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Venegas JJ, Weisz JM, Choi CY, Herringshaw RE, Nabelsi OA, Liang N. Social isolation increases impulsive choice with minor changes on metabolic function in middle-aged rats. Physiol Rep 2025; 13:e70184. [PMID: 39821966 PMCID: PMC11738651 DOI: 10.14814/phy2.70184] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2024] [Revised: 12/20/2024] [Accepted: 12/21/2024] [Indexed: 01/19/2025] Open
Abstract
The effects of social isolation (SI) during middle age remain unclear, so we tested the hypothesis that SI would lead to an increase in impulsive choice (IC), anxiety-like behavior, and metabolic dysfunction in middle-aged rats. Male and female rats were housed individually or in groups of four with same-sex housing mates at 11 months of age. Two months later, IC behavior was assessed using a delay-discounting task and anxiety-like behavior through a novelty-suppressed feeding (NSF) task. Lastly, glucose tolerance and insulin sensitivity following exposure to a high-fat diet were assessed using an oral glucose tolerance test (OGTT) and an insulin tolerance test (ITT). The results showed that socially isolated rats displayed more IC behavior than did group-housed rats of both sexes. However, no significant effect of housing was evident in the NSF task, OGTT, or ITT. Male rats had a higher plasma insulin concentration and insulin resistance index compared to females. Our findings demonstrate that SI in middle age is sufficient to increase IC behavior and highlight inherent sex-specific differences in metabolic profiles. These findings underscore the importance of investigating mechanisms that underlie the effects of social isolation during different stages of life.
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Affiliation(s)
- Jassmyn J. Venegas
- Department of PsychologyUniversity of Illinois Urbana‐ChampaignChampaignIllinoisUSA
| | - Jacob M. Weisz
- Department of PsychologyUniversity of Illinois Urbana‐ChampaignChampaignIllinoisUSA
| | - Chan Young Choi
- Department of PsychologyUniversity of Illinois Urbana‐ChampaignChampaignIllinoisUSA
| | - Ren E. Herringshaw
- Department of PsychologyUniversity of Illinois Urbana‐ChampaignChampaignIllinoisUSA
| | - Omar A. Nabelsi
- Department of PsychologyUniversity of Illinois Urbana‐ChampaignChampaignIllinoisUSA
| | - Nu‐Chu Liang
- Department of PsychologyUniversity of Illinois Urbana‐ChampaignChampaignIllinoisUSA
- Division of Nutritional SciencesUniversity of Illinois Urbana‐ChampaignUrbanaIllinoisUSA
- Neuroscience ProgramUniversity of Illinois Urbana‐ChampaignUrbanaIllinoisUSA
- Carl R. Woese Institute for Genomic BiologyUniversity of Illinois‐Urbana ChampaignUrbanaIllinoisUSA
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2
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Al-Onaizi M, Braysh K, Alkafeef SS, Altarrah D, Dannoon S, Alasousi D, Adel H, Al-Ajmi M, Kandari A, Najem R, Nizam R, Williams MR, John S, Thanaraj TA, Ahmad R, Al-Hussaini H, Al-Mulla F, Alzaid F. Glucose intolerance induces anxiety-like behaviors independent of obesity and insulin resistance in a novel model of nutritional metabolic stress. Nutr Neurosci 2024; 27:1143-1161. [PMID: 38319634 DOI: 10.1080/1028415x.2024.2310419] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2024]
Abstract
OBJECTIVES Type 2 diabetes (T2D) is a metabolic disease of major public health concern. It impacts peripheral tissues and the central nervous system, leading to systemic dysmetabolism and neurocognitive impairments, including memory deficits, anxiety, and depression. The metabolic determinants of these neurocognitive impairments remain unidentified. Here, we sought to address this question by developing a proprietary (P-) high-fat diet (HFD), in which glucose intolerance precedes weight gain and insulin resistance. METHODS The P-HFD model was nutritionally characterized, and tested in vivo in mice that underwent behavioral and metabolic testing. The diet was benchmarked against reference models. . RESULTS P-HFD has 42% kcal from fat, high monounsaturated/polyunsaturated fatty acid ratio, and 10% (w/v) sucrose in drinking water. When administered, from the early stages of glucose intolerance alone, animals exhibit anxiety-like behavior, without depression nor recognition memory deficits. Long-term P-HFD feeding leads to weight gain, brain glucose hypometabolism as well as impaired recognition memory. Using an established genetic model of T2D (db/db) and of diet-induced obesity (60% kcal from fat) we show that additional insulin resistance and obesity are associated with depressive-like behaviors and recognition memory deficits. DISCUSSION Our findings demonstrate that glucose intolerance alone can elicit anxiety-like behavior. Through this study, we also provide a novel nutritional model (P-HFD) to characterize the discrete effects of glucose intolerance on cognition, behavior, and the physiology of metabolic disease.
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Affiliation(s)
- Mohammed Al-Onaizi
- Faculty of Medicine, Department of Anatomy, Kuwait University, Kuwait City, Kuwait
- Dasman Diabetes Institute, Kuwait City, Kuwait
| | - Kawthar Braysh
- Faculty of Medicine, Department of Anatomy, Kuwait University, Kuwait City, Kuwait
| | - Selma S Alkafeef
- Faculty of Medicine, Department of Biochemistry, Kuwait University, Kuwait City, Kuwait
| | - Dana Altarrah
- Faculty of Public Health, Department of Social and Behavioral Science, Kuwait University, Kuwait City, Kuwait
| | - Shorouk Dannoon
- Faculty of Medicine, Department of Nuclear Medicine, Kuwait University, Kuwait City, Kuwait
| | - Dalal Alasousi
- Faculty of Science, Department of Biochemistry, Kuwait University, Kuwait City, Kuwait
| | - Hawraa Adel
- Faculty of Medicine, Department of Anatomy, Kuwait University, Kuwait City, Kuwait
| | - Mariam Al-Ajmi
- Faculty of Science, Department of Biochemistry, Kuwait University, Kuwait City, Kuwait
| | - Anwar Kandari
- Dasman Diabetes Institute, Kuwait City, Kuwait
- Ministry of Health, Kuwait City, Kuwait
| | - Rawan Najem
- Dasman Diabetes Institute, Kuwait City, Kuwait
| | | | | | - Sumi John
- Dasman Diabetes Institute, Kuwait City, Kuwait
| | | | | | - Heba Al-Hussaini
- Faculty of Medicine, Department of Anatomy, Kuwait University, Kuwait City, Kuwait
| | | | - Fawaz Alzaid
- Dasman Diabetes Institute, Kuwait City, Kuwait
- INSERM UMR-S1151, CNRS UMR-S8253, Université Paris Cité, Institut Necker Enfants Malades, Paris, France
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3
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Abdalla MMI. Insulin resistance as the molecular link between diabetes and Alzheimer's disease. World J Diabetes 2024; 15:1430-1447. [PMID: 39099819 PMCID: PMC11292327 DOI: 10.4239/wjd.v15.i7.1430] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/14/2024] [Revised: 04/08/2024] [Accepted: 05/06/2024] [Indexed: 07/08/2024] Open
Abstract
Diabetes mellitus (DM) and Alzheimer's disease (AD) are two major health concerns that have seen a rising prevalence worldwide. Recent studies have indicated a possible link between DM and an increased risk of developing AD. Insulin, while primarily known for its role in regulating blood sugar, also plays a vital role in protecting brain functions. Insulin resistance (IR), especially prevalent in type 2 diabetes, is believed to play a significant role in AD's development. When insulin signalling becomes dysfunctional, it can negatively affect various brain functions, making individuals more susceptible to AD's defining features, such as the buildup of beta-amyloid plaques and tau protein tangles. Emerging research suggests that addressing insulin-related issues might help reduce or even reverse the brain changes linked to AD. This review aims to explore the rela-tionship between DM and AD, with a focus on the role of IR. It also explores the molecular mechanisms by which IR might lead to brain changes and assesses current treatments that target IR. Understanding IR's role in the connection between DM and AD offers new possibilities for treatments and highlights the importance of continued research in this interdisciplinary field.
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Affiliation(s)
- Mona Mohamed Ibrahim Abdalla
- Department of Human Biology, School of Medicine, International Medical University, Bukit Jalil 57000, Kuala Lumpur, Malaysia
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4
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Martin H, Coursan A, Lallement J, Di Miceli M, Kandiah J, Raho I, Buttler J, Guilloux JP, De Deurwaerdere P, Layé S, Routh VH, Guiard BP, Magnan C, Cruciani-Guglielmacci C, Fioramonti X. Serotonergic neurons are involved in the counter-regulatory response to hypoglycemia. J Neuroendocrinol 2023; 35:e13344. [PMID: 37857383 DOI: 10.1111/jne.13344] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/11/2023] [Revised: 08/30/2023] [Accepted: 09/12/2023] [Indexed: 10/21/2023]
Abstract
OBJECTIVES Intensive insulin therapy provides optimal glycemic control in patients with diabetes. However, intensive insulin therapy causes so-called iatrogenic hypoglycemia as a major adverse effect. The ventromedial hypothalamus (VMH) has been described as the primary brain area initiating the counter-regulatory response (CRR). Nevertheless, the VMH receives projections from other brain areas which could participate in the regulation of the CRR. In particular, studies suggest a potential role of the serotonin (5-HT) network. Thus, the objective of this study was to determine the contribution of 5-HT neurons in CRR control. METHODS Complementary approaches have been used to test this hypothesis in quantifying the level of 5-HT in several brain areas by HPLC in response to insulin-induced hypoglycemia, measuring the electrical activity of dorsal raphe (DR) 5-HT neurons in response to insulin or decreased glucose level by patch-clamp electrophysiology; and measuring the CRR hormone glucagon as an index of the CRR to the modulation of the activity of 5-HT neurons using pharmacological or pharmacogenetic approaches. RESULTS HPLC measurements show that the 5HIAA/5HT ratio is increased in several brain regions including the VMH in response to insulin-induced hypoglycemia. Patch-clamp electrophysiological recordings show that insulin, but not decreased glucose level, increases the firing frequency of DR 5-HT neurons in the DR. In vivo, both the pharmacological inhibition of 5-HT neurons by intraperitoneal injection of the 5-HT1A receptor agonist 8-OH-DPAT or the chemogenetic inhibition of these neurons reduce glucagon secretion, suggesting an impaired CRR. CONCLUSION Taken together, these data highlight a new neuronal network involved in the regulation of the CRR. In particular, this study shows that DR 5-HT neurons detect iatrogenic hypoglycemia in response to the increased insulin level and may play an important role in the regulation of CRR.
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Affiliation(s)
- Hugo Martin
- Université Bordeaux, INRAE, Bordeaux INP, NutriNeuro, UMR 1286, Bordeaux, France
| | - Adeline Coursan
- Université Bordeaux, INRAE, Bordeaux INP, NutriNeuro, UMR 1286, Bordeaux, France
| | | | - Mathieu Di Miceli
- Worcester Biomedical Research Group, School of Science and the Environment, University of Worcester, Worcester, UK
| | - Janany Kandiah
- Université Paris Cité, BFA, UMR 8251, CNRS, Paris, France
| | - Ilyès Raho
- Université Paris Cité, BFA, UMR 8251, CNRS, Paris, France
| | - Jasmine Buttler
- INCIA, UMR CNRS, Bordeaux University, Neurocampus, Bordeaux, France
| | | | | | - Sophie Layé
- Université Bordeaux, INRAE, Bordeaux INP, NutriNeuro, UMR 1286, Bordeaux, France
| | - Vanessa H Routh
- Department of Pharmacology, Physiology and Neuroscience, Rutgers, New Jersey Medical School, The State University of New Jersey, Newark, New Jersey, USA
| | - Bruno P Guiard
- Centre de Recherches sur la Cognition Animale (CRCA), Centre de Biologie Intégrative (CBI), Toulouse, France
| | | | | | - Xavier Fioramonti
- Université Bordeaux, INRAE, Bordeaux INP, NutriNeuro, UMR 1286, Bordeaux, France
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5
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Oliveira A, Seixas R, Pereira F, Azevedo M, Martinho R, Serrão P, Moreira-Rodrigues M. Insulin enhances contextual fear memory independently of its effect in increasing plasma adrenaline. Life Sci 2023:121881. [PMID: 37356751 DOI: 10.1016/j.lfs.2023.121881] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2022] [Revised: 06/14/2023] [Accepted: 06/22/2023] [Indexed: 06/27/2023]
Abstract
AIMS Adrenaline enhances contextual fear memory consolidation possibly by activating liver β2-adrenoceptors causing transient hyperglycaemia. Contrastingly, insulin-induced hypoglycaemia may culminate in blood adrenaline increment, hidering the separation of each hormone's action in contextual fear memory. Therefore, an Ad-deficient mouse model was used aiming to investigate if contextual fear memory consolidation following insulin administration requires or not subsequent increases in plasma adrenaline, which occurs in response to insulin-induced hypoglycemia. MAIN METHODS Fear conditioning was performed in wild-type (WT) and adrenaline-deficient (Pnmt-KO) male mice (129 × 1/SvJ) treated with insulin (2 U/kg, intraperitoneal (i.p.)) or vehicle (0.9 % NaCl (i.p.)). Blood glucose was quantified. Catecholamines were quantified using HPLC with electrochemical detection. Quantitative real-time polymerase chain reaction was used to assess mRNA expression of hippocampal Nr4a1, Nr4a2, Nr4a3, and Bdnf genes. KEY FINDINGS Insulin-treated WT mice showed increased freezing behaviour when compared to vehicle-treated WT mice. Also, plasma dopamine, noradrenaline, and adrenaline increased in this group. Insulin-treated Pnmt-KO animals showed increased freezing behaviour when compared with respective vehicle. However, no changes in plasma or tissue catecholamines were identified in insulin-treated Pnmt-KO mice when compared with respective vehicle. Furthermore, insulin-treated Pnmt-KO mice presented increased Bdnf mRNA expression when compared to vehicle-treated Pnmt-KO mice. SIGNIFICANCE Concluding, enhanced freezing behaviour after insulin treatment, even in adrenaline absence, may indicate a key role of insulin in contextual fear memory. Insulin may cause central molecular changes promoting contextual fear memory formation and/or retrieval. This work may indicate a further role of insulin in the process of contextual fear memory modulation.
