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Fang RY, Pan XR, Zeng XX, Li ZZ, Chen BF, Zeng HM, Peng J. Gut-brain axis as a bridge in obesity and depression: Mechanistic exploration and therapeutic prospects. World J Psychiatry 2025; 15:101134. [PMID: 39831021 PMCID: PMC11684226 DOI: 10.5498/wjp.v15.i1.101134] [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: 09/05/2024] [Revised: 11/02/2024] [Accepted: 11/18/2024] [Indexed: 12/18/2024] Open
Abstract
A recent study by Wang et al, published in the World Journal of Psychiatry, provided preventative and therapeutic strategies for the comorbidity of obesity and depression. The gut-brain axis, which acts as a two-way communication system between the gastrointestinal tract and the central nervous system, plays a pivotal role in the pathogenesis of these conditions. Evidence suggests that metabolic byproducts, such as short-chain fatty acids, lipopolysaccharide and bile acids, which are generated by the gut microbiota, along with neurotransmitters and inflammatory mediators within the gut-brain axis, modulate the host's metabolic processes, neuronal regulation, and immune responses through diverse mechanisms. The interaction between obesity and depression via the gut-brain axis involves disruptions in the gut microbiota balance, inflammatory immune responses, and alterations in the neuroendocrine system. Modulating the gut-brain axis, for example, through a ketogenic diet, the use of probiotics, and the supplementation of antioxidants, offers new remedial approaches for obesity and depression. Future research that explores the mechanisms of the gut-brain axis is needed to provide more evidence for clinical treatment.
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Affiliation(s)
- Rui-Ying Fang
- The Second Clinical Medical College, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang 330006, Jiangxi Province, China
| | - Xiao-Rui Pan
- The Second Clinical Medical College, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang 330006, Jiangxi Province, China
| | - Xin-Xing Zeng
- The Second Clinical Medical College, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang 330006, Jiangxi Province, China
| | - Zheng-Zheng Li
- The Second Clinical Medical College, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang 330006, Jiangxi Province, China
| | - Bo-Fan Chen
- The Second Clinical Medical College, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang 330006, Jiangxi Province, China
| | - Hai-Min Zeng
- The Second Clinical Medical College, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang 330006, Jiangxi Province, China
| | - Jie Peng
- The Second Clinical Medical College, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang 330006, Jiangxi Province, China
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Lv JM, Gao YL, Wang LY, Li BD, Shan YL, Wu ZQ, Lu QM, Peng HY, Zhou TT, Li XM, Zhang LM. Inhibition of the P38 MAPK/NLRP3 pathway mitigates cognitive dysfunction and mood alterations in aged mice after abdominal surgery plus sevoflurane. Brain Res Bull 2024; 217:111059. [PMID: 39216556 DOI: 10.1016/j.brainresbull.2024.111059] [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: 05/19/2024] [Revised: 07/30/2024] [Accepted: 08/26/2024] [Indexed: 09/04/2024]
Abstract
BACKGROUND Cognitive dysfunction, encompassing perioperative psychological distress and cognitive impairment, is a prevalent postoperative complication within the elderly population, and in severe cases, it may lead to dementia. Building upon our prior research that unveiled a connection between postoperative mood fluctuations and cognitive dysfunction with the phosphorylation of P38, this present investigation aims to delve deeper into the involvement of the P38 MAPK/NLRP3 pathway in perioperative neurocognitive disorders (PND) in an abdominal exploratory laparotomy (AEL) aged mice model. METHODS C57BL/6 mice (male, 18-month-old) underwent AEL with 3 % anesthesia. Then, inhibitors targeting P38 MAPK (SB202190, 1 mg/kg) and GSK3β (TWS119, 10 mg/kg) were administered multiple times daily for 7 days post-surgery. The NLRP3-cKO AEL and WT AEL groups only underwent the AEL procedure. Behavioral assessments, including the open field test (OFT), novel object recognition (NOR), force swimming test (FST), and fear conditioning (FC), were initiated on postoperative day 14. Additionally, mice designated for neuroelectrophysiological monitoring had electrodes implanted on day 14 before surgery and underwent novel object recognition while their local field potential (LFP) was concurrently recorded on postoperative day 14. Lastly, after they were euthanasized, pathological analysis and western blot were performed. RESULTS SB202190, TWS119, and astrocyte-conditional knockout NLRP3 all ameliorated the cognitive impairment behaviors induced by AEL in mice and increased mean theta power during novel location exploration. However, it is worth noting that SB202190 may exacerbate postoperative depressive and anxiety-like behaviors in mice, while TWS119 may induce impulsive behaviors. CONCLUSIONS Our study suggests that anesthesia and surgical procedures induce alterations in mood and cognition, which may be intricately linked to the P38 MAPK/NLRP3 pathway.
