin also activated melanocortin neurons at various physiological glucose levels. Conclusions Our results demonstrate a requirement for PI3K signaling in the acute adiponectin-induced effects on the cellular activity of arcuate melanocortin neurons. Moreover, these data provide evidence for PI3K as a substrate for both leptin and adiponectin to regulate energy balance and glucose metabolism via melanocortin activity.
Adiponectin activates arcuate Pomc neurons. Adiponectin-induced activation of Pomc neurons requires PI3K (independent of AMPK). Adiponectin inhibits adjacent NPY/AgRP neurons (disinhibiting arcuate Pomc neurons). Leptin potentiates the effects of adiponectin arcuate Pomc neurons.
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Affiliation(s)
- Jia Sun
- Department of Endocrinology, Zhujiang Hospital, Southern Medical University, Guangzhou, China; Division of Hypothalamic Research, The University of Texas Southwestern Medical Center at Dallas, Dallas, TX, USA
| | - Yong Gao
- National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China; Division of Hypothalamic Research, The University of Texas Southwestern Medical Center at Dallas, Dallas, TX, USA
| | - Ting Yao
- Department of Physiology and Pathophysiology, Xi'an Jiaotong University School of Medicine, Xi'an, Shaanxi, China; Division of Hypothalamic Research, The University of Texas Southwestern Medical Center at Dallas, Dallas, TX, USA
| | - Yiru Huang
- Department of Neurosurgery, Zhujiang Hospital, Southern Medical University, Guangzhou, China; Division of Hypothalamic Research, The University of Texas Southwestern Medical Center at Dallas, Dallas, TX, USA
| | - Zhenyan He
- Department of Neurosurgery, Zhujiang Hospital, Southern Medical University, Guangzhou, China; Division of Hypothalamic Research, The University of Texas Southwestern Medical Center at Dallas, Dallas, TX, USA
| | - Xingxing Kong
- Division of Endocrinology, Beth Israel Deaconess Medical Center and Harvard Medical School, Harvard University, Boston, MA, 02115, USA
| | - Kai-Jiang Yu
- Department of Intensive Care Unit, The Third Affiliated Hospital, Harbin Medical University, No. 150 Haping St, Nangang District, Harbin, 150081, China
| | - Rui-Tao Wang
- Department of Intensive Care Unit, The Third Affiliated Hospital, Harbin Medical University, No. 150 Haping St, Nangang District, Harbin, 150081, China
| | - Hongbo Guo
- Department of Neurosurgery, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Jianqun Yan
- Department of Physiology and Pathophysiology, Xi'an Jiaotong University School of Medicine, Xi'an, Shaanxi, China
| | - Yongsheng Chang
- National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Hong Chen
- Department of Endocrinology, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Philipp E Scherer
- Touchstone Diabetes Center, Department of Internal Medicine, The University of Texas Southwestern Medical Center at Dallas, Dallas, TX, 75390, USA
| | - Tiemin Liu
- Department of Intensive Care Unit, The Third Affiliated Hospital, Harbin Medical University, No. 150 Haping St, Nangang District, Harbin, 150081, China; Division of Hypothalamic Research, The University of Texas Southwestern Medical Center at Dallas, Dallas, TX, USA
| | - Kevin W Williams
- Division of Hypothalamic Research, The University of Texas Southwestern Medical Center at Dallas, Dallas, TX, USA.
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Peterlin BL, Sacco S, Bernecker C, Scher AI. Adipokines and Migraine: A Systematic Review. Headache 2016; 56:622-44. [PMID: 27012149 DOI: 10.1111/head.12788] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/30/2015] [Indexed: 01/04/2023]
Abstract
BACKGROUND Migraine is comorbid with obesity. Recent research suggests an association between migraine and adipocytokines, proteins that are predominantly secreted from adipose tissue and which participate in energy homeostasis and inflammatory processes. OBJECTIVES In this review, we first briefly discuss the association between migraine and obesity and the importance of adipose tissue as a neuroendocrine organ. We then present a systematic review of the extant literature evaluating circulating levels of adiponectin and leptin in those with migraine. METHODS A search of the PubMed database was conducted using the keywords "migraine," "adiponectin," and "leptin." In addition reference lists of relevant articles were reviewed for possible inclusion. English language studies published between 2005 and 2015 evaluating circulating blood concentration of adiponectin or leptin in those with migraine were included. CONCLUSIONS While the existing data are suggestive that adipokines may be associated with migraine, substantial study design differences and conflicting results limit definitive conclusions. Future research utilizing carefully considered designs and methodology is warranted. In particular careful and systematic characterization of pain states at the time of samples, as well as systematic consideration of demographic (e.g., age, sex) and other vital covariates (e.g., obesity status, lipids) are needed to determine if adipokines play a role in migraine pathophysiology and if any adipokine represents a viable, novel migraine biomarker, or drug target.