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Affiliation(s)
- Ana Oliveira
- Department of Immuno-physiology and Pharmacology, Laboratory of General Physiology, School of Medicine and Biomedical Sciences (ICBAS), University of Porto (UP), Porto, Portugal; Center for Drug Discovery and Innovative Medicines, University of Porto (MedInUP), Porto, Portugal
| | - Rafaela Seixas
- Department of Immuno-physiology and Pharmacology, Laboratory of General Physiology, School of Medicine and Biomedical Sciences (ICBAS), University of Porto (UP), Porto, Portugal; Center for Drug Discovery and Innovative Medicines, University of Porto (MedInUP), Porto, Portugal
| | - Francisca Pereira
- Department of Immuno-physiology and Pharmacology, Laboratory of General Physiology, School of Medicine and Biomedical Sciences (ICBAS), University of Porto (UP), Porto, Portugal; Center for Drug Discovery and Innovative Medicines, University of Porto (MedInUP), Porto, Portugal
| | - Márcia Azevedo
- Department of Immuno-physiology and Pharmacology, Laboratory of General Physiology, School of Medicine and Biomedical Sciences (ICBAS), University of Porto (UP), Porto, Portugal; Center for Drug Discovery and Innovative Medicines, University of Porto (MedInUP), Porto, Portugal
| | - Raquel Martinho
- Department of Immuno-physiology and Pharmacology, Laboratory of General Physiology, School of Medicine and Biomedical Sciences (ICBAS), University of Porto (UP), Porto, Portugal; Center for Drug Discovery and Innovative Medicines, University of Porto (MedInUP), Porto, Portugal
| | - Paula Serrão
- Center for Drug Discovery and Innovative Medicines, University of Porto (MedInUP), Porto, Portugal; Department of Biomedicine, Faculty of Medicine, University of Porto (FMUP), Porto, Portugal
| | - Mónica Moreira-Rodrigues
- Department of Immuno-physiology and Pharmacology, Laboratory of General Physiology, School of Medicine and Biomedical Sciences (ICBAS), University of Porto (UP), Porto, Portugal; Center for Drug Discovery and Innovative Medicines, University of Porto (MedInUP), Porto, Portugal.
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6
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Yoon JH, Hwang J, Son SU, Choi J, You SW, Park H, Cha SY, Maeng S. How Can Insulin Resistance Cause Alzheimer's Disease? Int J Mol Sci 2023; 24:3506. [PMID: 36834911 PMCID: PMC9966425 DOI: 10.3390/ijms24043506] [Citation(s) in RCA: 34] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2022] [Revised: 01/17/2023] [Accepted: 01/27/2023] [Indexed: 02/12/2023] Open
Abstract
Alzheimer's disease (AD) is a neurodegenerative disorder associated with cognitive decline. Despite worldwide efforts to find a cure, no proper treatment has been developed yet, and the only effective countermeasure is to prevent the disease progression by early diagnosis. The reason why new drug candidates fail to show therapeutic effects in clinical studies may be due to misunderstanding the cause of AD. Regarding the cause of AD, the most widely known is the amyloid cascade hypothesis, in which the deposition of amyloid beta and hyperphosphorylated tau is the cause. However, many new hypotheses were suggested. Among them, based on preclinical and clinical evidence supporting a connection between AD and diabetes, insulin resistance has been pointed out as an important factor in the development of AD. Therefore, by reviewing the pathophysiological background of brain metabolic insufficiency and insulin insufficiency leading to AD pathology, we will discuss how can insulin resistance cause AD.
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Affiliation(s)
- Ji Hye Yoon
- Age-Tech Service Convergence Major, Graduate School of East–West Medical Science, Kyung Hee University, Yongin-si 17104, Republic of Korea
| | - JooHyun Hwang
- Age-Tech Service Convergence Major, Graduate School of East–West Medical Science, Kyung Hee University, Yongin-si 17104, Republic of Korea
| | - Sung Un Son
- Department of Comprehensive Health Science, Graduate School of East–West Medical Science, Kyung Hee University, Yongin-si 17104, Republic of Korea
| | - Junhyuk Choi
- Age-Tech Service Convergence Major, Graduate School of East–West Medical Science, Kyung Hee University, Yongin-si 17104, Republic of Korea
| | - Seung-Won You
- Department of Comprehensive Health Science, Graduate School of East–West Medical Science, Kyung Hee University, Yongin-si 17104, Republic of Korea
| | - Hyunwoo Park
- Department of Comprehensive Health Science, Graduate School of East–West Medical Science, Kyung Hee University, Yongin-si 17104, Republic of Korea
- Health Park Co., Ltd., Seoul 02447, Republic of Korea
| | - Seung-Yun Cha
- Department of Comprehensive Health Science, Graduate School of East–West Medical Science, Kyung Hee University, Yongin-si 17104, Republic of Korea
| | - Sungho Maeng
- Age-Tech Service Convergence Major, Graduate School of East–West Medical Science, Kyung Hee University, Yongin-si 17104, Republic of Korea
- Department of Comprehensive Health Science, Graduate School of East–West Medical Science, Kyung Hee University, Yongin-si 17104, Republic of Korea
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7
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Bakker W, Imbernon M, Salinas CG, Moro Chao DH, Hassouna R, Morel C, Martin C, Leger C, Denis RG, Castel J, Peter A, Heni M, Maetzler W, Nielsen HS, Duquenne M, Schwaninger M, Lundh S, Johan Hogendorf WF, Gangarossa G, Secher A, Hecksher-Sørensen J, Pedersen TÅ, Prevot V, Luquet S. Acute changes in systemic glycemia gate access and action of GLP-1R agonist on brain structures controlling energy homeostasis. Cell Rep 2022; 41:111698. [PMID: 36417883 PMCID: PMC9715912 DOI: 10.1016/j.celrep.2022.111698] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2020] [Revised: 08/19/2022] [Accepted: 10/20/2022] [Indexed: 11/23/2022] Open
Abstract
Therapies based on glucagon-like peptide-1 (GLP-1) long-acting analogs and insulin are often used in the treatment of metabolic diseases. Both insulin and GLP-1 receptors are expressed in metabolically relevant brain regions, suggesting a cooperative action. However, the mechanisms underlying the synergistic actions of insulin and GLP-1R agonists remain elusive. In this study, we show that insulin-induced hypoglycemia enhances GLP-1R agonists entry in hypothalamic and area, leading to enhanced whole-body fat oxidation. Mechanistically, this phenomenon relies on the release of tanycyctic vascular endothelial growth factor A, which is selectively impaired after calorie-rich diet exposure. In humans, low blood glucose also correlates with enhanced blood-to-brain passage of insulin, suggesting that blood glucose gates the passage other energy-related signals in the brain. This study implies that the preventing hyperglycemia is important to harnessing the full benefit of GLP-1R agonist entry in the brain and action onto lipid mobilization and body weight loss.
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Affiliation(s)
- Wineke Bakker
- Université Paris Cité, CNRS, Unité de Biologie Fonctionnelle et Adaptative, 75013 Paris, France,Global Drug Discovery, Novo Nordisk A/S, Måløv, Denmark,Corresponding author
| | - Monica Imbernon
- University Lille, Inserm, CHU Lille, Laboratory of Development and Plasticity of the Neuroendocrine Brain, Lille Neuroscience & Cognition, EGID, UMR-S 1172, 59000 Lille, France
| | - Casper Gravesen Salinas
- Global Drug Discovery, Novo Nordisk A/S, Måløv, Denmark,Image Analysis & Computer Graphics, Department of Applied Mathematics and Computer Science, Technical University of Denmark, Kgs. Lyngby, Denmark,Gubra ApS, Hørsholm Kongevej 11B, 2970 Hørsholm, Denmark
| | | | - Rim Hassouna
- Université Paris Cité, CNRS, Unité de Biologie Fonctionnelle et Adaptative, 75013 Paris, France
| | - Chloe Morel
- Université Paris Cité, CNRS, Unité de Biologie Fonctionnelle et Adaptative, 75013 Paris, France
| | - Claire Martin
- Université Paris Cité, CNRS, Unité de Biologie Fonctionnelle et Adaptative, 75013 Paris, France
| | - Caroline Leger
- Université Paris Cité, CNRS, Unité de Biologie Fonctionnelle et Adaptative, 75013 Paris, France
| | - Raphael G.P. Denis
- Université Paris Cité, CNRS, Unité de Biologie Fonctionnelle et Adaptative, 75013 Paris, France,Institut Cochin, Université Paris Cité, INSERM U1016, CNRS UMR 8104, 75014 Paris, France
| | - Julien Castel
- Université Paris Cité, CNRS, Unité de Biologie Fonctionnelle et Adaptative, 75013 Paris, France
| | - Andreas Peter
- Institute of Diabetes Research and Metabolic Diseases (IDM) of the Helmholtz Center Munich at the University of Tübingen, Tübingen, Germany,German Center for Diabetes Research (DZD), Tübingen, Germany,Institute for Clinical Chemistry and Pathobiochemistry, Department for Diagnostic Laboratory Medicine, University Hospital of Tübingen, Tübingen, Germany
| | - Martin Heni
- Department of Internal Medicine IV, Division of Endocrinology, Diabetology and Nephrology, University of Tübingen, Tübingen, Germany,Institute of Diabetes Research and Metabolic Diseases (IDM) of the Helmholtz Center Munich at the University of Tübingen, Tübingen, Germany,German Center for Diabetes Research (DZD), Tübingen, Germany
| | - Walter Maetzler
- Department of Neurodegenerative Diseases, Center of Neurology, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany,German Center for Neurodegenerative Diseases, Tübingen, Germany,Department of Neurology, University of Kiel, Kiel, Germany
| | | | - Manon Duquenne
- University Lille, Inserm, CHU Lille, Laboratory of Development and Plasticity of the Neuroendocrine Brain, Lille Neuroscience & Cognition, EGID, UMR-S 1172, 59000 Lille, France
| | - Markus Schwaninger
- Institute for Experimental and Clinical Pharmacology and Toxicology, University of Lübeck, Lübeck, Germany
| | - Sofia Lundh
- Global Drug Discovery, Novo Nordisk A/S, Måløv, Denmark
| | | | - Giuseppe Gangarossa
- Université Paris Cité, CNRS, Unité de Biologie Fonctionnelle et Adaptative, 75013 Paris, France
| | - Anna Secher
- Global Drug Discovery, Novo Nordisk A/S, Måløv, Denmark
| | - Jacob Hecksher-Sørensen
- Global Drug Discovery, Novo Nordisk A/S, Måløv, Denmark,Gubra ApS, Hørsholm Kongevej 11B, 2970 Hørsholm, Denmark
| | | | - Vincent Prevot
- University Lille, Inserm, CHU Lille, Laboratory of Development and Plasticity of the Neuroendocrine Brain, Lille Neuroscience & Cognition, EGID, UMR-S 1172, 59000 Lille, France
| | - Serge Luquet
- Université Paris Cité, CNRS, Unité de Biologie Fonctionnelle et Adaptative, 75013 Paris, France,Corresponding author
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8
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Chen W, Cai W, Hoover B, Kahn CR. Insulin action in the brain: cell types, circuits, and diseases. Trends Neurosci 2022; 45:384-400. [PMID: 35361499 PMCID: PMC9035105 DOI: 10.1016/j.tins.2022.03.001] [Citation(s) in RCA: 70] [Impact Index Per Article: 23.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2021] [Revised: 02/10/2022] [Accepted: 03/03/2022] [Indexed: 10/18/2022]
Abstract
Since its discovery over 100 years ago, insulin has been recognized as a key hormone in control of glucose homeostasis. Deficiencies of insulin signaling are central to diabetes and many other disorders. The brain is among the targets of insulin action, and insulin resistance is a major contributor to many diseases, including brain disorders. Here, we summarize key roles of insulin action in the brain and how this involves different brain cell types. Disordered brain insulin signaling can also contribute to neuropsychiatric diseases, affecting brain circuits involved in mood and cognition. Understanding of insulin signaling in different brain cell types/circuits and how these are altered in disease may lead to the development of new therapeutic approaches to these challenging disorders.
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9
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Skovsø S, Panzhinskiy E, Kolic J, Cen HH, Dionne DA, Dai XQ, Sharma RB, Elghazi L, Ellis CE, Faulkner K, Marcil SAM, Overby P, Noursadeghi N, Hutchinson D, Hu X, Li H, Modi H, Wildi JS, Botezelli JD, Noh HL, Suk S, Gablaski B, Bautista A, Kim R, Cras-Méneur C, Flibotte S, Sinha S, Luciani DS, Nislow C, Rideout EJ, Cytrynbaum EN, Kim JK, Bernal-Mizrachi E, Alonso LC, MacDonald PE, Johnson JD. Beta-cell specific Insr deletion promotes insulin hypersecretion and improves glucose tolerance prior to global insulin resistance. Nat Commun 2022; 13:735. [PMID: 35136059 PMCID: PMC8826929 DOI: 10.1038/s41467-022-28039-8] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2021] [Accepted: 01/05/2022] [Indexed: 01/23/2023] Open
Abstract
Insulin receptor (Insr) protein is present at higher levels in pancreatic β-cells than in most other tissues, but the consequences of β-cell insulin resistance remain enigmatic. Here, we use an Ins1cre knock-in allele to delete Insr specifically in β-cells of both female and male mice. We compare experimental mice to Ins1cre-containing littermate controls at multiple ages and on multiple diets. RNA-seq of purified recombined β-cells reveals transcriptomic consequences of Insr loss, which differ between female and male mice. Action potential and calcium oscillation frequencies are increased in Insr knockout β-cells from female, but not male mice, whereas only male βInsrKO islets have reduced ATP-coupled oxygen consumption rate and reduced expression of genes involved in ATP synthesis. Female βInsrKO and βInsrHET mice exhibit elevated insulin release in ex vivo perifusion experiments, during hyperglycemic clamps, and following i.p. glucose challenge. Deletion of Insr does not alter β-cell area up to 9 months of age, nor does it impair hyperglycemia-induced proliferation. Based on our data, we adapt a mathematical model to include β-cell insulin resistance, which predicts that β-cell Insr knockout improves glucose tolerance depending on the degree of whole-body insulin resistance. Indeed, glucose tolerance is significantly improved in female βInsrKO and βInsrHET mice compared to controls at 9, 21 and 39 weeks, and also in insulin-sensitive 4-week old males. We observe no improved glucose tolerance in older male mice or in high fat diet-fed mice, corroborating the prediction that global insulin resistance obscures the effects of β-cell specific insulin resistance. The propensity for hyperinsulinemia is associated with mildly reduced fasting glucose and increased body weight. We further validate our main in vivo findings using an Ins1-CreERT transgenic line and find that male mice have improved glucose tolerance 4 weeks after tamoxifen-mediated Insr deletion. Collectively, our data show that β-cell insulin resistance in the form of reduced β-cell Insr contributes to hyperinsulinemia in the context of glucose stimulation, thereby improving glucose homeostasis in otherwise insulin sensitive sex, dietary and age contexts.