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Affiliation(s)
- Jin-Meng Lv
- Hebei Province Cangzhou Hospital of Integrated Traditional and Western Medicine, Cangzhou, China; Hebei Key Laboratory of Integrated Traditional and Western Medicine in Osteoarthrosis Research (Preparing), Cangzhou, China; Hebei Province Key Laboratory of Integrated Traditional and Western Medicine in Neurological Rehabilitation, Cangzhou, China.
| | - Yi-Long Gao
- Department of Urology, West China Hospital, Sichuan University, Chengdu 610041, China.
| | - Lu-Ying Wang
- Hebei Province Cangzhou Hospital of Integrated Traditional and Western Medicine, Cangzhou, China.
| | - Bao-Dong Li
- Hebei Province Cangzhou Hospital of Integrated Traditional and Western Medicine, Cangzhou, China.
| | - Yong-Lin Shan
- Hebei Province Cangzhou Hospital of Integrated Traditional and Western Medicine, Cangzhou, China.
| | - Zi-Qiang Wu
- Hebei Province Dongguang Traditional Chinese Medicine Hospital, Cangzhou, China.
| | - Qing-Meng Lu
- Hebei Province Cangxian Hospital, Cangzhou, China.
| | - Heng-Yue Peng
- Affiliated Stomatology Hospital of China Medical University, Shenyang, China.
| | - Ting-Ting Zhou
- Hebei Key Laboratory of Integrated Traditional and Western Medicine in Osteoarthrosis Research (Preparing), Cangzhou, China.
| | - Xiao-Ming Li
- Hebei Key Laboratory of Integrated Traditional and Western Medicine in Osteoarthrosis Research (Preparing), Cangzhou, China.
| | - Li-Min Zhang
- Hebei Province Key Laboratory of Integrated Traditional and Western Medicine in Neurological Rehabilitation, Cangzhou, China; Department of Anesthesia and Trauma Research, Hebei Province Cangzhou Hospital of Integrated Traditional and Western Medicine, Cangzhou, China.
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Khawagi WY, Al-Kuraishy HM, Hussein NR, Al-Gareeb AI, Atef E, Elhussieny O, Alexiou A, Papadakis M, Jabir MS, Alshehri AA, Saad HM, Batiha GES. Depression and type 2 diabetes: A causal relationship and mechanistic pathway. Diabetes Obes Metab 2024; 26:3031-3044. [PMID: 38802993 DOI: 10.1111/dom.15630] [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: 03/09/2024] [Revised: 04/16/2024] [Accepted: 04/16/2024] [Indexed: 05/29/2024]
Abstract
Depression is a mood disorder that may increase risk for the development of insulin resistance (IR) and type 2 diabetes (T2D), and vice versa. However, the mechanistic pathway linking depression and T2D is not fully elucidated. The aim of this narrative review, therefore, was to discuss the possible link between depression and T2D. The coexistence of T2D and depression is twice as great compared to the occurrence of either condition independently. Hyperglycaemia and dyslipidaemia promote the incidence of depression by enhancing inflammation and reducing brain serotonin (5-hydroxytryptamine [5HT]). Dysregulation of insulin signalling in T2D impairs brain 5HT signalling, leading to the development of depression. Furthermore, depression is associated with the development of hyperglycaemia and poor glycaemic control. Psychological stress and depression promote the development of T2D. In conclusion, T2D could be a potential risk factor for the development of depression through the induction of inflammatory reactions and oxidative stress that affect brain neurotransmission. In addition, chronic stress in depression may induce the development of T2D through dysregulation of the hypothalamic-pituitary-adrenal axis and increase circulating cortisol levels, which triggers IR and T2D.