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Affiliation(s)
- B Lee Peterlin
- Johns Hopkins University School of Medicine, Department of Neurology, Baltimore, MD, USA
| | - Simona Sacco
- University of L'Aquila, Department of Applied Clinical Sciences and Biotechnology, Institute of Neurology, L'Aquila, Italy
| | - Claudia Bernecker
- Medical University of Graz, Clinical Institute of Medical and Chemical Laboratory Diagnostics, Graz, Austria.,Medical University of Graz, Department of Blood Group Serology and Transfusion Medicine, Graz, Austria
| | - Ann I Scher
- Uniformed Services University, Bethesda, MD, USA
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10
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Cancelliere NM, Black EAE, Ferguson AV. Neurohumoral Integration of Cardiovascular Function by the Lamina Terminalis. Curr Hypertens Rep 2016; 17:93. [PMID: 26531751 DOI: 10.1007/s11906-015-0602-9] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/23/2023]
Abstract
The mechanisms involved in cardiovascular regulation, such as vascular tone, fluid volume and blood osmolarity, are quite often mediated by signals circulating in the periphery, such as angiotensin II and sodium concentration. Research has identified areas within the lamina terminalis (LT), specifically the sensory circumventricular organs (CVOs), the subfornical organ and the organum vasculosum of the lamina terminalis, as playing crucial roles detecting and integrating information derived from these circulating signals. The median preoptic nucleus (MnPO) is a third integrative structure within the LT that influences cardiovascular homeostasis, although to date, its role is not as clearly elucidated. More recent studies have demonstrated that the CVOs are not only essential in the detection of traditional cardiovascular signals but also signals primarily considered to be important in the regulation of metabolic, reproductive and inflammatory processes that have now also been implicated in cardiovascular regulation. In this review, we highlight the critical roles played by the LT in the detection and integration of circulating signals that provide critical feedback control information contributing to cardiovascular regulation.
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Affiliation(s)
- Nicole M Cancelliere
- Department of Biomedical and Molecular Sciences, Queen's University, Kingston, ON, K7L 3N6, Canada
| | - Emily A E Black
- Department of Biomedical and Molecular Sciences, Queen's University, Kingston, ON, K7L 3N6, Canada
| | - Alastair V Ferguson
- Department of Biomedical and Molecular Sciences, Queen's University, Kingston, ON, K7L 3N6, Canada.
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11
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Hindmarch CCT, Ferguson AV. Physiological roles for the subfornical organ: a dynamic transcriptome shaped by autonomic state. J Physiol 2015; 594:1581-9. [PMID: 26227400 DOI: 10.1113/jp270726] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2015] [Accepted: 07/26/2015] [Indexed: 12/15/2022] Open
Abstract
The subfornical organ (SFO) is a circumventricular organ recognized for its ability to sense and integrate hydromineral and hormonal circulating fluid balance signals, information which is transmitted to central autonomic nuclei to which SFO neurons project. While the role of SFO was once synonymous with physiological responses to osmotic, volumetric and cardiovascular challenge, recent data suggest that SFO neurons also sense and integrate information from circulating signals of metabolic status. Using microarrays, we have confirmed the expression of receptors already described in the SFO, and identified many novel transcripts expressed in this circumventricular organ including receptors for many of the critical circulating energy balance signals such as adiponectin, apelin, endocannabinoids, leptin, insulin and peptide YY. This transcriptome analysis also identified SFO transcripts, the expressions of which are significantly changed by either 72 h dehydration, or 48 h starvation, compared to fed and euhydrated controls. Expression and potential roles for many of these targets are yet to be confirmed and elucidated. Subsequent validation of data for adiponectin and leptin receptors confirmed that receptors for both are expressed in the SFO, that discrete populations of neurons in this tissue are functionally responsive to these adipokines, and that such responsiveness is regulated by physiological state. Thus, transcriptomic analysis offers great promise for understanding the integrative complexity of these physiological systems, especially with development of technologies allowing description of the entire transcriptome of single, carefully phenotyped, SFO neurons. These data will ultimately elucidate mechanisms through which these uniquely positioned neurons respond to and integrate complex circulating signals.