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Affiliation(s)
- Søs Skovsø
- Diabetes Research Group, Life Sciences Institute, and Department of Cellular and Physiological Sciences, University of British Columbia, Vancouver, BC, Canada
| | - Evgeniy Panzhinskiy
- Diabetes Research Group, Life Sciences Institute, and Department of Cellular and Physiological Sciences, University of British Columbia, Vancouver, BC, Canada
| | - Jelena Kolic
- Diabetes Research Group, Life Sciences Institute, and Department of Cellular and Physiological Sciences, University of British Columbia, Vancouver, BC, Canada
| | - Haoning Howard Cen
- Diabetes Research Group, Life Sciences Institute, and Department of Cellular and Physiological Sciences, University of British Columbia, Vancouver, BC, Canada
| | - Derek A Dionne
- Diabetes Research Group, Life Sciences Institute, and Department of Cellular and Physiological Sciences, University of British Columbia, Vancouver, BC, Canada
| | - Xiao-Qing Dai
- Alberta Diabetes Institute and Department of Pharmacology, University of Alberta, Edmonton, Canada
| | - Rohit B Sharma
- Division of Endocrinology, Diabetes and Metabolism and the Weill Center for Metabolic Health, Weill Cornell Medicine, New York, NY, USA
| | - Lynda Elghazi
- Department of Ophthalmology and Visual Sciences, University of Michigan Kellogg Eye Center, Ann Arbor, MI, USA
| | - Cara E Ellis
- Diabetes Research Group, Life Sciences Institute, and Department of Cellular and Physiological Sciences, University of British Columbia, Vancouver, BC, Canada
| | - Katharine Faulkner
- Department of Mathematics, University of British Columbia, Vancouver, BC, Canada
| | - Stephanie A M Marcil
- Diabetes Research Group, Life Sciences Institute, and Department of Cellular and Physiological Sciences, University of British Columbia, Vancouver, BC, Canada
| | - Peter Overby
- Diabetes Research Group, Life Sciences Institute, and Department of Cellular and Physiological Sciences, University of British Columbia, Vancouver, BC, Canada
| | - Nilou Noursadeghi
- Diabetes Research Group, Life Sciences Institute, and Department of Cellular and Physiological Sciences, University of British Columbia, Vancouver, BC, Canada
| | - Daria Hutchinson
- Diabetes Research Group, Life Sciences Institute, and Department of Cellular and Physiological Sciences, University of British Columbia, Vancouver, BC, Canada
| | - Xiaoke Hu
- Diabetes Research Group, Life Sciences Institute, and Department of Cellular and Physiological Sciences, University of British Columbia, Vancouver, BC, Canada
| | - Hong Li
- Diabetes Research Group, Life Sciences Institute, and Department of Cellular and Physiological Sciences, University of British Columbia, Vancouver, BC, Canada
| | - Honey Modi
- Diabetes Research Group, Life Sciences Institute, and Department of Cellular and Physiological Sciences, University of British Columbia, Vancouver, BC, Canada
| | - Jennifer S Wildi
- Diabetes Research Group, Life Sciences Institute, and Department of Cellular and Physiological Sciences, University of British Columbia, Vancouver, BC, Canada
| | - J Diego Botezelli
- Diabetes Research Group, Life Sciences Institute, and Department of Cellular and Physiological Sciences, University of British Columbia, Vancouver, BC, Canada
| | - Hye Lim Noh
- Program in Molecular Medicine University of Massachusetts Medical School, Worcester, MA, USA
- Charles River Laboratories, Shrewsbury, MA, USA
| | - Sujin Suk
- Program in Molecular Medicine University of Massachusetts Medical School, Worcester, MA, USA
| | - Brian Gablaski
- Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Massachusetts Medical School, Worcester, MA, USA
- Charles River Laboratories, Shrewsbury, MA, USA
| | - Austin Bautista
- Alberta Diabetes Institute and Department of Pharmacology, University of Alberta, Edmonton, Canada
| | - Ryekjang Kim
- Alberta Diabetes Institute and Department of Pharmacology, University of Alberta, Edmonton, Canada
| | - Corentin Cras-Méneur
- Department of Internal Medicine, Division of Metabolism, Endocrinology and Diabetes, University of Michigan, Ann Arbor, MI, USA
| | - Stephane Flibotte
- UBC Life Sciences Institute Bioinformatics Facility, University of British Columbia, Vancouver, BC, Canada
| | - Sunita Sinha
- UBC Sequencing and Bioinformatics Consortium, Pharmaceutical Sciences, University of British Columbia, Vancouver, BC, Canada
| | - Dan S Luciani
- BC Children's Hospital Research Institute, Department of Surgery, Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada
| | - Corey Nislow
- UBC Sequencing and Bioinformatics Consortium, Pharmaceutical Sciences, University of British Columbia, Vancouver, BC, Canada
| | - Elizabeth J Rideout
- Diabetes Research Group, Life Sciences Institute, and Department of Cellular and Physiological Sciences, University of British Columbia, Vancouver, BC, Canada
| | - Eric N Cytrynbaum
- Department of Mathematics, University of British Columbia, Vancouver, BC, Canada
| | - Jason K Kim
- Program in Molecular Medicine University of Massachusetts Medical School, Worcester, MA, USA
- Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Massachusetts Medical School, Worcester, MA, USA
| | - Ernesto Bernal-Mizrachi
- Division of Endocrinology, Diabetes and Metabolism, University of Miami Miller School of Medicine and Miami VA Health Care System, Miami, FL, USA
| | - Laura C Alonso
- Division of Endocrinology, Diabetes and Metabolism and the Weill Center for Metabolic Health, Weill Cornell Medicine, New York, NY, USA
| | - Patrick E MacDonald
- Alberta Diabetes Institute and Department of Pharmacology, University of Alberta, Edmonton, Canada
| | - James D Johnson
- Diabetes Research Group, Life Sciences Institute, and Department of Cellular and Physiological Sciences, University of British Columbia, Vancouver, BC, Canada.
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10
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Choi JH, Kim MS. Homeostatic Regulation of Glucose Metabolism by the Central Nervous System. Endocrinol Metab (Seoul) 2022; 37:9-25. [PMID: 35255598 PMCID: PMC8901968 DOI: 10.3803/enm.2021.1364] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/09/2021] [Accepted: 02/07/2022] [Indexed: 12/04/2022] Open
Abstract
Evidence for involvement of the central nervous system (CNS) in the regulation of glucose metabolism dates back to the 19th century, although the majority of the research on glucose metabolism has focused on the peripheral metabolic organs. Due to recent advances in neuroscience, it has now become clear that the CNS is indeed vital for maintaining glucose homeostasis. To achieve normoglycemia, specific populations of neurons and glia in the hypothalamus sense changes in the blood concentrations of glucose and of glucoregulatory hormones such as insulin, leptin, glucagon-like peptide 1, and glucagon. This information is integrated and transmitted to other areas of the brain where it eventually modulates various processes in glucose metabolism (i.e., hepatic glucose production, glucose uptake in the brown adipose tissue and skeletal muscle, pancreatic insulin and glucagon secretion, renal glucose reabsorption, etc.). Errors in these processes lead to hyper- or hypoglycemia. We here review the current understanding of the brain regulation of glucose metabolism.
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Affiliation(s)
- Jong Han Choi
- Division of Endocrinology and Metabolism, Konkuk University Medical Center, Seoul,
Korea
| | - Min-Seon Kim
- Division of Endocrinology and Metabolism, Asan Medical Center, University of Ulsan College of Medicine, Seoul,
Korea
- Appeptite Regulation Laboratory, Asan Institute for Life Sciences, University of Ulsan College of Medicine, Seoul,
Korea
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11
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Stranahan AM. Visceral adiposity, inflammation, and hippocampal function in obesity. Neuropharmacology 2021; 205:108920. [PMID: 34902347 DOI: 10.1016/j.neuropharm.2021.108920] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2021] [Revised: 11/09/2021] [Accepted: 12/08/2021] [Indexed: 02/06/2023]
Abstract
The 'apple-shaped' anatomical pattern that accompanies visceral adiposity increases risk for multiple chronic diseases, including conditions that impact the brain, such as diabetes and hypertension. However, distinguishing between the consequences of visceral obesity, as opposed to visceral adiposity-associated metabolic and cardiovascular pathologies, presents certain challenges. This review summarizes current literature on relationships between adipose tissue distribution and cognition in preclinical models and highlights unanswered questions surrounding the potential role of tissue- and cell type-specific insulin resistance in these effects. While gaps in knowledge persist related to insulin insensitivity and cognitive impairment in obesity, several recent studies suggest that cells of the neurovascular unit contribute to hippocampal synaptic dysfunction, and this review interprets those findings in the context of progressive metabolic dysfunction in the CNS. Signalling between cerebrovascular endothelial cells, astrocytes, microglia, and neurons has been linked with memory deficits in visceral obesity, and this article describes the cellular changes in each of these populations with respect to their role in amplification or diminution of peripheral signals. The picture emerging from these studies, while incomplete, implicates pro-inflammatory cytokines, insulin resistance, and hyperglycemia in various stages of obesity-induced hippocampal dysfunction. As in the parable of the five blind wanderers holding different parts of an elephant, considerable work remains in order to assemble a model for the underlying mechanisms linking visceral adiposity with age-related cognitive decline.
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Affiliation(s)
- Alexis M Stranahan
- Department of Neuroscience and Regenerative Medicine, Medical College of Georgia, Augusta University, 1462 Laney Walker Blvd, Augusta, GA, 30912, USA.
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12
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Abstract
The Akt isoforms-AS160-GLUT4 axis is the primary axis that governs glucose homeostasis in the body. The first step on the path to insulin resistance is deregulated Akt isoforms. This could be Akt isoform expression, its phosphorylation, or improper isoform-specific redistribution to the plasma membrane in a specific tissue system. The second step is deregulated AS160 expression, its phosphorylation, improper dissociation from glucose transporter storage vesicles (GSVs), or its inability to bind to 14-3-3 proteins, thus not allowing it to execute its function. The final step is improper GLUT4 translocation and aberrant glucose uptake. These processes lead to insulin resistance in a tissue-specific way affecting the whole-body glucose homeostasis, eventually progressing to an overt diabetic phenotype. Thus, the relationship between these three key proteins and their proper regulation comes out as the defining axis of insulin signaling and -resistance. This review summarizes the role of this central axis in insulin resistance and disease in a new light.
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Affiliation(s)
- Medha Sharma
- Kusuma School of Biological Sciences, Indian Institute of Technology-Delhi, Hauz Khas, New Delhi, 110016, India
| | - Chinmoy Sankar Dey
- Kusuma School of Biological Sciences, Indian Institute of Technology-Delhi, Hauz Khas, New Delhi, 110016, India.
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13
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Milstein JL, Ferris HA. The brain as an insulin-sensitive metabolic organ. Mol Metab 2021; 52:101234. [PMID: 33845179 PMCID: PMC8513144 DOI: 10.1016/j.molmet.2021.101234] [Citation(s) in RCA: 120] [Impact Index Per Article: 30.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/10/2020] [Revised: 03/26/2021] [Accepted: 04/07/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND The brain was once thought of as an insulin-insensitive organ. We now know that the insulin receptor is present throughout the brain and serves important functions in whole-body metabolism and brain function. Brain insulin signaling is involved not only in brain homeostatic processes but also neuropathological processes such as cognitive decline and Alzheimer's disease. SCOPE OF REVIEW In this review, we provide an overview of insulin signaling within the brain and the metabolic impact of brain insulin resistance and discuss Alzheimer's disease, one of the neurologic diseases most closely associated with brain insulin resistance. MAJOR CONCLUSIONS While brain insulin signaling plays only a small role in central nervous system glucose regulation, it has a significant impact on the brain's metabolic health. Normal insulin signaling is important for mitochondrial functioning and normal food intake. Brain insulin resistance contributes to obesity and may also play an important role in neurodegeneration.
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Affiliation(s)
- Joshua L Milstein
- Center for Brain Immunology and Glia, University of Virginia, Charlottesville, VA, USA; Department of Neuroscience, University of Virginia, Charlottesville, VA, USA
| | - Heather A Ferris
- Center for Brain Immunology and Glia, University of Virginia, Charlottesville, VA, USA; Department of Neuroscience, University of Virginia, Charlottesville, VA, USA; Division of Endocrinology and Metabolism, University of Virginia, Charlottesville, VA, USA.