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Affiliation(s)
- Wael Y Khawagi
- Department of Clinical Pharmacy, College of Pharmacy, Taif University, Taif, Saudi Arabia
| | - Hayder M Al-Kuraishy
- Department of Clinical Pharmacology and Medicine, College of Medicine, Mustansiriyah University, Baghdad, Iraq
| | - Nawar R Hussein
- College of Pharmacy, Pharmacology Department, Al-Farahidi University, Baghdad, Iraq
| | - Ali I Al-Gareeb
- Department of Clinical Pharmacology and Medicine, College of Medicine, Mustansiriyah University, Baghdad, Iraq
| | - Esraa Atef
- Respiratory Therapy Department, Mohammed Al-Mana College for Medical Sciences, Dammam, Saudi Arabia
| | - Omnya Elhussieny
- Department of Histology and Cytology, Faculty of Veterinary Medicine, Matrouh University, Marsa Matruh, Egypt
| | - Athanasios Alexiou
- University Centre for Research & Development, Chandigarh University Chandigarh-Ludhiana Highway, Mohali, India
- Department of Research and Development, Funogen, Athens, Greece
- Department of Research and Development, AFNP Med, Wien, Austria
- Department of Science and Engineering, Novel Global Community Educational Foundation, Hebersham, New South Wales, Australia
| | - Marios Papadakis
- Department of Surgery II, University Hospital Witten-Herdecke, University of Witten-Herdecke, Wuppertal, Germany
| | - Majid S Jabir
- Applied Science Department, University of Technology, Baghdad, Iraq
| | - Abdullah A Alshehri
- Department of Clinical Pharmacy, College of Pharmacy, Taif University, Taif, Saudi Arabia
| | - Hebatallah M Saad
- Department of Pathology, Faculty of Veterinary Medicine, Matrouh University, Marsa Matruh, Egypt
| | - Gaber El-Saber Batiha
- Department of Pharmacology and Therapeutics, Faculty of Veterinary Medicine, Damanhour University, Damanhour, Egypt
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Anthony DC, Probert F, Gorlova A, Hebert J, Radford-Smith D, Nefedova Z, Umriukhin A, Nedorubov A, Cespuglio R, Shulgin B, Lyundup A, Lesch KP, Strekalova T. Impact of Serotonin Transporter Absence on Brain Insulin Receptor Expression, Plasma Metabolome Changes, and ADHD-like Behavior in Mice fed a Western Diet. Biomolecules 2024; 14:884. [PMID: 39199273 PMCID: PMC11351952 DOI: 10.3390/biom14080884] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2024] [Revised: 07/02/2024] [Accepted: 07/15/2024] [Indexed: 09/01/2024] Open
Abstract
The impaired function of the serotonin transporter (SERT) in humans has been linked to a higher risk of obesity and type 2 diabetes, especially as people age. Consuming a "Western diet" (WD), which is high in saturated fats, cholesterol, and sugars, can induce metabolic syndrome. Previous research indicated that mice carrying a targeted inactivation of the Sert gene (knockout, KO) and fed a WD display significant metabolic disturbances and behaviors reminiscent of ADHD. These abnormalities might be mediated via a dysfunction in insulin receptor (IR) signaling, which is also associated with adult ADHD. However, the impact of Sert deficiency on IR signaling and systemic metabolic changes has not been thoroughly explored. In this study, we conducted a detailed analysis of locomotor behavior in wild-type (WT) and KO mice fed a WD or control diet. We investigated changes in the blood metabolome and examined, via PCR, the expression of insulin receptor A and B isoforms and key regulators of their function in the brain. Twelve-month-old KO mice and their WT littermates were fed a WD for three weeks. Nuclear magnetic resonance spectroscopy analysis of plasma samples showed that KO mice on a WD had higher levels of lipids and lipoproteins and lower levels of glucose, lactate, alanine, valine, and isoleucine compared to other groups. SERT-KO mice on the control diet exhibited increased brain levels of both IR A and B isoforms, accompanied by a modest increase in the negative regulator ENPP. The KO mice also displayed anxiety-like behavior and reduced exploratory activity in an open field test. However, when the KO animals were fed a WD, the aberrant expression levels of IR isoforms in the KO mice and locomotor behavior were ameliorated indicating a complex interaction between genetic and dietary factors that might contribute to ADHD-like symptoms. Overall, our findings suggest that the lack of Sert leads to a unique metabolic phenotype in aged mice, characterized by dysregulated IR-related pathways. These changes are exacerbated by WD in the blood metabolome and are associated with behavioral abnormalities.
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Affiliation(s)
- Daniel C. Anthony
- Department of Pharmacology, Oxford University, Oxford OX1 3QT, UK; (D.C.A.); (F.P.); (J.H.); (D.R.-S.)
| | - Fay Probert
- Department of Pharmacology, Oxford University, Oxford OX1 3QT, UK; (D.C.A.); (F.P.); (J.H.); (D.R.-S.)
- Department of Chemistry, Oxford University, Oxford OX1 2JD, UK
| | - Anna Gorlova
- Research and Education Resource Center, Peoples Friendship University of Russia (RUDN University), 117198 Moscow, Russia; (A.G.); (R.C.); (A.L.)
| | - Jenna Hebert
- Department of Pharmacology, Oxford University, Oxford OX1 3QT, UK; (D.C.A.); (F.P.); (J.H.); (D.R.-S.)
| | - Daniel Radford-Smith
- Department of Pharmacology, Oxford University, Oxford OX1 3QT, UK; (D.C.A.); (F.P.); (J.H.); (D.R.-S.)
| | - Zlata Nefedova
- Department of Normal Physiology, Sechenov First Moscow State Medical University, 119991 Moscow, Russia; (Z.N.); (A.U.); (A.N.)
| | - Aleksei Umriukhin
- Department of Normal Physiology, Sechenov First Moscow State Medical University, 119991 Moscow, Russia; (Z.N.); (A.U.); (A.N.)
| | - Andrey Nedorubov
- Department of Normal Physiology, Sechenov First Moscow State Medical University, 119991 Moscow, Russia; (Z.N.); (A.U.); (A.N.)
| | - Raymond Cespuglio
- Research and Education Resource Center, Peoples Friendship University of Russia (RUDN University), 117198 Moscow, Russia; (A.G.); (R.C.); (A.L.)
| | - Boris Shulgin
- Laboratory of Engineering Profile Physical and Chemical Methods of Analysis, Korkyt Ata Kyzylorda University, Kyzylorda 120014, Kazakhstan;
| | - Aleksey Lyundup
- Research and Education Resource Center, Peoples Friendship University of Russia (RUDN University), 117198 Moscow, Russia; (A.G.); (R.C.); (A.L.)