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Affiliation(s)
- Charles Colin Thomas Hindmarch
- School of Clinical Sciences, Dorothy Hodgkin Building, University of Bristol, Bristol, BS1 3NY, UK.,Department of Physiology, Faculty of Medicine, University of Malaya, 50603, Kuala Lumpur, Malaysia
| | - Alastair V Ferguson
- Department of Biomedical and Molecular Sciences, Queen's University, Kingston, ON, Canada, K7L 3N6
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12
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Wędrychowicz A, Zając A, Pilecki M, Kościelniak B, Tomasik PJ. Peptides from adipose tissue in mental disorders. World J Psychiatry 2014; 4:103-111. [PMID: 25540725 PMCID: PMC4274582 DOI: 10.5498/wjp.v4.i4.103] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/26/2014] [Revised: 11/14/2014] [Accepted: 12/10/2014] [Indexed: 02/05/2023] Open
Abstract
Adipose tissue is a dynamic endocrine organ that is essential to regulation of metabolism in humans. A new approach to mental disorders led to research on involvement of adipokines in the etiology of mental disorders and mood states and their impact on the health status of psychiatric patients, as well as the effects of treatment for mental health disorders on plasma levels of adipokines. There is evidence that disturbances in adipokine secretion are important in the pathogenesis, clinical presentation and outcome of mental disorders. Admittedly leptin and adiponectin are involved in pathophysiology of depression. A lot of disturbances in secretion and plasma levels of adipokines are observed in eating disorders with a significant impact on the symptoms and course of a disease. It is still a question whether observed dysregulation of adipokines secretion are primary or secondary. Moreover findings in this area are somewhat inconsistent, owing to differences in patient age, sex, socioeconomic status, smoking habits, level of physical activity, eating pathology, general health or medication. This was the rationale for our detailed investigation into the role of the endocrine functions of adipose tissue in mental disorders. It seems that we are continually at the beginning of understanding of the relation between adipose tissue and mental disorders.
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13
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Kuksis M, Ferguson AV. Cellular actions of nesfatin-1 in the subfornical organ. J Neuroendocrinol 2014; 26:237-46. [PMID: 24612143 DOI: 10.1111/jne.12143] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/18/2013] [Revised: 02/19/2014] [Accepted: 02/22/2014] [Indexed: 11/27/2022]
Abstract
Nesfatin-1, a centrally acting anorexigenic peptide, is produced in several brain areas involved in metabolic processes and has been implicated in the control of ingestive behaviours and cardiovascular functions. The present study aimed to determine whether the subfornical organ (SFO), a central nervous system (CNS) site that has been extensively implicated in the regulation of appetite and thirst, may represent a potential site for central actions of nesfatin-1. We first used the reverse transcriptase-polymerase chain reaction and were able to confirm the presence of mRNA for the nucleobindin-2 gene in the SFO. We then used whole-cell patch clamp recordings to investigate the influence of nesfatin-1 on the membrane potential of dissociated SFO neurones. A total of 80.3% (49 of 61) of neurones tested showed a response to nesfatin-1 (100 nm, 10 nm and 1 nm). Of these, 47.5% depolarised, with a mean depolarisation of 8.2 ± 0.9 mV (n = 29) and 32.8% hyperpolarised with a mean hyperpolarisation of -8.9 ± 1.2 mV (n = 20). Peak magnitudes were seen at a concentration of 1 nm nesfatin-1, whereas no effect was observed at 100 pm nesftain-1 (n = 3). Furthermore, voltage clamp ramp and step protocols revealed a nesfatin-1 induced activation of the delayed rectifier potassium conductance, IK . Pharmacological blockade of this conductance greatly reduced the magnitude and occurrence of the observed hyperpolarisations. The present study thus demonstrates that nesfatin-1 has the ability to influence the membrane potential of SFO neurones, and thus identifies the SFO as a potential site at which nesfatin-1 may act to regulate ingestive behaviour and cardiovascular control.