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14
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Shankar K, Takemi S, Gupta D, Varshney S, Mani BK, Osborne-Lawrence S, Metzger NP, Richard CP, Berglund ED, Zigman JM. Ghrelin cell-expressed insulin receptors mediate meal- and obesity-induced declines in plasma ghrelin. JCI Insight 2021; 6:e146983. [PMID: 34473648 PMCID: PMC8492315 DOI: 10.1172/jci.insight.146983] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2020] [Accepted: 08/04/2021] [Indexed: 01/20/2023] Open
Abstract
Mechanisms underlying postprandial and obesity-associated plasma ghrelin reductions are incompletely understood. Here, using ghrelin cell-selective insulin receptor-KO (GhIRKO) mice, we tested the impact of insulin, acting via ghrelin cell-expressed insulin receptors (IRs), to suppress ghrelin secretion. Insulin reduced ghrelin secretion from cultured gastric mucosal cells of control mice but not from those of GhIRKO mice. Acute insulin challenge and insulin infusion during both hyperinsulinemic-hypoglycemic clamps and hyperinsulinemic-euglycemic clamps lowered plasma ghrelin in control mice but not GhIRKO mice. Thus, ghrelin cell-expressed IRs are required for insulin-mediated reductions in plasma ghrelin. Furthermore, interventions that naturally raise insulin (glucose gavage, refeeding following fasting, and chronic high-fat diet) also lowered plasma ghrelin only in control mice - not GhIRKO mice. Thus, meal- and obesity-associated increases in insulin, acting via ghrelin cell-expressed IRs, represent a major, direct negative modulator of ghrelin secretion in vivo, as opposed to ingested or metabolized macronutrients. Refed GhIRKO mice exhibited reduced plasma insulin, highlighting ghrelin's actions to inhibit insulin release via a feedback loop. Moreover, GhIRKO mice required reduced glucose infusion rates during hyperinsulinemic-hypoglycemic clamps, suggesting that suppressed ghrelin release resulting from direct insulin action on ghrelin cells usually limits ghrelin's full potential to protect against insulin-induced hypoglycemia.
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Affiliation(s)
- Kripa Shankar
- Center for Hypothalamic Research, Department of Internal Medicine, UT Southwestern Medical Center, Dallas, Texas, USA
| | - Shota Takemi
- Center for Hypothalamic Research, Department of Internal Medicine, UT Southwestern Medical Center, Dallas, Texas, USA
- Area of Regulatory Biology, Division of Life Science, Graduate School of Science and Engineering, Saitama University, Sakuraku, Saitama, Japan
| | - Deepali Gupta
- Center for Hypothalamic Research, Department of Internal Medicine, UT Southwestern Medical Center, Dallas, Texas, USA
| | - Salil Varshney
- Center for Hypothalamic Research, Department of Internal Medicine, UT Southwestern Medical Center, Dallas, Texas, USA
| | - Bharath K. Mani
- Center for Hypothalamic Research, Department of Internal Medicine, UT Southwestern Medical Center, Dallas, Texas, USA
| | - Sherri Osborne-Lawrence
- Center for Hypothalamic Research, Department of Internal Medicine, UT Southwestern Medical Center, Dallas, Texas, USA
| | - Nathan P. Metzger
- Center for Hypothalamic Research, Department of Internal Medicine, UT Southwestern Medical Center, Dallas, Texas, USA
| | - Corine P. Richard
- Center for Hypothalamic Research, Department of Internal Medicine, UT Southwestern Medical Center, Dallas, Texas, USA
| | - Eric D. Berglund
- Center for Hypothalamic Research, Department of Internal Medicine, UT Southwestern Medical Center, Dallas, Texas, USA
| | - Jeffrey M. Zigman
- Center for Hypothalamic Research, Department of Internal Medicine, UT Southwestern Medical Center, Dallas, Texas, USA
- Division of Endocrinology, Department of Internal Medicine, and
- Department of Psychiatry, UT Southwestern Medical Center, Dallas, Texas, USA
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15
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Scherer T, Sakamoto K, Buettner C. Brain insulin signalling in metabolic homeostasis and disease. Nat Rev Endocrinol 2021; 17:468-483. [PMID: 34108679 DOI: 10.1038/s41574-021-00498-x] [Citation(s) in RCA: 94] [Impact Index Per Article: 23.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 04/22/2021] [Indexed: 02/06/2023]
Abstract
Insulin signalling in the central nervous system regulates energy homeostasis by controlling metabolism in several organs and by coordinating organ crosstalk. Studies performed in rodents, non-human primates and humans over more than five decades using intracerebroventricular, direct hypothalamic or intranasal application of insulin provide evidence that brain insulin action might reduce food intake and, more importantly, regulates energy homeostasis by orchestrating nutrient partitioning. This Review discusses the metabolic pathways that are under the control of brain insulin action and explains how brain insulin resistance contributes to metabolic disease in obesity, the metabolic syndrome and type 2 diabetes mellitus.
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Affiliation(s)
- Thomas Scherer
- Division of Endocrinology and Metabolism, Department of Medicine III, Medical University of Vienna, Vienna, Austria.
| | - Kenichi Sakamoto
- Division of Endocrinology, Metabolism & Nutrition, Department of Medicine, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, USA
| | - Christoph Buettner
- Division of Endocrinology, Metabolism & Nutrition, Department of Medicine, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, USA.
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16
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Cai W, Zhang X, Batista TM, García-Martín R, Softic S, Wang G, Ramirez AK, Konishi M, O'Neill BT, Kim JH, Kim JK, Kahn CR. Peripheral Insulin Regulates a Broad Network of Gene Expression in Hypothalamus, Hippocampus, and Nucleus Accumbens. Diabetes 2021; 70:1857-1873. [PMID: 34031123 PMCID: PMC8385615 DOI: 10.2337/db20-1119] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/03/2020] [Accepted: 05/09/2021] [Indexed: 11/13/2022]
Abstract
The brain is now recognized as an insulin-sensitive tissue; however, the role of changing insulin concentrations in the peripheral circulation in gene expression in the brain is largely unknown. Here, we performed a hyperinsulinemic-euglycemic clamp on 3-month-old male C57BL/6 mice for 3 h. We show that, in comparison with results in saline-infused controls, increases in peripheral insulin within the physiological range regulate expression of a broad network of genes in the brain. Insulin regulates distinct pathways in the hypothalamus (HTM), hippocampus, and nucleus accumbens. Insulin shows its most robust effect in the HTM and regulates multiple genes involved in neurotransmission, including upregulating expression of multiple subunits of GABA-A receptors, Na+ and K+ channels, and SNARE proteins; differentially modulating glutamate receptors; and suppressing multiple neuropeptides. Insulin also strongly modulates metabolic genes in the HTM, suppressing genes in the glycolysis and pentose phosphate pathways, while increasing expression of genes regulating pyruvate dehydrogenase and long-chain fatty acyl-CoA and cholesterol biosynthesis, thereby rerouting of carbon substrates from glucose metabolism to lipid metabolism required for the biogenesis of membranes for neuronal and glial function and synaptic remodeling. Furthermore, based on the transcriptional signatures, these changes in gene expression involve neurons, astrocytes, oligodendrocytes, microglia, and endothelial cells. Thus, peripheral insulin acutely and potently regulates expression of a broad network of genes involved in neurotransmission and brain metabolism. Dysregulation of these pathways could have dramatic effects in normal physiology and diabetes.
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Affiliation(s)
- Weikang Cai
- Section of Integrative Physiology and Metabolism, Joslin Diabetes Center, Harvard Medical School, Boston, MA
- Department of Biomedical Sciences, New York Institute of Technology, College of Osteopathic Medicine, Old Westbury, NY
| | - Xuemei Zhang
- Section of Integrative Physiology and Metabolism, Joslin Diabetes Center, Harvard Medical School, Boston, MA
| | - Thiago M Batista
- Section of Integrative Physiology and Metabolism, Joslin Diabetes Center, Harvard Medical School, Boston, MA
| | - Rubén García-Martín
- Section of Integrative Physiology and Metabolism, Joslin Diabetes Center, Harvard Medical School, Boston, MA
| | - Samir Softic
- Section of Integrative Physiology and Metabolism, Joslin Diabetes Center, Harvard Medical School, Boston, MA
- Department of Pediatrics, University of Kentucky, College of Medicine, Lexington, KY
| | - Guoxiao Wang
- Section of Integrative Physiology and Metabolism, Joslin Diabetes Center, Harvard Medical School, Boston, MA
| | - Alfred K Ramirez
- Section of Integrative Physiology and Metabolism, Joslin Diabetes Center, Harvard Medical School, Boston, MA
| | - Masahiro Konishi
- Section of Integrative Physiology and Metabolism, Joslin Diabetes Center, Harvard Medical School, Boston, MA
| | - Brian T O'Neill
- Section of Integrative Physiology and Metabolism, Joslin Diabetes Center, Harvard Medical School, Boston, MA
- Division of Endocrinology and Metabolism, Fraternal Order of Eagles Diabetes Research Center, University of Iowa Carver College of Medicine, Iowa City, IA
| | - Jong Hun Kim
- Program in Molecular Medicine, Department of Medicine, University of Massachusetts Medical School, Worcester, MA
- Department of Food Science and Biotechnology, Sungshin University, Seoul, South Korea
| | - Jason K Kim
- Program in Molecular Medicine, Department of Medicine, University of Massachusetts Medical School, Worcester, MA
- Division of Endocrinology, Metabolism, and Diabetes, Department of Medicine, University of Massachusetts Medical School, Worcester, MA
| | - C Ronald Kahn
- Section of Integrative Physiology and Metabolism, Joslin Diabetes Center, Harvard Medical School, Boston, MA
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17
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Agrawal R, Reno CM, Sharma S, Christensen C, Huang Y, Fisher SJ. Insulin action in the brain regulates both central and peripheral functions. Am J Physiol Endocrinol Metab 2021; 321:E156-E163. [PMID: 34056920 PMCID: PMC8321819 DOI: 10.1152/ajpendo.00642.2020] [Citation(s) in RCA: 66] [Impact Index Per Article: 16.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
Abstract
The brain has been traditionally thought to be insensitive to insulin, primarily because insulin does not stimulate glucose uptake/metabolism in the brain (as it does in classic insulin-sensitive tissues such as muscle, liver, and fat). However, over the past 20 years, research in this field has identified unique actions of insulin in the brain. There is accumulating evidence that insulin crosses into the brain and regulates central nervous system functions such as feeding, depression, and cognitive behavior. In addition, insulin acts in the brain to regulate systemic functions such as hepatic glucose production, lipolysis, lipogenesis, reproductive competence, and the sympathoadrenal response to hypoglycemia. Decrements in brain insulin action (or brain insulin resistance) can be observed in obesity, type 2 diabetes (T2DM), aging, and Alzheimer's disease (AD), indicating a possible link between metabolic and cognitive health. Here, we describe recent findings on the pleiotropic actions of insulin in the brain and highlight the precise sites, specific neuronal population, and roles for supportive astrocytic cells through which insulin acts in the brain. In addition, we also discuss how boosting brain insulin action could be a therapeutic option for people at an increased risk of developing metabolic and cognitive diseases such as AD and T2DM. Overall, this perspective article serves to highlight some of these key scientific findings, identify unresolved issues, and indicate future directions of research in this field that would serve to improve the lives of people with metabolic and cognitive dysfunctions.
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Affiliation(s)
- Rahul Agrawal
- Division of Endocrinology, Metabolism and Diabetes, Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, Utah
| | - Candace M Reno
- Division of Endocrinology, Metabolism and Diabetes, Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, Utah
| | - Sunny Sharma
- Division of Endocrinology, Metabolism and Diabetes, Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, Utah
| | - Camille Christensen
- Division of Endocrinology, Metabolism and Diabetes, Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, Utah
| | - Yiqing Huang
- Division of Endocrinology, Metabolism and Diabetes, Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, Utah
| | - Simon J Fisher
- Division of Endocrinology, Metabolism and Diabetes, Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, Utah
- Department of Biochemistry, University of Utah School of Medicine, Salt Lake City, Utah
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18
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Mitchell CS, Begg DP. The regulation of food intake by insulin in the central nervous system. J Neuroendocrinol 2021; 33:e12952. [PMID: 33656205 DOI: 10.1111/jne.12952] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/06/2020] [Revised: 01/31/2021] [Accepted: 02/03/2021] [Indexed: 01/02/2023]
Abstract
Food intake and energy expenditure are regulated by peripheral signals providing feedback on nutrient status and adiposity to the central nervous system. One of these signals is the pancreatic hormone, insulin. Unlike peripheral administration of insulin, which often causes weight gain, central administration of insulin leads to a reduction in food intake and body weight when administered long-term. This is a result of feedback processes in regions of the brain that regulate food intake. Within the hypothalamus, the arcuate nucleus (ARC) contains subpopulations of neurones that produce orexinergic neuropeptides agouti-related peptide (AgRP)/neuropeptide Y (NPY) and anorexigenic neuropeptides, pro-opiomelanocortin (POMC)/cocaine- and amphetamine-regulated transcript (CART). Intracerebroventricular infusion of insulin down-regulates the expression of AgRP/NPY at the same time as up-regulating expression of POMC/CART. Recent evidence suggests that insulin activity within the amygdala may play an important role in regulating energy balance. Insulin infusion into the central nucleus of the amygdala (CeA) can decrease food intake, possibly by modulating activity of NPY and other neurone subpopulations. Insulin signalling within the CeA can also influence stress-induced obesity. Overall, it is evident that the CeA is a critical target for insulin signalling and the regulation of energy balance.