- Endocrinology Research Centre, Dmitry Ulyanov Str. 19, 117036 Moscow, Russia
| | - Klaus Peter Lesch
- Division of Molecular Psychiatry, Center of Mental Health, University Hospital Würzburg, 97080 Würzburg, Germany;
- Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, Center of Mental Health, University Hospital Würzburg, 97080 Würzburg, Germany
| | - Tatyana Strekalova
- Department of Pharmacology, Oxford University, Oxford OX1 3QT, UK; (D.C.A.); (F.P.); (J.H.); (D.R.-S.)
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El-Sayed NS, Khalil NA, Saleh SR, Aly RG, Basta M. The Possible Neuroprotective Effect of Caffeic Acid on Cognitive Changes and Anxiety-Like Behavior Occurring in Young Rats Fed on High-Fat Diet and Exposed to Chronic Stress: Role of β-Catenin/GSK-3B Pathway. J Mol Neurosci 2024; 74:61. [PMID: 38954245 DOI: 10.1007/s12031-024-02232-4] [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: 01/09/2024] [Accepted: 05/28/2024] [Indexed: 07/04/2024]
Abstract
Lifestyle influences physical and cognitive development during the period of adolescence greatly. The most important of these lifestyle factors are diet and stress. Therefore, the aim of this study was to investigate the impact of high fat diet (HFD) and chronic mild stress on cognitive function and anxiety-like behaviors in young rats and to study the role of caffeic acid as a potential treatment for anxiety and cognitive dysfunction. Forty rats were assigned into 4 groups: control, HFD, HFD + stress, and caffeic acid-treated group. Rats were sacrificed after neurobehavioral testing. We detected memory impairment and anxiety-like behavior in rats which were more exaggerated in stressed rats. Alongside the behavioral changes, there were biochemical and histological changes. HFD and/or stress decreased hippocampal brain-derived neurotrophic factor (BDNF) levels and induced oxidative and inflammatory changes in the hippocampus. In addition, they suppressed Wnt/β-catenin pathway which was associated with activation of glycogen synthase kinase 3β (GSK3β). HFD and stress increased arginase 1 and inducible nitric oxide synthase (iNOS) levels as well. These disturbances were found to be aggravated in stressed rats than HFD group. However, caffeic acid was able to reverse these deteriorations leading to memory improvement and ameliorating anxiety-like behavior. So, the current study highlights an important neuroprotective role for caffeic acid that may guard against induction of cognitive dysfunction and anxiety disorders in adolescents who are exposed to HFD and/or stress.
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Affiliation(s)
- Norhan S El-Sayed
- Department of Medical Physiology, Faculty of Medicine, University of Alexandria, Alexandria, Egypt.
- Department of Medical Physiology, Faculty of Medicine, Alexandria University, Alexandria, Egypt.
| | - Nehal Adel Khalil
- Department of Medical Biochemistry, Faculty of Medicine, University of Alexandria, Alexandria, Egypt
| | - Samar R Saleh
- Department of Biochemistry, Faculty of Science, Alexandria University, Baghdad St., Moharam Bek, Alexandria, 21511, Egypt
- Bioscreening and Preclinical Trial Lab, Department of Biochemistry, Faculty of Science, Alexandria University, Baghdad St., Moharam Bek, Alexandria, 21511, Egypt
| | - Rania G Aly
- Department of pathology, Faculty of Medicine, University of Alexandria, Alexandria, Egypt
| | - Marianne Basta
- Department of Medical Physiology, Faculty of Medicine, University of Alexandria, Alexandria, Egypt
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Vily-Petit J, Taki A, Sinet F, Soty M, Guiard B, Zemdegs J, Malleret G, Stefanutti A, Mithieux G, Gautier-Stein A. Absence of the Peptide Transporter 1 Induces a Prediabetic and Depressive-Like Phenotype in Mice. Neuroendocrinology 2024; 115:226-241. [PMID: 38852578 DOI: 10.1159/000539499] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/01/2024] [Accepted: 05/22/2024] [Indexed: 06/11/2024]
Abstract
INTRODUCTION Protein-enriched diets improve glycemic control in diabetes or emotional behavior in depressive patients. In mice, these benefits depend on intestinal gluconeogenesis activation by di-/tripeptides. Intestinal di-/tripeptides absorption is carried out by the peptide transporter 1, PEPT1. The lack of PEPT1 might thus alter glucose and emotional balance. METHODS To determine the effects of PEPT1 deficiency under standard dietary conditions or during a dietary challenge known to promote both metabolic and cognitive dysfunction, insulin sensitivity, anxiety, and depressive-like traits, hippocampal serotonin (5-HT) and insulin signaling pathway were measured in wild-type (WT) and Pept1-/- mice fed either a chow or a high-fat high-sucrose (HF-HS) diet. RESULTS Pept1-/- mice exhibited slight defects in insulin sensitivity and emotional behavior, which were aggravated by an HF-HS diet. Pept1-/- mice fed a chow diet had lower hippocampal 5-HT levels and exhibited cerebral insulin resistance under HF-HS diet. These defects were independent of intestinal gluconeogenesis but might be linked to increased plasma amino acids levels. CONCLUSION Pept1-/- mice develop prediabetic and depressive-like traits and could thus be used to develop strategies to prevent or cure both diseases.