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Affiliation(s)
- M Kuksis
- Department of Biomedical and Molecular Sciences, Queen's University, Kingston, Ontario, Canada
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14
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Ahmed ASF, Dai L, Ho W, Ferguson AV, Sharkey KA. The subfornical organ: a novel site of action of cholecystokinin. Am J Physiol Regul Integr Comp Physiol 2014; 306:R363-73. [PMID: 24430886 DOI: 10.1152/ajpregu.00462.2013] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
The subfornical organ (SFO) is an important sensory circumventricular organ implicated in the regulation of fluid homeostasis and energy balance. We investigated whether the SFO is activated by the hormone cholecystokinin (CCK). CCK₁ and CCK₂ receptors were identified in the SFO by RT-PCR. Dissociated SFO neurons that responded to CCK (40/77), were mostly depolarized (9.2 ± 0.9 mV, 30/77), but some were hyperpolarized (-7.3 ± 1.1 mV, 10/77). We next examined the responses of SFO neurons in vivo to CCK (16 μg/kg ip), in the presence and absence of CCK₁ or CCK₂ receptor antagonists (devazepide; 600 μg/kg and L-365,260; 100 μg/kg, respectively), using the functional activation markers c-Fos and phosphorylated extracellular signal-related kinase (p-ERK). The nucleus of the solitary tract (NTS) served as a control for CCK-induced activity. There was a significant increase in c-Fos expression in the NTS (259.2 ± 20.8 neurons) compared with vehicle (47.5 ± 2.5). Similarly, in the SFO, c-Fos was expressed in 40.5 ± 10.6 neurons in CCK-treated compared with 6.6 ± 2.7 in vehicle-treated rats (P < 0.01). Devazepide significantly reduced the effects of CCK in the NTS but not in SFO. L-365,260 blocked the effects of CCK in both brain regions. CCK increased the number of p-ERK neurons in NTS (27.0 ± 4.0) as well as SFO (18.0 ± 4.0), compared with vehicle (8.0 ± 2.6 and 4.3 ± 0.6, respectively; P < 0.05). Both devazepide and L-365,260 reduced CCK-induced p-ERK in NTS, but only L-365,260 reduced it in the SFO. In conclusion, the SFO represents a novel brain region at which circulating CCK may act via CCK₂ receptors to influence central autonomic control.
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Affiliation(s)
- Al-Shaimaa F Ahmed
- Hotchkiss Brain Institute, Department of Physiology and Pharmacology, University of Calgary, Calgary, Alberta, Canada; and
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Mimee A, Smith PM, Ferguson AV. Circumventricular organs: Targets for integration of circulating fluid and energy balance signals? Physiol Behav 2013; 121:96-102. [DOI: 10.1016/j.physbeh.2013.02.012] [Citation(s) in RCA: 46] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2012] [Revised: 01/26/2013] [Accepted: 02/14/2013] [Indexed: 01/22/2023]
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Nesfatin-1 induces Fos expression and elicits dipsogenic responses in subfornical organ. Behav Brain Res 2013; 250:343-50. [DOI: 10.1016/j.bbr.2013.05.036] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2013] [Revised: 05/13/2013] [Accepted: 05/20/2013] [Indexed: 02/01/2023]
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Dai L, Smith PM, Kuksis M, Ferguson AV. Apelin acts in the subfornical organ to influence neuronal excitability and cardiovascular function. J Physiol 2013; 591:3421-32. [PMID: 23629509 DOI: 10.1113/jphysiol.2013.254144] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022] Open
Abstract
Apelin is an adipocyte-derived hormone involved in the regulation of water balance, food intake and the cardiovascular system partially through actions in the CNS. The subfornical organ (SFO) is a circumventricular organ with identified roles in body fluid homeostasis, cardiovascular control and energy balance. The SFO lacks a normal blood-brain barrier, and is thus able to detect circulating signalling molecules such as angiotensin II and leptin. In this study, we investigated actions of apelin-13, the predominant apelin isoform in brain and circulatory system, on the excitability of dissociated SFO neurons using electrophysiological approaches, and determined the cardiovascular consequences of direct administration into the SFO of anaesthetized rats. Whole cell current clamp recording revealed that bath-applied 100 nm apelin-13 directly influences the excitability of the majority of SFO neurons by eliciting either depolarizing (31.8%, mean 7.0 ± 0.8 mV) or hyperpolarizing (28.6%, mean -10.4 ± 1.8 mV) responses. Using voltage-clamp techniques, we also identified modulatory actions of apelin-13 on specific ion channels, demonstrating that apelin-13 activates a non-selective cationic conductance to depolarize SFO neurons while activation of the delayed rectifier potassium conductance underlies hyperpolarizing effects. In anaesthetized rats, microinjection of apelin into SFO decreased both blood pressure (BP) (mean area under the curve -1492.3 ± 357.1 mmHg.s, n = 5) and heart rate (HR) (-32.4 ± 10.39 beats, n = 5). Our data suggest that circulating apelin can directly affect BP and HR as a consequence of the ability of this peptide to modulate the excitability of SFO neurons.