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Affiliation(s)
| | - Denovan P Begg
- School of Psychology, UNSW Sydney, Sydney, NSW, Australia
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19
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Glucose transporters in brain in health and disease. Pflugers Arch 2020; 472:1299-1343. [PMID: 32789766 PMCID: PMC7462931 DOI: 10.1007/s00424-020-02441-x] [Citation(s) in RCA: 307] [Impact Index Per Article: 61.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2020] [Revised: 07/20/2020] [Accepted: 07/24/2020] [Indexed: 12/15/2022]
Abstract
Energy demand of neurons in brain that is covered by glucose supply from the blood is ensured by glucose transporters in capillaries and brain cells. In brain, the facilitative diffusion glucose transporters GLUT1-6 and GLUT8, and the Na+-d-glucose cotransporters SGLT1 are expressed. The glucose transporters mediate uptake of d-glucose across the blood-brain barrier and delivery of d-glucose to astrocytes and neurons. They are critically involved in regulatory adaptations to varying energy demands in response to differing neuronal activities and glucose supply. In this review, a comprehensive overview about verified and proposed roles of cerebral glucose transporters during health and diseases is presented. Our current knowledge is mainly based on experiments performed in rodents. First, the functional properties of human glucose transporters expressed in brain and their cerebral locations are described. Thereafter, proposed physiological functions of GLUT1, GLUT2, GLUT3, GLUT4, and SGLT1 for energy supply to neurons, glucose sensing, central regulation of glucohomeostasis, and feeding behavior are compiled, and their roles in learning and memory formation are discussed. In addition, diseases are described in which functional changes of cerebral glucose transporters are relevant. These are GLUT1 deficiency syndrome (GLUT1-SD), diabetes mellitus, Alzheimer’s disease (AD), stroke, and traumatic brain injury (TBI). GLUT1-SD is caused by defect mutations in GLUT1. Diabetes and AD are associated with changed expression of glucose transporters in brain, and transporter-related energy deficiency of neurons may contribute to pathogenesis of AD. Stroke and TBI are associated with changes of glucose transporter expression that influence clinical outcome.
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20
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Griffith CM, Macklin LN, Cai Y, Sharp AA, Yan XX, Reagan LP, Strader AD, Rose GM, Patrylo PR. Impaired Glucose Tolerance and Reduced Plasma Insulin Precede Decreased AKT Phosphorylation and GLUT3 Translocation in the Hippocampus of Old 3xTg-AD Mice. J Alzheimers Dis 2020; 68:809-837. [PMID: 30775979 DOI: 10.3233/jad-180707] [Citation(s) in RCA: 35] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Several studies have demonstrated that mouse models of Alzheimer's disease (AD) can exhibit impaired peripheral glucose tolerance. Further, in the APP/PS1 mouse model, this is observed prior to the appearance of AD-related neuropathology (e.g., amyloid-β plaques; Aβ) or cognitive impairment. In the current study, we examined whether impaired glucose tolerance also preceded AD-like changes in the triple transgenic model of AD (3xTg-AD). Glucose tolerance testing (GTT), insulin ELISAs, and insulin tolerance testing (ITT) were performed at ages prior to (1-3 months and 6-8 months old) and post-pathology (16-18 months old). Additionally, we examined for altered insulin signaling in the hippocampus. Western blots were used to evaluate the two-primary insulin signaling pathways: PI3K/AKT and MAPK/ERK. Since the PI3K/AKT pathway affects several downstream targets associated with metabolism (e.g., GSK3, glucose transporters), western blots were used to examine possible alterations in the expression, translocation, or activation of these targets. We found that 3xTg-AD mice display impaired glucose tolerance as early as 1 month of age, concomitant with a decrease in plasma insulin levels well prior to the detection of plaques (∼14 months old), aggregates of hyperphosphorylated tau (∼18 months old), and cognitive decline (≥18 months old). These alterations in peripheral metabolism were seen at all time points examined. In comparison, PI3K/AKT, but not MAPK/ERK, signaling was altered in the hippocampus only in 18-20-month-old 3xTg-AD mice, a time point at which there was a reduction in GLUT3 translocation to the plasma membrane. Taken together, our results provide further evidence that disruptions in energy metabolism may represent a foundational step in the development of AD.
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Affiliation(s)
- Chelsea M Griffith
- Department of Physiology, Southern Illinois University School of Medicine, Carbondale, IL, USA.,Center for Integrated Research in Cognitive and Neural Sciences, Southern Illinois University, Carbondale, IL, USA
| | - Lauren N Macklin
- Department of Physiology, Southern Illinois University School of Medicine, Carbondale, IL, USA.,Center for Integrated Research in Cognitive and Neural Sciences, Southern Illinois University, Carbondale, IL, USA
| | - Yan Cai
- Department of Anatomy and Neurobiology, Central South University Xiangya School of Medicine, Changsha, Hunan, China.,Key Laboratory of Hunan Province in Neurodegenerative Disorders, Changsha, Hunan, China
| | - Andrew A Sharp
- Department of Physiology, Southern Illinois University School of Medicine, Carbondale, IL, USA.,Department of Anatomy, Southern Illinois University School of Medicine, Carbondale, IL, USA.,Center for Integrated Research in Cognitive and Neural Sciences, Southern Illinois University, Carbondale, IL, USA
| | - Xiao-Xin Yan
- Department of Anatomy and Neurobiology, Central South University Xiangya School of Medicine, Changsha, Hunan, China.,Key Laboratory of Hunan Province in Neurodegenerative Disorders, Changsha, Hunan, China
| | - Lawrence P Reagan
- Department of Pharmacology, Physiology & Neuroscience, University of South Carolina, Columbia, SC, USA.,WJB Dorn Veterans Affairs Medical Center, Columbia, SC, USA
| | - April D Strader
- Department of Physiology, Southern Illinois University School of Medicine, Carbondale, IL, USA.,Center for Integrated Research in Cognitive and Neural Sciences, Southern Illinois University, Carbondale, IL, USA
| | - Gregory M Rose
- Department of Physiology, Southern Illinois University School of Medicine, Carbondale, IL, USA.,Department of Anatomy, Southern Illinois University School of Medicine, Carbondale, IL, USA.,Center for Integrated Research in Cognitive and Neural Sciences, Southern Illinois University, Carbondale, IL, USA
| | - Peter R Patrylo
- Department of Physiology, Southern Illinois University School of Medicine, Carbondale, IL, USA.,Department of Anatomy, Southern Illinois University School of Medicine, Carbondale, IL, USA.,Center for Integrated Research in Cognitive and Neural Sciences, Southern Illinois University, Carbondale, IL, USA
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21
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Abstract
In health hypoglycaemia is rare and occurs only in circumstances like extreme sports. Hypoglycaemia in type 1 Diabetes (T1D) and advanced type 2 Diabetes (T2D) are the result of interplay between absolute or relative insulin access and defective glucose counterregulation. The basic mechanism is, failure of decreasing insulin and failure of the compensatory increasing counterregulatory hormones at the background of falling blood glucose. Any person with Diabetes on anti-diabetic medication who behaves oddly in any way whatsoever is hypoglycaemic until proven otherwise. Hypoglycaemia can be a terrifying experience for a patient with Diabetes. By definition, hypoglycaemic symptoms are subjective and vary from person to person and even episode to episode in same person. Fear of iatrogenic hypoglycaemia is a major barrier in achieving optimum glycaemic control and quality of life which limits the reduction of diabetic complications. Diabetes patients with comorbidities especially with chronic renal failure, hepatic dysfunction, major limb amputation, terminal illness, cognitive dysfunction etc. are more vulnerable to hypoglycaemia. In most cases, prompt glucose intake reverts hypoglycaemia. Exogenous insulin in T1D and insulin treated advanced T2D have no control by pancreatic regulation. Moreover, failure of increase of glucagon and attenuated secretion in epinephrine causes the defective glucose counterregulation. In this comprehensive review, I will try to touch all related topics for better understanding of hypoglycaemia.
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22
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Fuente-Martín E, Mellado-Gil JM, Cobo-Vuilleumier N, Martín-Montalvo A, Romero-Zerbo SY, Diaz Contreras I, Hmadcha A, Soria B, Martin Bermudo F, Reyes JC, Bermúdez-Silva FJ, Lorenzo PI, Gauthier BR. Dissecting the Brain/Islet Axis in Metabesity. Genes (Basel) 2019; 10:genes10050350. [PMID: 31072002 PMCID: PMC6562925 DOI: 10.3390/genes10050350] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2019] [Revised: 05/02/2019] [Accepted: 05/02/2019] [Indexed: 12/17/2022] Open
Abstract
The high prevalence of type 2 diabetes mellitus (T2DM), together with the fact that current treatments are only palliative and do not avoid major secondary complications, reveals the need for novel approaches to treat the cause of this disease. Efforts are currently underway to identify therapeutic targets implicated in either the regeneration or re-differentiation of a functional pancreatic islet β-cell mass to restore insulin levels and normoglycemia. However, T2DM is not only caused by failures in β-cells but also by dysfunctions in the central nervous system (CNS), especially in the hypothalamus and brainstem. Herein, we review the physiological contribution of hypothalamic neuronal and glial populations, particularly astrocytes, in the control of the systemic response that regulates blood glucose levels. The glucosensing capacity of hypothalamic astrocytes, together with their regulation by metabolic hormones, highlights the relevance of these cells in the control of glucose homeostasis. Moreover, the critical role of astrocytes in the response to inflammation, a process associated with obesity and T2DM, further emphasizes the importance of these cells as novel targets to stimulate the CNS in response to metabesity (over-nutrition-derived metabolic dysfunctions). We suggest that novel T2DM therapies should aim at stimulating the CNS astrocytic response, as well as recovering the functional pancreatic β-cell mass. Whether or not a common factor expressed in both cell types can be feasibly targeted is also discussed.
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Affiliation(s)
- Esther Fuente-Martín
- Andalusian Center of Molecular Biology and Regenerative Medicine-CABIMER, Junta de Andalucia-University of Pablo de Olavide-University of Seville-CSIC, 41092 Seville, Spain.
| | - Jose M Mellado-Gil
- Andalusian Center of Molecular Biology and Regenerative Medicine-CABIMER, Junta de Andalucia-University of Pablo de Olavide-University of Seville-CSIC, 41092 Seville, Spain.
| | - Nadia Cobo-Vuilleumier
- Andalusian Center of Molecular Biology and Regenerative Medicine-CABIMER, Junta de Andalucia-University of Pablo de Olavide-University of Seville-CSIC, 41092 Seville, Spain.
| | - Alejandro Martín-Montalvo
- Andalusian Center of Molecular Biology and Regenerative Medicine-CABIMER, Junta de Andalucia-University of Pablo de Olavide-University of Seville-CSIC, 41092 Seville, Spain.
| | - Silvana Y Romero-Zerbo
- Instituto de Investigación Biomédica de Málaga-IBIMA, UGC Endocrinología y Nutrición. Hospital Regional Universitario de Málaga, 29009 Málaga, Spain.
| | - Irene Diaz Contreras
- Andalusian Center of Molecular Biology and Regenerative Medicine-CABIMER, Junta de Andalucia-University of Pablo de Olavide-University of Seville-CSIC, 41092 Seville, Spain.
- Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), 28029 Madrid, Spain.
| | - Abdelkrim Hmadcha
- Andalusian Center of Molecular Biology and Regenerative Medicine-CABIMER, Junta de Andalucia-University of Pablo de Olavide-University of Seville-CSIC, 41092 Seville, Spain.
- Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), 28029 Madrid, Spain.
| | - Bernat Soria
- Andalusian Center of Molecular Biology and Regenerative Medicine-CABIMER, Junta de Andalucia-University of Pablo de Olavide-University of Seville-CSIC, 41092 Seville, Spain.
- Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), 28029 Madrid, Spain.
| | - Francisco Martin Bermudo
- Andalusian Center of Molecular Biology and Regenerative Medicine-CABIMER, Junta de Andalucia-University of Pablo de Olavide-University of Seville-CSIC, 41092 Seville, Spain.
- Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), 28029 Madrid, Spain.
| | - Jose C Reyes
- Andalusian Center of Molecular Biology and Regenerative Medicine-CABIMER, Junta de Andalucia-University of Pablo de Olavide-University of Seville-CSIC, 41092 Seville, Spain.
| | - Francisco J Bermúdez-Silva
- Instituto de Investigación Biomédica de Málaga-IBIMA, UGC Endocrinología y Nutrición. Hospital Regional Universitario de Málaga, 29009 Málaga, Spain.
- Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), 28029 Madrid, Spain.
| | - Petra I Lorenzo
- Andalusian Center of Molecular Biology and Regenerative Medicine-CABIMER, Junta de Andalucia-University of Pablo de Olavide-University of Seville-CSIC, 41092 Seville, Spain.
| | - Benoit R Gauthier
- Andalusian Center of Molecular Biology and Regenerative Medicine-CABIMER, Junta de Andalucia-University of Pablo de Olavide-University of Seville-CSIC, 41092 Seville, Spain.
- Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), 28029 Madrid, Spain.
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23
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Insulin signaling in the hippocampus and amygdala regulates metabolism and neurobehavior. Proc Natl Acad Sci U S A 2019; 116:6379-6384. [PMID: 30765523 DOI: 10.1073/pnas.1817391116] [Citation(s) in RCA: 154] [Impact Index Per Article: 25.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023] Open
Abstract
Previous studies have shown that insulin and IGF-1 signaling in the brain, especially the hypothalamus, is important for regulation of systemic metabolism. Here, we develop mice in which we have specifically inactivated both insulin receptors (IRs) and IGF-1 receptors (IGF1Rs) in the hippocampus (Hippo-DKO) or central amygdala (CeA-DKO) by stereotaxic delivery of AAV-Cre into IRlox/lox/IGF1Rlox/lox mice. Consequently, both Hippo-DKO and CeA-DKO mice have decreased levels of the GluA1 subunit of glutamate AMPA receptor and display increased anxiety-like behavior, impaired cognition, and metabolic abnormalities, including glucose intolerance. Hippo-DKO mice also display abnormal spatial learning and memory whereas CeA-DKO mice have impaired cold-induced thermogenesis. Thus, insulin/IGF-1 signaling has common roles in the hippocampus and central amygdala, affecting synaptic function, systemic glucose homeostasis, behavior, and cognition. In addition, in the hippocampus, insulin/IGF-1 signaling is important for spatial learning and memory whereas insulin/IGF-1 signaling in the central amygdala controls thermogenesis via regulation of neural circuits innervating interscapular brown adipose tissue.