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Affiliation(s)
| | - Amelie Taki
- INSERM UMR-S1213, Université Claude Bernard Lyon 1, Lyon, France
| | - Flore Sinet
- INSERM UMR-S1213, Université Claude Bernard Lyon 1, Lyon, France
| | - Maud Soty
- INSERM UMR-S1213, Université Claude Bernard Lyon 1, Lyon, France
| | - Bruno Guiard
- CRCA - UMR - Université Paul Sabatier, Toulouse, France
| | | | - Gael Malleret
- Forgetting and Cortical Dynamics, Lyon Neuroscience Research Center, Lyon, France
| | - Anne Stefanutti
- INSERM UMR-S1213, Université Claude Bernard Lyon 1, Lyon, France
| | - Gilles Mithieux
- INSERM UMR-S1213, Université Claude Bernard Lyon 1, Lyon, France,
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Martin H, Bullich S, Martinat M, Chataigner M, Di Miceli M, Simon V, Clark S, Butler J, Schell M, Chopra S, Chaouloff F, Kleinridders A, Cota D, De Deurwaerdere P, Pénicaud L, Layé S, Guiard BP, Fioramonti X. Insulin modulates emotional behavior through a serotonin-dependent mechanism. Mol Psychiatry 2024; 29:1610-1619. [PMID: 36207585 DOI: 10.1038/s41380-022-01812-3] [Citation(s) in RCA: 14] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/22/2021] [Revised: 09/19/2022] [Accepted: 09/21/2022] [Indexed: 11/08/2022]
Abstract
Type-2 Diabetes (T2D) is characterized by insulin resistance and accompanied by psychiatric comorbidities including major depressive disorders (MDD). Patients with T2D are twice more likely to suffer from MDD and clinical studies have shown that insulin resistance is positively correlated with the severity of depressive symptoms. However, the potential contribution of central insulin signaling in MDD in patients with T2D remains elusive. Here we hypothesized that insulin modulates the serotonergic (5-HT) system to control emotional behavior and that insulin resistance in 5-HT neurons contributes to the development of mood disorders in T2D. Our results show that insulin directly modulates the activity of dorsal raphe (DR) 5-HT neurons to dampen 5-HT neurotransmission through a 5-HT1A receptor-mediated inhibitory feedback. In addition, insulin-induced 5-HT neuromodulation is necessary to promote anxiolytic-like effect in response to intranasal insulin delivery. Interestingly, such an anxiolytic effect of intranasal insulin as well as the response of DR 5-HT neurons to insulin are both blunted in high-fat diet-fed T2D animals. Altogether, these findings point to a novel mechanism by which insulin directly modulates the activity of DR 5-HT neurons to dampen 5-HT neurotransmission and control emotional behaviors, and emphasize the idea that impaired insulin-sensitivity in these neurons is critical for the development of T2D-associated mood disorders.
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Affiliation(s)
- Hugo Martin
- Univ. Bordeaux, INRAE, Bordeaux INP, NutriNeuro, UMR 1286, F-33000, Bordeaux, France
| | - Sébastien Bullich
- Centre de Recherches sur la Cognition Animale (CRCA), Centre de Biologie Intégrative (CBI), CNRS UMR5169, Toulouse, France
| | - Maud Martinat
- Univ. Bordeaux, INRAE, Bordeaux INP, NutriNeuro, UMR 1286, F-33000, Bordeaux, France
| | - Mathilde Chataigner
- Univ. Bordeaux, INRAE, Bordeaux INP, NutriNeuro, UMR 1286, F-33000, Bordeaux, France
| | - Mathieu Di Miceli
- Univ. Bordeaux, INRAE, Bordeaux INP, NutriNeuro, UMR 1286, F-33000, Bordeaux, France
- Worcester Biomedical Research Group, University of Worcester, WR2 6AJ, Worcester, UK
| | - Vincent Simon
- University of Bordeaux, Neurocentre Magendie, INSERM U1215, Bordeaux, France
| | - Samantha Clark
- University of Bordeaux, Neurocentre Magendie, INSERM U1215, Bordeaux, France
| | - Jasmine Butler
- INCIA, UMR CNRS, Bordeaux University, Neurocampus, Bordeaux, France
| | - Mareike Schell
- University of Potsdam, Institute of Nutritional Science, Molecular and Experimental Nutritional Medicine, Nuthetal, Germany
| | - Simran Chopra
- University of Potsdam, Institute of Nutritional Science, Molecular and Experimental Nutritional Medicine, Nuthetal, Germany
| | - Francis Chaouloff
- University of Bordeaux, Neurocentre Magendie, INSERM U1215, Bordeaux, France
| | - Andre Kleinridders
- University of Potsdam, Institute of Nutritional Science, Molecular and Experimental Nutritional Medicine, Nuthetal, Germany
| | - Daniela Cota
- University of Bordeaux, Neurocentre Magendie, INSERM U1215, Bordeaux, France
| | | | - Luc Pénicaud
- RESTORE, UMR INSERM 1301/CNRS 5070/Université Paul Sabatier/EFS/ENVT, Toulouse, France
| | - Sophie Layé
- Univ. Bordeaux, INRAE, Bordeaux INP, NutriNeuro, UMR 1286, F-33000, Bordeaux, France
| | - Bruno P Guiard
- Centre de Recherches sur la Cognition Animale (CRCA), Centre de Biologie Intégrative (CBI), CNRS UMR5169, Toulouse, France
| | - Xavier Fioramonti
- Univ. Bordeaux, INRAE, Bordeaux INP, NutriNeuro, UMR 1286, F-33000, Bordeaux, France.