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Affiliation(s)
- Li Dai
- Biomedical and Molecular Sciences, Department of Physiology, Queen's University, Kingston, ON K7L 3N6, Canada
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Smith PM, Ferguson AV. Cardiovascular actions of leptin in the subfornical organ are abolished by diet-induced obesity. J Neuroendocrinol 2012; 24:504-10. [PMID: 22103447 DOI: 10.1111/j.1365-2826.2011.02257.x] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
The subfornical organ (SFO), a sensory circumventricular organ lacking the normal blood-brain barrier with well documented roles in cardiovascular regulation, has recently been identified as a potential site at which the adipokine, leptin, may act to influence central autonomic pathways. Systemic and central leptin administration has been shown to increase blood pressure and it has been suggested that selective leptin resistance contributes to obesity-related hypertension. Given the relationship between obesity and hypertension, the present study aimed to investigate the cardiovascular consequences of the direct administration of leptin into the SFO of young lean rats and in the diet-induced obesity (DIO) rat model, which has been shown to be leptin-resistant. Leptin administration (500 fmol) directly into the SFO of young rats resulted in rapid decreases in blood pressure (BP) [mean area under the curve (AUC) = -677.8 ± 167.1 mmHg*s; n = 9], without an effect on heart rate (mean AUC = -21.2 ± 13.4 beats; n = 9), and these effects were found to be dose-related as microinjection of 5 pmol of leptin into the SFO had a larger effect on BP (mean AUC = -972.3 ± 280.1 mmHg*s; n = 4). These BP effects were also shown to be site-specific as microinjection of leptin into non-SFO regions or into the ventricle was without effect on BP (non-SFO: mean AUC = -22.4 ± 55.3 mmHg*s; n = 4; ventricle: mean AUC = 194.0 ± 173.0 mmHg*s; n = 6). By contrast, microinjection of leptin into leptin-resistant DIO rats was without effect on BP (mean AUC = 205.2 ± 75.1 mmHg*s; n = 4). These observations suggest that the SFO may be an important relay centre through which leptin, in normal weight, leptin responsive rats, acts to maintain BP within normal physiological limits through descending autonomic pathways involved in cardiovascular control and that, in obese, leptin-resistant, rats leptin no longer influences SFO neurones, resulting in an elevated BP, thus contributing to obesity-related hypertension.
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Affiliation(s)
- P M Smith
- Department of Physiology, Queen's University, Kingston, Ontario, Canada
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Cai H, Cong WN, Ji S, Rothman S, Maudsley S, Martin B. Metabolic dysfunction in Alzheimer's disease and related neurodegenerative disorders. Curr Alzheimer Res 2012; 9:5-17. [PMID: 22329649 DOI: 10.2174/156720512799015064] [Citation(s) in RCA: 227] [Impact Index Per Article: 17.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2011] [Revised: 07/17/2011] [Accepted: 08/09/2011] [Indexed: 01/14/2023]
Abstract
Alzheimer's disease and other related neurodegenerative diseases are highly debilitating disorders that affect millions of people worldwide. Efforts towards developing effective treatments for these disorders have shown limited efficacy at best, with no true cure to this day being present. Recent work, both clinical and experimental, indicates that many neurodegenerative disorders often display a coexisting metabolic dysfunction which may exacerbate neurological symptoms. It stands to reason therefore that metabolic pathways may themselves contain promising therapeutic targets for major neurodegenerative diseases. In this review, we provide an overview of some of the most recent evidence for metabolic dysregulation in Alzheimer's disease, Huntington's disease, and Parkinson's disease, and discuss several potential mechanisms that may underlie the potential relationships between metabolic dysfunction and etiology of nervous system degeneration. We also highlight some prominent signaling pathways involved in the link between peripheral metabolism and the central nervous system that are potential targets for future therapies, and we will review some of the clinical progress in this field. It is likely that in the near future, therapeutics with combinatorial neuroprotective and 'eumetabolic' activities may possess superior efficacies compared to less pluripotent remedies.