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24
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Agrawal R, Vieira-de-Abreu A, Durupt G, Taylor C, Chan O, Fisher SJ. Insulin regulates GLUT4 in the ventromedial hypothalamus to restore the sympathoadrenal response to hypoglycemia in diabetic rats. Am J Physiol Endocrinol Metab 2018; 315:E1286-E1295. [PMID: 30226996 PMCID: PMC6336954 DOI: 10.1152/ajpendo.00324.2018] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
It is proposed that the impaired counterregulatory response (CRR) to hypoglycemia in insulin-deficient diabetes may be due to chronic brain insulin deficiency. To test this hypothesis, streptozotocin-induced diabetic Sprague-Dawley rats were infused with insulin (3 mU/day) or artificial cerebrospinal fluid (aCSF) bilaterally into the ventromedial hypothalamus (VMH) for 2 wk and compared with nondiabetic rats. Rats underwent hyperinsulinemic (50 mU·kg-1·min-1)-hypoglycemic (~45 mg/dl) clamps. Diabetic rats demonstrated an impaired CRR to hypoglycemia, noted by a high glucose infusion rate and blunted epinephrine and glucagon responses. The defective sympathoadrenal response was restored by chronic infusion of insulin into the VMH. Diabetic rats had decreased VMH Akt phosphorylation and decreased VMH glucose transporter 4 (GLUT4) content, which was also restored by chronic infusion of insulin into the VMH. Separate experiments in nondiabetic rats in which GLUT4 translocation into the VMH was inhibited with an infusion of indinavir were notable for an impaired CRR to hypoglycemia, indicated by increased glucose infusion rate and diminished epinephrine and glucagon responses. Results suggest that, in this model of diabetes, VMH insulin deficiency impairs the sympathoadrenal response to hypoglycemia and that chronic infusion of insulin into the VMH is sufficient to normalize the sympathoadrenal response to hypoglycemia via restoration of GLUT4 expression in the VMH.
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Affiliation(s)
- Rahul Agrawal
- Division of Endocrinology, Metabolism, and Diabetes, University of Utah School of Medicine , Salt Lake City, Utah
| | - Adriana Vieira-de-Abreu
- Division of Endocrinology, Metabolism, and Diabetes, University of Utah School of Medicine , Salt Lake City, Utah
| | - Griffin Durupt
- Division of Endocrinology, Metabolism, and Diabetes, University of Utah School of Medicine , Salt Lake City, Utah
| | - Casey Taylor
- Division of Endocrinology, Metabolism, and Diabetes, University of Utah School of Medicine , Salt Lake City, Utah
| | - Owen Chan
- Division of Endocrinology, Metabolism, and Diabetes, University of Utah School of Medicine , Salt Lake City, Utah
| | - Simon J Fisher
- Division of Endocrinology, Metabolism, and Diabetes, University of Utah School of Medicine , Salt Lake City, Utah
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25
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Cai W, Xue C, Sakaguchi M, Konishi M, Shirazian A, Ferris HA, Li ME, Yu R, Kleinridders A, Pothos EN, Kahn CR. Insulin regulates astrocyte gliotransmission and modulates behavior. J Clin Invest 2018; 128:2914-2926. [PMID: 29664737 DOI: 10.1172/jci99366] [Citation(s) in RCA: 157] [Impact Index Per Article: 22.4] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2017] [Accepted: 04/10/2018] [Indexed: 01/16/2023] Open
Abstract
Complications of diabetes affect tissues throughout the body, including the central nervous system. Epidemiological studies show that diabetic patients have an increased risk of depression, anxiety, age-related cognitive decline, and Alzheimer's disease. Mice lacking insulin receptor (IR) in the brain or on hypothalamic neurons display an array of metabolic abnormalities; however, the role of insulin action on astrocytes and neurobehaviors remains less well studied. Here, we demonstrate that astrocytes are a direct insulin target in the brain and that knockout of IR on astrocytes causes increased anxiety- and depressive-like behaviors in mice. This can be reproduced in part by deletion of IR on astrocytes in the nucleus accumbens. At a molecular level, loss of insulin signaling in astrocytes impaired tyrosine phosphorylation of Munc18c. This led to decreased exocytosis of ATP from astrocytes, resulting in decreased purinergic signaling on dopaminergic neurons. These reductions contributed to decreased dopamine release from brain slices. Central administration of ATP analogs could reverse depressive-like behaviors in mice with astrocyte IR knockout. Thus, astrocytic insulin signaling plays an important role in dopaminergic signaling, providing a potential mechanism by which astrocytic insulin action may contribute to increased rates of depression in people with diabetes, obesity, and other insulin-resistant states.
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Affiliation(s)
- Weikang Cai
- Section of Integrative Physiology and Metabolism, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts, USA
| | - Chang Xue
- Program in Pharmacology and Experimental Therapeutics and Pharmacology and Drug Development, Sackler School of Graduate Biomedical Sciences and Department of Immunology, Tufts University School of Medicine, Boston, Massachusetts, USA
| | - Masaji Sakaguchi
- Section of Integrative Physiology and Metabolism, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts, USA.,Department of Metabolic Medicine, Kumamoto University, Kumamoto, Japan
| | - Masahiro Konishi
- Section of Integrative Physiology and Metabolism, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts, USA
| | - Alireza Shirazian
- Public Health and Professional Degree Programs, Tufts University School of Medicine, Boston, Massachusetts, USA
| | - Heather A Ferris
- Section of Integrative Physiology and Metabolism, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts, USA.,Division of Endocrinology and Metabolism, Department of Medicine, University of Virginia, Charlottesville, Virginia, USA
| | - Mengyao E Li
- Section of Integrative Physiology and Metabolism, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts, USA
| | - Ruichao Yu
- Section of Pathophysiology and Molecular Pharmacology, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts, USA
| | - Andre Kleinridders
- Section of Integrative Physiology and Metabolism, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts, USA.,German Institute of Human Nutrition Potsdam-Rehbrücke, Nuthetal, Germany.,National Center for Diabetes Research (DZD), Neuherberg, Germany
| | - Emmanuel N Pothos
- Program in Pharmacology and Experimental Therapeutics and Pharmacology and Drug Development, Sackler School of Graduate Biomedical Sciences and Department of Immunology, Tufts University School of Medicine, Boston, Massachusetts, USA
| | - C Ronald Kahn
- Section of Integrative Physiology and Metabolism, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts, USA
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26
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Reno CM, Puente EC, Sheng Z, Daphna-Iken D, Bree AJ, Routh VH, Kahn BB, Fisher SJ. Brain GLUT4 Knockout Mice Have Impaired Glucose Tolerance, Decreased Insulin Sensitivity, and Impaired Hypoglycemic Counterregulation. Diabetes 2017; 66:587-597. [PMID: 27797912 PMCID: PMC5319720 DOI: 10.2337/db16-0917] [Citation(s) in RCA: 65] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/27/2016] [Accepted: 10/12/2016] [Indexed: 12/12/2022]
Abstract
GLUT4 in muscle and adipose tissue is important in maintaining glucose homeostasis. However, the role of insulin-responsive GLUT4 in the central nervous system has not been well characterized. To assess its importance, a selective knockout of brain GLUT4 (BG4KO) was generated by crossing Nestin-Cre mice with GLUT4-floxed mice. BG4KO mice had a 99% reduction in GLUT4 protein expression throughout the brain. Despite normal feeding and fasting glycemia, BG4KO mice were glucose intolerant, demonstrated hepatic insulin resistance, and had reduced glucose uptake in the brain. In response to hypoglycemia, BG4KO mice had impaired glucose sensing, noted by impaired epinephrine and glucagon responses and impaired c-fos activation in the hypothalamic paraventricular nucleus. Moreover, in vitro glucose sensing of glucose-inhibitory neurons from the ventromedial hypothalamus was impaired in BG4KO mice. In summary, BG4KO mice are glucose intolerant, insulin resistant, and have impaired glucose sensing, indicating a critical role for brain GLUT4 in sensing and responding to changes in blood glucose.
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Affiliation(s)
- Candace M Reno
- Division of Endocrinology, Metabolism, and Lipid Research, Department of Medicine, Washington University in St. Louis, St. Louis, MO
- Division of Endocrinology, Metabolism, and Diabetes, Department of Internal Medicine, University of Utah, Salt Lake City, UT
| | - Erwin C Puente
- Division of Endocrinology, Metabolism, and Lipid Research, Department of Medicine, Washington University in St. Louis, St. Louis, MO
| | - Zhenyu Sheng
- Department of Pharmacology and Physiology, Rutgers New Jersey Medical School, Newark, NJ
| | - Dorit Daphna-Iken
- Division of Endocrinology, Metabolism, and Lipid Research, Department of Medicine, Washington University in St. Louis, St. Louis, MO
| | - Adam J Bree
- Division of Endocrinology, Metabolism, and Lipid Research, Department of Medicine, Washington University in St. Louis, St. Louis, MO
| | - Vanessa H Routh
- Department of Pharmacology and Physiology, Rutgers New Jersey Medical School, Newark, NJ
| | - Barbara B Kahn
- Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA
| | - Simon J Fisher
- Division of Endocrinology, Metabolism, and Lipid Research, Department of Medicine, Washington University in St. Louis, St. Louis, MO
- Division of Endocrinology, Metabolism, and Diabetes, Department of Internal Medicine, University of Utah, Salt Lake City, UT
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27
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Abstract
We present clinical, electroencephalographic and low-resolution electromagnetic tomography data that support combined treatment with insulin and a monoamine oxidase inhibitor in a patient with type 1 diabetes. We suggest that brain imaging data can identify a subgroup of patients who are likely to benefit from an insulin regimen and monoamine oxidase inhibition to improve glycaemic control, cardiovascular function, normalize the circadian rhythm and restore perception of glycaemic awareness.
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Affiliation(s)
- Hamlin Emory
- Emory Neurophysiologic Institute, Los Angeles, CA, USA
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28
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Kleinridders A. Deciphering Brain Insulin Receptor and Insulin-Like Growth Factor 1 Receptor Signalling. J Neuroendocrinol 2016; 28:10.1111/jne.12433. [PMID: 27631195 PMCID: PMC5129466 DOI: 10.1111/jne.12433] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/01/2016] [Revised: 09/12/2016] [Accepted: 09/12/2016] [Indexed: 12/16/2022]
Abstract
Insulin receptor (IR) and insulin-like growth factor 1 receptor (IGF1R) are highly conserved receptor tyrosine kinases that share signalling proteins and are ubiquitously expressed in the brain. Central application of insulin or IGF1 exerts several similar physiological outcomes, varying in strength, whereas disruption of the corresponding receptors in the brain leads to remarkably different effects on brain size and physiology, thus highlighting the unique effects of the corresponding hormone receptors. Central insulin/IGF1 resistance impacts upon various levels of the IR/IGF1R signalling pathways and is a feature of the metabolic syndrome and neurodegenerative diseases such as Alzheimer's disease. The intricacy of brain insulin and IGF1 signalling represents a challenge for the identification of specific IR and IGF1R signalling differences in pathophysiological conditions. The present perspective sheds light on signalling differences and methodologies for specifically deciphering brain IR and IGF1R signalling.
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Affiliation(s)
- A. Kleinridders
- German Institute of Human Nutrition Potsdam‐RehbrueckeCentral Regulation of MetabolismNuthetalGermany
- German Center for Diabetes Research (DZD)NeuherbergGermany
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29
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Rosario W, Singh I, Wautlet A, Patterson C, Flak J, Becker TC, Ali A, Tamarina N, Philipson LH, Enquist LW, Myers MG, Rhodes CJ. The Brain-to-Pancreatic Islet Neuronal Map Reveals Differential Glucose Regulation From Distinct Hypothalamic Regions. Diabetes 2016; 65:2711-23. [PMID: 27207534 PMCID: PMC5001176 DOI: 10.2337/db15-0629] [Citation(s) in RCA: 75] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/13/2015] [Accepted: 04/06/2016] [Indexed: 12/24/2022]
Abstract
The brain influences glucose homeostasis, partly by supplemental control over insulin and glucagon secretion. Without this central regulation, diabetes and its complications can ensue. Yet, the neuronal network linking to pancreatic islets has never been fully mapped. Here, we refine this map using pseudorabies virus (PRV) retrograde tracing, indicating that the pancreatic islets are innervated by efferent circuits that emanate from the hypothalamus. We found that the hypothalamic arcuate nucleus (ARC), ventromedial nucleus (VMN), and lateral hypothalamic area (LHA) significantly overlap PRV and the physiological glucose-sensing enzyme glucokinase. Then, experimentally lowering glucose sensing, specifically in the ARC, resulted in glucose intolerance due to deficient insulin secretion and no significant effect in the VMN, but in the LHA it resulted in a lowering of the glucose threshold that improved glucose tolerance and/or improved insulin sensitivity, with an exaggerated counter-regulatory response for glucagon secretion. No significant effect on insulin sensitivity or metabolic homeostasis was noted. Thus, these data reveal novel direct neuronal effects on pancreatic islets and also render a functional validation of the brain-to-islet neuronal map. They also demonstrate that distinct regions of the hypothalamus differentially control insulin and glucagon secretion, potentially in partnership to help maintain glucose homeostasis and guard against hypoglycemia.