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Yu H, Yu B, Qin X, Shan W. A unique inflammation-related mechanism by which high-fat diets induce depression-like behaviors in mice. J Affect Disord 2023; 339:180-193. [PMID: 37437725 DOI: 10.1016/j.jad.2023.07.005] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/03/2023] [Revised: 06/03/2023] [Accepted: 07/08/2023] [Indexed: 07/14/2023]
Abstract
BACKGROUND High-fat diet (HFD) consumption is an important reason for promoting depression, but the mechanism is unclear. The present study aims to explore the relationship between metabolic disturbance and HFD-induced depression-like behaviors. METHODS Depression models were established by HFD consumption and chronic unpredictable mild stress (CUMS) in mice. Enzyme-linked immunosorbent assay, western blotting, real-time polymerase chain reaction, gas chromatography and metabolomic analysis were undertaken to investigate the 5-hydroxytryptamine (5-HT) system, neuroinflammation and to identify altered lipid metabolic pathways. RESULTS Depression-like behaviors, impaired 5-HT neurotransmission and disordered lipid metabolism were observed upon HFD consumption. Despite a similar reduction of high-density lipoprotein cholesterol in CUMS and HFD group, high levels of body low-density lipoprotein cholesterol in the HFD group could help distinguish HFD from CUMS. Levels of interleukin (IL)-1β, IL-6, tumor necrosis factor (TNF)-α and inflammation-related metabolites were increased in HFD mice, so a link between depression and inflammation was postulated. Different metabolites were enriched in the two groups. The linoleic acid (LA) metabolic pathway and expression of fatty acid desaturase (FADS)1 and FADS2 (key enzymes in LA metabolic pathway) were enhanced significantly in HFD mice compared with the control group. LIMITATIONS Causality analyses for HFD and inflammation-related features were not undertaken. CONCLUSIONS HFD-induced depression-like behaviors was characterized by more severely disordered metabolism of lipids (especially in the LA metabolic pathway) and increased levels of inflammatory mediators, which might be the reasons for the disturbance of serotonergic system in hippocampus.
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Affiliation(s)
- Haining Yu
- College of Pharmaceutical Science, Zhejiang University of Technology, 310014, Hangzhou, China.
| | - Bixian Yu
- College of Pharmaceutical Science, Zhejiang University of Technology, 310014, Hangzhou, China
| | - Xiuyuan Qin
- College of Pharmaceutical Science, Zhejiang University of Technology, 310014, Hangzhou, China
| | - Weiguang Shan
- College of Pharmaceutical Science, Zhejiang University of Technology, 310014, Hangzhou, China
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Wang P, Kong FZ, Hong XH, Zhang L, Zhao WH, Yang JC, Zhang H. Neuronal Nitric Oxide Synthase Regulates Depression-like Behaviors in Shortening-Induced Obese Mice. Nutrients 2022; 14:4302. [PMID: 36296987 PMCID: PMC9609729 DOI: 10.3390/nu14204302] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2022] [Revised: 10/08/2022] [Accepted: 10/11/2022] [Indexed: 11/21/2022] Open
Abstract
Shortening is mainly derived from the partial hydrogenation of palm oil and widely used in fast food. Food processed with shortening contains high levels of industrial trans fatty acids. Studies have shown that there is a correlation between industrial trans fatty acids, obesity, and depression. However, the regulatory effect of neuronal nitric oxide synthase (nNOS) on depression in obese patients is still unknown. The purpose of this study was to explore mood changes in obese mice fed a high shortening diet, and to determine the regulatory effect of nNOS on depressive-like behaviors in obese mice. We used a high shortening diet-induced obesity mouse model to systematically assess the metabolic response, behavioral changes, prefrontal and hippocampal nNOS protein levels, and the effect of nNOS inhibitors (7-nitroindole) on depression-like behavior in obese mice. Interestingly, obese mice on a 9-week high-shortening diet developed short-term spatial working memory impairment and anxiety-like behavior, and obesity may be a risk factor for cognitive impairment and mood disorders. In animals fed a high shortening diet for 12 weeks, obese mice developed depression-like behavior and had significantly elevated levels of nNOS protein expression in the hippocampus and prefrontal lobe. Administration of the nNOS inhibitor 7-nitroindole could improve depression-like behaviors in obese mice, further suggesting that inhibition of nNOS is helpful for depression associated with obesity.