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Affiliation(s)
- Huan Cai
- Metabolism Unit, National Institute on Aging, Baltimore, MD 21224, USA
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Medeiros N, Dai L, Ferguson AV. Glucose-responsive neurons in the subfornical organ of the rat--a novel site for direct CNS monitoring of circulating glucose. Neuroscience 2011; 201:157-65. [PMID: 22108616 DOI: 10.1016/j.neuroscience.2011.11.028] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2011] [Revised: 11/09/2011] [Accepted: 11/10/2011] [Indexed: 11/28/2022]
Abstract
Glucose-sensitive neurons have been identified in a number of CNS regions including metabolic control centers of the hypothalamus. The location of these regions behind the blood-brain barrier restricts them to sensing central, but not circulating glucose concentrations. In this study, we have used patch-clamp electrophysiology to examine whether neurons in a specialized region lacking the blood-brain barrier, the subfornical organ (SFO), are also glucose sensitive. In dissociated SFO neurons, altering the bath concentration of glucose (1 mM, 5 mM, 10 mM) influenced the excitability of 49% of neurons tested (n=67). Glucose-inhibited (GI) neurons depolarized in response to decreased glucose (n=10; mean, 4.6±1.0 mV) or hyperpolarized in response to increased glucose (n=8; mean,-4.4±0.8 mV). In contrast, glucose-excited (GE) neurons depolarized in response to increased glucose (n=9; mean, 6.4±0.4 mV) or hyperpolarized in response to decreased glucose (n=6; mean,-4.8±0.6 mV). Using voltage-clamp recordings, we also identified GI (outward current to increased glucose) and GE (inward current to increased glucose) SFO neurons. The mean glucose-induced inward current had a reversal potential of -24±12 mV (n=5), while GE responses were maintained during sodium-dependent glucose transporter inhibition, supporting the conclusion that GE properties result from the activation of a nonselective cation conductance (NSCC). The glucose-induced outward current had a mean reversal potential of -78±1.2 mV (n=5), while GI responses were not observed in the presence of glibenclamide, suggesting that these properties result from the modulation of K(ATP) channels. These data demonstrate that SFO neurons are glucose responsive, further emphasizing the potential roles of this circumventricular organ as an important sensor and integrator of circulating signals of energy status.
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Affiliation(s)
- N Medeiros
- Department of Biomedical and Molecular Sciences, Queen's University, Kingston, ON K7L 3N6, Canada.
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Smith PM, Ferguson AV. Circulating signals as critical regulators of autonomic state--central roles for the subfornical organ. Am J Physiol Regul Integr Comp Physiol 2010; 299:R405-15. [PMID: 20463185 DOI: 10.1152/ajpregu.00103.2010] [Citation(s) in RCA: 69] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/23/2023]
Abstract
To maintain homeostasis autonomic control centers in the hypothalamus and medulla must respond appropriately to both external and internal stimuli. Although protected behind the blood-brain barrier, neurons in these autonomic control centers are known to be influenced by changing levels of important signaling molecules in the systemic circulation (e.g., osmolarity, glucose concentrations, and regulatory peptides). The subfornical organ belongs to a group of specialized central nervous system structures, the circumventricular organs, which are characterized by the lack of the normal blood-brain barrier, such that circulating lipophobic substances may act on neurons within this region and via well-documented efferent neural projections to hypothalamic autonomic control centers, influence autonomic function. This review focuses on the role of the subfornical organ in sensing peripheral signals and transmitting this information to autonomic control centers in the hypothalamus.
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Affiliation(s)
- Pauline M Smith
- Dept. of Physiology, Queen's Univ., Kingston, Ontario, Canada K7L 3N6
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