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Affiliation(s)
- Wilfredo Rosario
- Kovler Diabetes Center, Department of Medicine, Section of Endocrinology, Diabetes and Metabolism, University of Chicago, Chicago, IL
| | - Inderroop Singh
- Kovler Diabetes Center, Department of Medicine, Section of Endocrinology, Diabetes and Metabolism, University of Chicago, Chicago, IL
| | - Arnaud Wautlet
- Kovler Diabetes Center, Department of Medicine, Section of Endocrinology, Diabetes and Metabolism, University of Chicago, Chicago, IL
| | - Christa Patterson
- Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI
| | - Jonathan Flak
- Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI
| | - Thomas C Becker
- Duke Molecular Physiology Institute and Sarah W. Stedman Nutrition and Metabolism Center, Duke University, Durham, NC
| | - Almas Ali
- Kovler Diabetes Center, Department of Medicine, Section of Endocrinology, Diabetes and Metabolism, University of Chicago, Chicago, IL
| | - Natalia Tamarina
- Kovler Diabetes Center, Department of Medicine, Section of Endocrinology, Diabetes and Metabolism, University of Chicago, Chicago, IL
| | - Louis H Philipson
- Kovler Diabetes Center, Department of Medicine, Section of Endocrinology, Diabetes and Metabolism, University of Chicago, Chicago, IL
| | - Lynn W Enquist
- Department of Molecular Biology, Princeton University, Princeton, NJ
| | - Martin G Myers
- Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI
| | - Christopher J Rhodes
- Kovler Diabetes Center, Department of Medicine, Section of Endocrinology, Diabetes and Metabolism, University of Chicago, Chicago, IL
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30
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Lee SH, Zabolotny JM, Huang H, Lee H, Kim YB. Insulin in the nervous system and the mind: Functions in metabolism, memory, and mood. Mol Metab 2016; 5:589-601. [PMID: 27656397 PMCID: PMC5021669 DOI: 10.1016/j.molmet.2016.06.011] [Citation(s) in RCA: 123] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/25/2016] [Revised: 06/21/2016] [Accepted: 06/22/2016] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Insulin, a pleotrophic hormone, has diverse effects in the body. Recent work has highlighted the important role of insulin's action in the nervous system on glucose and energy homeostasis, memory, and mood. SCOPE OF REVIEW Here we review experimental and clinical work that has broadened the understanding of insulin's diverse functions in the central and peripheral nervous systems, including glucose and body weight homeostasis, memory and mood, with particular emphasis on intranasal insulin. MAJOR CONCLUSIONS Implications for the treatment of obesity, type 2 diabetes, dementia, and mood disorders are discussed in the context of brain insulin action. Intranasal insulin may have potential in the treatment of central nervous system-related metabolic disorders.
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Affiliation(s)
- Seung-Hwan Lee
- Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Beth Israel Deaconess Medical Center, and Harvard Medical School, 330 Brookline Ave., Boston, MA 02216, USA; Division of Endocrinology and Metabolism, Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, 222 Banpo-daero, Seocho-gu, Seoul 06591, South Korea.
| | - Janice M Zabolotny
- Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Beth Israel Deaconess Medical Center, and Harvard Medical School, 330 Brookline Ave., Boston, MA 02216, USA.
| | - Hu Huang
- Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Beth Israel Deaconess Medical Center, and Harvard Medical School, 330 Brookline Ave., Boston, MA 02216, USA; Human Performance Laboratory, Department of Kinesiology and Physiology, East Carolina Diabetes and Obesity Institute, East Carolina University, 115 Heart Dr., Greenville, NC 27858, USA.
| | - Hyon Lee
- Department of Neurology, Neuroscience Research Institute, Gachon University Gil Medical Center, 21 Namdong-daero 774 beon-gil, Namdong-gu, Incheon 21565, South Korea.
| | - Young-Bum Kim
- Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Beth Israel Deaconess Medical Center, and Harvard Medical School, 330 Brookline Ave., Boston, MA 02216, USA.
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31
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Affiliation(s)
| | - C Ronald Kahn
- Joslin Diabetes Center, Harvard Medical School, Boston, MA
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32
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Lee J, Kim K, Yu SW, Kim EK. Wnt3a upregulates brain-derived insulin by increasing NeuroD1 via Wnt/β-catenin signaling in the hypothalamus. Mol Brain 2016; 9:24. [PMID: 26956881 PMCID: PMC4782570 DOI: 10.1186/s13041-016-0207-5] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2015] [Accepted: 02/26/2016] [Indexed: 12/15/2022] Open
Abstract
Background Insulin plays diverse roles in the brain. Although insulin produced by pancreatic β-cells that crosses the blood–brain barrier is a major source of brain insulin, recent studies suggest that insulin is also produced locally within the brain. However, the mechanisms underlying the production of brain-derived insulin (BDI) are not yet known. Results Here, we examined the effect of Wnt3a on BDI production in a hypothalamic cell line and hypothalamic tissue. In N39 hypothalamic cells, Wnt3a treatment significantly increased the expression of the Ins2 gene, which encodes the insulin isoform predominant in the mouse brain, by activating Wnt/β-catenin signaling. The concentration of insulin was higher in culture medium of Wnt3a-treated cells than in that of untreated cells. Interestingly, neurogenic differentiation 1 (NeuroD1), a target of Wnt/β-catenin signaling and one of transcription factors for insulin, was also induced by Wnt3a treatment in a time- and dose-dependent manner. In addition, the treatment of BIO, a GSK3 inhibitor, also increased the expression of Ins2 and NeuroD1. Knockdown of NeuroD1 by lentiviral shRNAs reduced the basal expression of Ins2 and suppressed Wnt3a-induced Ins2 expression. To confirm the Wnt3a-induced increase in Ins2 expression in vivo, Wnt3a was injected into the hypothalamus of mice. Wnt3a increased the expression of NeuroD1 and Ins2 in the hypothalamus in a manner similar to that observed in vitro. Conclusion Taken together, these results suggest that BDI production is regulated by the Wnt/β-catenin/NeuroD1 pathway in the hypothalamus. Our findings will help to unravel the regulation of BDI production in the hypothalamus. Electronic supplementary material The online version of this article (doi:10.1186/s13041-016-0207-5) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Jaemeun Lee
- Department of Brain and Cognitive Sciences, Daegu Gyeongbuk Institute of Science and Technology (DGIST), 333 Techno Jungang-daero, Hyeonpung-myeon, Dalseong-gun, Daegu, 42988, South Korea.
| | - Kyungchan Kim
- Department of Brain and Cognitive Sciences, Daegu Gyeongbuk Institute of Science and Technology (DGIST), 333 Techno Jungang-daero, Hyeonpung-myeon, Dalseong-gun, Daegu, 42988, South Korea.
| | - Seong-Woon Yu
- Department of Brain and Cognitive Sciences, Daegu Gyeongbuk Institute of Science and Technology (DGIST), 333 Techno Jungang-daero, Hyeonpung-myeon, Dalseong-gun, Daegu, 42988, South Korea.
| | - Eun-Kyoung Kim
- Department of Brain and Cognitive Sciences, Daegu Gyeongbuk Institute of Science and Technology (DGIST), 333 Techno Jungang-daero, Hyeonpung-myeon, Dalseong-gun, Daegu, 42988, South Korea. .,Neurometabolomics Research Center, Daegu Gyeongbuk Institute of Science and Technology (DGIST), 333 Techno Jungang-daero, Hyeonpung-myeon, Dalseong-gun, Daegu, 42988, South Korea.
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Ralevski A, Horvath TL. Developmental programming of hypothalamic neuroendocrine systems. Front Neuroendocrinol 2015; 39:52-8. [PMID: 26391503 DOI: 10.1016/j.yfrne.2015.09.002] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/06/2015] [Revised: 09/17/2015] [Accepted: 09/17/2015] [Indexed: 12/30/2022]
Abstract
There is increasing evidence to suggest that the perinatal environment may alter the developmental programming of hypothalamic neuroendocrine systems in a manner that predisposes offspring to the development of metabolic syndrome. Although it is unclear how these effects might be mediated, it has been shown that changes in neuroendocrine programing during critical periods of development, either via maternal metabolic programming or other factors, can alter a fetus's metabolic fate. This review summarizes the hypothalamic circuits that mediate energy homeostasis and discusses the various factors that may influence the development and functioning of these neural systems, as well as the possible cognitive impairments that may arise as a result of these metabolic influences.
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Affiliation(s)
- Alexandra Ralevski
- Program in Integrative Cell Signaling and Neurobiology of Metabolism, Section of Comparative Medicine, Yale University School of Medicine, New Haven, CT 06510, USA
| | - Tamas L Horvath
- Program in Integrative Cell Signaling and Neurobiology of Metabolism, Section of Comparative Medicine, Yale University School of Medicine, New Haven, CT 06510, USA.
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34
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Insulin resistance in brain alters dopamine turnover and causes behavioral disorders. Proc Natl Acad Sci U S A 2015; 112:3463-8. [PMID: 25733901 DOI: 10.1073/pnas.1500877112] [Citation(s) in RCA: 319] [Impact Index Per Article: 31.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Diabetes and insulin resistance are associated with altered brain imaging, depression, and increased rates of age-related cognitive impairment. Here we demonstrate that mice with a brain-specific knockout of the insulin receptor (NIRKO mice) exhibit brain mitochondrial dysfunction with reduced mitochondrial oxidative activity, increased levels of reactive oxygen species, and increased levels of lipid and protein oxidation in the striatum and nucleus accumbens. NIRKO mice also exhibit increased levels of monoamine oxidase A and B (MAO A and B) leading to increased dopamine turnover in these areas. Studies in cultured neurons and glia cells indicate that these changes in MAO A and B are a direct consequence of loss of insulin signaling. As a result, NIRKO mice develop age-related anxiety and depressive-like behaviors that can be reversed by treatment with MAO inhibitors, as well as the tricyclic antidepressant imipramine, which inhibits MAO activity and reduces oxidative stress. Thus, insulin resistance in brain induces mitochondrial and dopaminergic dysfunction leading to anxiety and depressive-like behaviors, demonstrating a potential molecular link between central insulin resistance and behavioral disorders.
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Abstract
The pancreatic hormone insulin plays a well-described role in the periphery, based principally on its ability to lower circulating glucose levels via activation of glucose transporters. However, insulin also acts within the central nervous system (CNS) to alter a number of physiological outcomes ranging from energy balance and glucose homeostasis to cognitive performance. Insulin is transported into the CNS by a saturable receptor-mediated process that is proposed to be dependent on the insulin receptor. Transport of insulin into the brain is dependent on numerous factors including diet, glycemia, a diabetic state and notably, obesity. Obesity leads to a marked decrease in insulin transport from the periphery into the CNS and the biological basis of this reduction of transport remains unresolved. Despite decades of research into the effects of central insulin on a wide range of physiological functions and its transport from the periphery to the CNS, numerous questions remain unanswered including which receptor is responsible for transport and the precise mechanisms of action of insulin within the brain.
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Affiliation(s)
- Denovan P Begg
- School of Psychology, University of New South Wales (UNSW, Australia), Sydney, New South Wales, Australia.
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36
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Brain insulin receptors link stress and metabolism. Mol Metab 2015; 4:77-8. [PMID: 25685693 PMCID: PMC4314538 DOI: 10.1016/j.molmet.2014.12.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
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37
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Pitchaimani V, Arumugam S, Thandavarayan RA, Karuppagounder V, Sreedhar R, Afrin R, Harima M, Suzuki H, Miyashita S, Nomoto M, Sone H, Suzuki K, Watanabe K. Fasting mediated increase in p-BADser155 and p-AKTser473 in the prefrontal cortex of mice. Neurosci Lett 2014; 579:134-9. [DOI: 10.1016/j.neulet.2014.07.009] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2014] [Revised: 06/24/2014] [Accepted: 07/08/2014] [Indexed: 11/17/2022]
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Abstract
Insulin receptors, as well as IGF-1 receptors and their postreceptor signaling partners, are distributed throughout the brain. Insulin acts on these receptors to modulate peripheral metabolism, including regulation of appetite, reproductive function, body temperature, white fat mass, hepatic glucose output, and response to hypoglycemia. Insulin signaling also modulates neurotransmitter channel activity, brain cholesterol synthesis, and mitochondrial function. Disruption of insulin action in the brain leads to impairment of neuronal function and synaptogenesis. In addition, insulin signaling modulates phosphorylation of tau protein, an early component in the development of Alzheimer disease. Thus, alterations in insulin action in the brain can contribute to metabolic syndrome, and the development of mood disorders and neurodegenerative diseases.
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Affiliation(s)
- André Kleinridders
- Section on Integrative Physiology and Metabolism, Joslin Diabetes Center and Department of Medicine, Harvard Medical School, Boston, MA
| | - Heather A Ferris
- Section on Integrative Physiology and Metabolism, Joslin Diabetes Center and Department of Medicine, Harvard Medical School, Boston, MA
| | - Weikang Cai
- Section on Integrative Physiology and Metabolism, Joslin Diabetes Center and Department of Medicine, Harvard Medical School, Boston, MA
| | - C Ronald Kahn
- Section on Integrative Physiology and Metabolism, Joslin Diabetes Center and Department of Medicine, Harvard Medical School, Boston, MA
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39
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Ulrich-Lai YM, Ryan KK. Neuroendocrine circuits governing energy balance and stress regulation: functional overlap and therapeutic implications. Cell Metab 2014; 19:910-25. [PMID: 24630812 PMCID: PMC4047143 DOI: 10.1016/j.cmet.2014.01.020] [Citation(s) in RCA: 76] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Significant comorbidities between obesity-related metabolic disease and stress-related psychological disorders suggest important functional interactions between energy balance and brain stress integration. Largely overlapping neural circuits control these systems, and this anatomical arrangement optimizes opportunities for mutual influence. Here we first review the current literature identifying effects of metabolic neuroendocrine signals on stress regulation, and vice versa. Next, the contributions of reward-driven food intake to these metabolic and stress interactions are discussed. Lastly, we consider the interrelationships between metabolism, stress, and reward in light of their important implications in the development of therapies for metabolism- or stress-related disease.
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Affiliation(s)
- Yvonne M Ulrich-Lai
- Department of Psychiatry and Behavioral Neuroscience, University of Cincinnati College of Medicine, Cincinnati, OH 45237, USA
| | - Karen K Ryan
- Department of Internal Medicine, Division of Endocrinology, Diabetes and Metabolism, University of Cincinnati College of Medicine, Cincinnati, OH 45237, USA.