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Affiliation(s)
- Ping Wang
- Department of the Joint Laboratory of Biological Psychiatry, Mental Health Center of Shantou University, Shantou 515000, China
| | - Fan-Zhi Kong
- Department of the Joint Laboratory of Biological Psychiatry, Mental Health Center of Shantou University, Shantou 515000, China
| | - Xiao-Hong Hong
- Department of the Joint Laboratory of Biological Psychiatry, Mental Health Center of Shantou University, Shantou 515000, China
| | - Li Zhang
- Department of the Joint Laboratory of Biological Psychiatry, Mental Health Center of Shantou University, Shantou 515000, China
| | - Wan-Hong Zhao
- Department of the Joint Laboratory of Biological Psychiatry, Mental Health Center of Shantou University, Shantou 515000, China
| | - Jin-Cui Yang
- Department of the Joint Laboratory of Biological Psychiatry, Mental Health Center of Shantou University, Shantou 515000, China
| | - Heng Zhang
- Department of Medical Examination Center, Mental Health Center of Shantou University, Shantou 515000, China
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10
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Shared metabolic and neuroimmune mechanisms underlying Type 2 Diabetes Mellitus and Major Depressive Disorder. Prog Neuropsychopharmacol Biol Psychiatry 2021; 111:110351. [PMID: 34000290 DOI: 10.1016/j.pnpbp.2021.110351] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/23/2021] [Revised: 05/12/2021] [Accepted: 05/12/2021] [Indexed: 12/25/2022]
Abstract
Type 2 Diabetes Mellitus (T2DM) is a chronic metabolic disease with symptoms that go beyond the domain of glucose metabolism. In fact, research has shown that T2DM is accompanied by neurodegeneration and neuroinflammation. Interestingly, Major Depressive Disorder (MDD), a mood disorder characterized mainly by depressed mood and anhedonia is a key feature of T2DM. A body of evidence demonstrates that there are many shared neuroimmune mechanisms underlying the pathophysiology of T2DM and MDD. Therefore, here we review the state-of-art regarding the underlying factors common to both T2DM and MDD. Furthermore, we briefly discuss how depressive symptoms in diabetic patients could be tackled by using novel therapeutic approaches uncovered by these shared mechanisms. Understanding the comorbidity of depression in diabetic patients is essential to fully address T2DM pathophysiology and treatment.
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11
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Wu X, Wang J, Song L, Guan Y, Cao C, Cui Y, Zhang Y, Liu C. Catalpol Weakens Depressive-like Behavior in Mice with Streptozotocin-induced Hyperglycemia via PI3K/AKT/Nrf2/HO-1 Signaling Pathway. Neuroscience 2021; 473:102-118. [PMID: 34358633 DOI: 10.1016/j.neuroscience.2021.07.029] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2021] [Revised: 07/25/2021] [Accepted: 07/27/2021] [Indexed: 12/15/2022]
Abstract
Depression has huge social risks of high incidence, disability, and suicide. Its prevalence and harm in people with hyperglycemia are 2-3 times higher than in normal people. However, antidepressants with precise curative effects and clear mechanisms for patients with hyperglycemia are currently lacking. Prescriptions containing Radix Rehmannia glutinosa Libosch., a traditional medicinal herb with a wide range of nutritional and medicinal values, are often used as antidepressants in Chinese clinical medicine. Catalpol is one of the main effective compounds of Radix R. glutinosa, with multiple biological activities such as hypoglycemia. Here, the antidepressant effect of catalpol on the pathological state of streptozotocin (STZ)-induced hyperglycemia and the underlying molecular mechanisms were analyzed. Results showed that administering catalpol orally to hyperglycemic mice for 21 consecutive days significantly reversed the abnormalities in tail suspension, forced swimming, and open field tests. Catalpol also reversed the abnormal phosphorylation of phosphoinositide 3-kinase (PI3K) and protein kinase B (AKT) and the abnormal levels of nuclear factor erythroid 2-related factor 2 (Nrf2) protein, heme oxygenase-1 (HO-1), and antioxidants, including superoxide dismutase, glutathione peroxidase, glutathione-s transferase, reduced glutathione, and malondialdehyde in the hippocampus and frontal cortex of STZ-induced hyperglycemic mice. Thus, catalpol attenuates depressive-like behavior in pathological hyperglycemic state, and the antidepressant mechanism could at least be partly attributed to the upregulation of the PI3K/AKT/Nrf2/HO-1 signaling pathway in both brain regions, thus restoring the balance between oxidative and antioxidant damage. These data expanded the scientific understanding of catalpol and provided preclinical experimental evidence for its application.