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40
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Heinrich G, Meece K, Wardlaw SL, Accili D. Preserved energy balance in mice lacking FoxO1 in neurons of Nkx2.1 lineage reveals functional heterogeneity of FoxO1 signaling within the hypothalamus. Diabetes 2014; 63:1572-82. [PMID: 24487022 PMCID: PMC3994959 DOI: 10.2337/db13-0651] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Transcription factor forkhead box O1 (FoxO1) regulates energy expenditure (EE), food intake, and hepatic glucose production. These activities have been mapped to specific hypothalamic neuronal populations using cell type-specific knockout experiments in mice. To parse out the integrated output of FoxO1-dependent transcription from different neuronal populations and multiple hypothalamic regions, we used transgenic mice expressing Cre recombinase from the Nkx2.1 promoter to ablate loxP-flanked Foxo1 alleles from a majority of hypothalamic neurons (Foxo1KO(Nkx2.1) mice). This strategy resulted in the expected inhibition of FoxO1 expression, but only produced a transient reduction of body weight as well as a decreased body length. The transient decrease of body weight in male mice was accompanied by decreased fat mass. Male Foxo1KO(Nkx2.1) mice show food intake similar to that in wild-type controls, and, although female knockout mice eat less, they do so in proportion to a reduced body size. EE is unaffected in Foxo1KO(Nkx2.1) mice, although small increases in body temperature are present. Unlike other neuron-specific Foxo1 knockout mice, Foxo1KO(Nkx2.1) mice are not protected from diet-induced obesity. These studies indicate that, unlike the metabolic effects of highly restricted neuronal subsets (proopiomelanocortin, neuropeptide Y/agouti-related peptide, and steroidogenic factor 1), those of neurons derived from the Nkx2.1 lineage either occur in a FoxO1-independent fashion or are compensated for through developmental plasticity.
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Affiliation(s)
- Garrett Heinrich
- Berrie Diabetes Center, Department of Medicine, College of Physicians & Surgeons, Columbia University, New York, NY
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41
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Xu E, Schwab M, Marette A. Role of protein tyrosine phosphatases in the modulation of insulin signaling and their implication in the pathogenesis of obesity-linked insulin resistance. Rev Endocr Metab Disord 2014; 15:79-97. [PMID: 24264858 DOI: 10.1007/s11154-013-9282-4] [Citation(s) in RCA: 54] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Insulin resistance is a major disorder that links obesity to type 2 diabetes mellitus (T2D). It involves defects in the insulin actions owing to a reduced ability of insulin to trigger key signaling pathways in major metabolic tissues. The pathogenesis of insulin resistance involves several inhibitory molecules that interfere with the tyrosine phosphorylation of the insulin receptor and its downstream effectors. Among those, growing interest has been developed toward the protein tyrosine phosphatases (PTPs), a large family of enzymes that can inactivate crucial signaling effectors in the insulin signaling cascade by dephosphorylating their tyrosine residues. Herein we briefly review the role of several PTPs that have been shown to be implicated in the regulation of insulin action, and then focus on the Src homology 2 (SH2) domain-containing SHP1 and SHP2 enzymes, since recent reports have indicated major roles for these PTPs in the control of insulin action and glucose metabolism. Finally, the therapeutic potential of targeting PTPs for combating insulin resistance and alleviating T2D will be discussed.
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Affiliation(s)
- Elaine Xu
- Department of Medicine, Cardiology Axis of the Institut Universitaire de Cardiologie et de Pneumologie de Québec (Hôpital Laval), Ste-Foy, Québec, Canada, G1V 4G2
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Abstract
Autonomic neuropathy complicates diabetes by increasing patient morbidity and mortality. Surprisingly, considering its importance, development and exploitation of animal models has lagged behind the wealth of information collected for somatic symmetrical sensory neuropathy. Nonetheless, animal studies have resulted in a variety of insights into the pathogenesis, neuropathology, and pathophysiology of diabetic autonomic neuropathy (DAN) with significant and, in some cases, remarkable correspondence between rodent models and human disease. Particularly in the study of alimentary dysfunction, findings in intrinsic intramural ganglia, interstitial cells of Cajal and the extrinsic parasympathetic and sympathetic ganglia serving the bowel vie for recognition as the chief mechanism. A body of work focused on neuropathologic findings in experimental animals and human subjects has demonstrated that axonal and dendritic pathology in sympathetic ganglia with relative neuron preservation represents one of the neuropathologic hallmarks of DAN but it is unlikely to represent the entire story. There is a surprising selectivity of the diabetic process for subpopulations of neurons and nerve terminals within intramural, parasympathetic, and sympathetic ganglia and innervation of end organs, afflicting some while sparing others, and differing between vascular and other targets within individual end organs. Rather than resulting from a simple deficit in one limb of an effector pathway, autonomic dysfunction may proceed from the inability to integrate portions of several complex pathways. The selectivity of the diabetic process appears to confound a simple global explanation (e.g., ischemia) of DAN. Although the search for a single unifying pathogenetic hypothesis continues, it is possible that autonomic neuropathy will have multiple pathogenetic mechanisms whose interplay may require therapies consisting of a cocktail of drugs. The role of multiple neurotrophic substances, antioxidants (general or pathway specific), inhibitors of formation of advanced glycosylation end products and drugs affecting the polyol pathway may be complex and therapeutic elements may have both salutary and untoward effects. This review has attempted to present the background and current findings and hypotheses, focusing on autonomic elements including and beyond the typical parasympathetic and sympathetic nervous systems to include visceral sensory and enteric nervous systems.
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Affiliation(s)
- Robert E Schmidt
- Department of Pathology and Immunology, Washington University School of Medicine, Saint Louis, MO, USA.
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43
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44
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Begg DP, Mul JD, Liu M, Reedy BM, D'Alessio DA, Seeley RJ, Woods SC. Reversal of diet-induced obesity increases insulin transport into cerebrospinal fluid and restores sensitivity to the anorexic action of central insulin in male rats. Endocrinology 2013; 154:1047-54. [PMID: 23337529 PMCID: PMC3578991 DOI: 10.1210/en.2012-1929] [Citation(s) in RCA: 40] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/20/2023]
Abstract
Diet-induced obesity (DIO) reduces the ability of centrally administered insulin to reduce feeding behavior and also reduces the transport of insulin from the periphery to the central nervous system (CNS). The current study was designed to determine whether reversal of high-fat DIO restores the anorexic efficacy of central insulin and whether this is accompanied by restoration of the compromised insulin transport. Adult male Long-Evans rats were initially maintained on either a low-fat chow diet (LFD) or a high-fat diet (HFD). After 22 weeks, half of the animals on the HFD were changed to the LFD, whereas the other half continued on the HFD for an additional 8 weeks, such that there were 3 groups: 1) a LFD control group (Con; n = 18), 2) a HFD-fed, DIO group (n = 17), and 3) a HFD to LFD, DIO-reversal group (DIO-rev; n = 18). The DIO reversal resulted in a significant reduction of body weight and epididymal fat weight relative to the DIO group. Acute central insulin administration (8 mU) reduced food intake and caused weight loss in Con and DIO-rev but not DIO rats. Fasting cerebrospinal fluid insulin was higher in DIO than Con animals. However, after a peripheral bolus injection of insulin, cerebrospinal fluid insulin increased in Con and DIO-rev rats but not in the DIO group. These data provide support for previous reports that DIO inhibits both the central effects of insulin and insulin's transport to the CNS. Importantly, DIO-rev restored sensitivity to the effects of central insulin on food intake and insulin transport into the CNS.
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Affiliation(s)
- Denovan P Begg
- Departments of Psychiatry and Behavioral Neuroscience, University of Cincinnati, Cincinnati, OH 45237, USA.
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45
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Begg DP, Woods SC. Interactions between the central nervous system and pancreatic islet secretions: a historical perspective. ADVANCES IN PHYSIOLOGY EDUCATION 2013; 37:53-60. [PMID: 23471249 PMCID: PMC3776474 DOI: 10.1152/advan.00167.2012] [Citation(s) in RCA: 40] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/11/2012] [Accepted: 01/14/2013] [Indexed: 05/10/2023]
Abstract
The endocrine pancreas is richly innervated with sympathetic and parasympathetic projections from the brain. In the mid-20th century, it was established that α-adrenergic activation inhibits, whereas cholinergic stimulation promotes, insulin secretion; this demonstrated the importance of the sympathetic and parasympathetic systems in pancreatic endocrine function. It was later established that insulin injected peripherally could act within the brain, leading to the discovery of insulin and insulin receptors within the brain and the receptor-mediated transport of insulin into the central nervous system from endothelial cells. The insulin receptor within the central nervous system is widely distributed, reflecting insulin's diverse range of actions, including acting as an adiposity signal to reduce food intake and increase energy expenditure, regulation of systemic glucose responses, altering sympathetic activity, and involvement in cognitive function. As observed with central insulin administration, the pancreatic hormones glucagon, somatostatin, pancreatic polypeptide, and amylin can each also reduce food intake. Pancreatic and also gut hormones are released cephalically, in what is an important mechanism to prepare the body for a meal and prevent excessive postprandial hyperglycemia.
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Affiliation(s)
- Denovan P Begg
- Department of Psychiatry and Behavioral Neuroscience, University of Cincinnati, Cincinnati, OH 45237, USA
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46
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Vogt MC, Brüning JC. CNS insulin signaling in the control of energy homeostasis and glucose metabolism - from embryo to old age. Trends Endocrinol Metab 2013; 24:76-84. [PMID: 23265947 DOI: 10.1016/j.tem.2012.11.004] [Citation(s) in RCA: 129] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/17/2012] [Revised: 11/07/2012] [Accepted: 11/13/2012] [Indexed: 10/27/2022]
Abstract
Central nervous system (CNS) insulin signaling regulates energy and glucose homeostasis by acting on hypothalamic neurocircuits and higher brain circuits such as the dopaminergic system. However, overnutrition, obesity, and type 2 diabetes mellitus (T2DM) induce insulin resistance selectively in different regions of the brain, thereby impairing energy homeostasis and augmenting disease progression. Moreover, fetal hyperinsulinemia in response to maternal overnutrition, obesity, and diabetes disrupts hypothalamic neurocircuit development and predisposes to metabolic disorders later in life. In light of the current obesity and diabetes epidemic, we review the molecular basis of insulin action and resistance in the CNS, mechanisms which are causal to the development of these metabolic disorders, both in the neonate and in the adult.
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Affiliation(s)
- Merly C Vogt
- Max Planck Institute for Neurological Research, D-50931 Cologne, Germany
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47
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Williamson R, McNeilly A, Sutherland C. Insulin resistance in the brain: an old-age or new-age problem? Biochem Pharmacol 2012; 84:737-45. [PMID: 22634336 DOI: 10.1016/j.bcp.2012.05.007] [Citation(s) in RCA: 46] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2012] [Revised: 05/08/2012] [Accepted: 05/08/2012] [Indexed: 01/21/2023]
Abstract
Life expectancy is rising however with more people living longer there is a concomitant rise in the incidence of dementia. In addition to age-related cognitive decline there is a higher risk of going on to develop vascular dementia and Alzheimer's disease associated with aspects of modern lifestyle. Most worryingly, recent data reports accelerated cognitive decline in adolescents associated with poor diet (high fat and calorie intake). Thus the increase in dementia in 'old-age' may have as much to do with 'new-age' lifestyle as it does with normal ageing. It would seem wise therefore to investigate the molecular connections between lifestyle and cognitive decline in more detail. Epidemiological evidence suggests an increased risk of developing dementia (including Alzheimer's disease) in individuals with obesity and type 2 diabetes but also in those with poor insulin sensitivity without diabetes, implicating a mechanistic link between adiposity, insulin sensitivity and dementia. Insulin receptors are expressed in the brain and physiological roles for insulin in the CNS are starting to be delineated. Indeed disrupted neuronal insulin action may underlie the link between diabetes and neurodegenerative disorders. This review discusses the difficulties in quantifying insulin sensitivity of the brain and why it is vital that we develop technology for this purpose so that we can establish its role in this 'new-age' dementia. This has particular relevance to the design and interpretation of clinical trials in progress to assess potential benefits of insulin and insulin sensitisers on prevention of cognitive decline.
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Ramnanan CJ, Edgerton DS, Cherrington AD. Evidence against a physiologic role for acute changes in CNS insulin action in the rapid regulation of hepatic glucose production. Cell Metab 2012; 15:656-64. [PMID: 22560218 PMCID: PMC3348512 DOI: 10.1016/j.cmet.2012.03.006] [Citation(s) in RCA: 45] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
This Perspective will discuss the physiologic relevance of data that suggest CNS insulin action is required for the rapid suppression of hepatic glucose production. It will also review data from experiments on the conscious dog, which show that although the canine brain can sense insulin and, thereby, regulate hepatic glucoregulatory enzyme expression, CNS insulin action is not essential for the rapid suppression of glucose production caused by the hormone. Insulin's direct hepatic effects are dominant, thus it appears that insulin's central effects are redundant in the acute regulation of hepatic glucose metabolism.
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Affiliation(s)
- Christopher J Ramnanan
- Vanderbilt University School of Medicine, Department of Molecular Physiology and Biophysics, Nashville, TN 37232, USA
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49
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Abstract
Lipid sensing and insulin signaling in the brain independently triggers a negative feedback system to lower glucose production and food intake. Here, we discuss the underlying molecular and neuronal mechanisms of lipid sensing and insulin signaling in the hypothalamus and how these mechanisms are affected in response to high-fat feeding. We propose that high-fat feeding concurrently disrupts hypothalamic insulin-signaling and lipid-sensing mechanisms and that experiments aimed to restore both insulin action and lipid sensing in the brain could effectively lower glucose production and food intake to restore metabolic homeostasis in type 2 diabetes and obesity.
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Affiliation(s)
- Jessica T Y Yue
- Toronto General Research Institute, University Health Network, Toronto, Canada
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50
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Abstract
Insulin acts throughout the body to reduce circulating energy and to increase energy storage. Within the brain, insulin produces a net catabolic effect by reducing food intake and increasing energy expenditure; this is evidenced by the hypophagia and increased brown adipose tissue sympathetic nerve activity induced by central insulin infusion. Reducing the activity of the brain insulin system via administration of insulin antibodies, receptor antisense treatment, or receptor knockdown results in hyperphagia and increased adiposity. However, despite decades of research into the role of central insulin in food intake, many questions remain to be answered, including the underlying mechanism of action.
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Affiliation(s)
- Denovan P Begg
- Department of Psychiatry and Behavioral Neuroscience, University of Cincinnati, OH 45237, USA
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