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Affiliation(s)
- Xiaohui Wu
- College of Pharmacy, Henan University of Chinese Medicine, Zhengzhou 450046, China
| | - Junming Wang
- College of Pharmacy, Henan University of Chinese Medicine, Zhengzhou 450046, China; Co-construction Collaborative Innovation Center for Chinese Medicine and Respiratory Diseases by Henan & Education Ministry of P.R. China, Henan University of Chinese Medicine, Zhengzhou 450046, China.
| | - Lingling Song
- College of Pharmacy, Henan University of Chinese Medicine, Zhengzhou 450046, China
| | - Yuechen Guan
- College of Pharmacy, Henan University of Chinese Medicine, Zhengzhou 450046, China
| | - Can Cao
- College of Pharmacy, Henan University of Chinese Medicine, Zhengzhou 450046, China
| | - Ying Cui
- College of Pharmacy, Henan University of Chinese Medicine, Zhengzhou 450046, China; Co-construction Collaborative Innovation Center for Chinese Medicine and Respiratory Diseases by Henan & Education Ministry of P.R. China, Henan University of Chinese Medicine, Zhengzhou 450046, China
| | - Yueyue Zhang
- College of Pharmacy, Henan University of Chinese Medicine, Zhengzhou 450046, China
| | - Chen Liu
- College of Pharmacy, Henan University of Chinese Medicine, Zhengzhou 450046, China
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12
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Huq SN, Warner AK, Buckhaults K, Sachs BD. The Effects of Brain Serotonin Deficiency on Responses to High Fat Diet in Female Mice. Front Neurosci 2021; 15:683103. [PMID: 34276291 PMCID: PMC8282998 DOI: 10.3389/fnins.2021.683103] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2021] [Accepted: 05/13/2021] [Indexed: 12/11/2022] Open
Abstract
Clinical studies have reported an increased risk of depression and anxiety disorders among individuals who are obese, and women are more likely than men to suffer from depression, anxiety, and obesity. However, the effects of obesity-promoting diets on depression- and anxiety-like behavior remain controversial. A recent study from our group used the tryptophan hydroxylase 2 (R439H) knock-in mouse line to evaluate the impact of genetic brain serotonin (5-HT) deficiency on behavioral responses to high fat diet (HFD) in male mice. That study indicated that chronic exposure to HFD induced pro-anxiety-like effects in the open field test and antidepressant-like effects in the forced swim test in wild-type males. Interestingly, the antidepressant-like effect of HFD, but not the anxiogenic effect, was blocked by brain 5-HT deficiency in males. The current work sought to repeat these studies in females. Our new data suggest that females are less susceptible than males to HFD-induced weight gain and HFD-induced alterations in behavior. In addition, the effects of chronic HFD on the expression of inflammation-related genes in the hippocampus were markedly different in females than we had previously reported in males, and HFD was shown to impact the expression of several inflammation-related genes in a genotype-dependent manner. Together, our findings highlight the importance of brain 5-HT and sex in regulating behavioral and molecular responses to HFD. Our results may have important implications for our understanding of the clinically observed sex differences in the consequences of obesity.
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Affiliation(s)
- Shama N Huq
- Department of Psychological and Brain Sciences, College of Liberal Arts and Sciences, Villanova University, Villanova, PA, United States
| | - Allison K Warner
- Department of Psychological and Brain Sciences, College of Liberal Arts and Sciences, Villanova University, Villanova, PA, United States
| | - Kerry Buckhaults
- Department of Psychological and Brain Sciences, College of Liberal Arts and Sciences, Villanova University, Villanova, PA, United States
| | - Benjamin D Sachs
- Department of Psychological and Brain Sciences, College of Liberal Arts and Sciences, Villanova University, Villanova, PA, United States.,Department of Psychological and Brain Sciences, Villanova University, Villanova, PA, United States
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13
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da Silva LO, da Silva Aragão R, Duarte Barros MDL, Nogueira Ferraz-Pereira K, Lins Pinheiro I, Galindo LCM. Maternal exposure to high-fat diet modifies anxiety-like/depression-like behaviors and compounds of Serotonergic System in offspring: A preclinical systematic review. Int J Dev Neurosci 2021; 81:371-385. [PMID: 33788300 DOI: 10.1002/jdn.10110] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2020] [Revised: 03/08/2021] [Accepted: 03/25/2021] [Indexed: 12/18/2022] Open
Abstract
Maternal nutrition affects offspring physiology and behavior including susceptibility to mental health-related states. Perinatal high-fat diet (HFD) consumption has been associated with lower levels of serotonin as well as the development of anxiety-like and depression-like behaviors in offspring. The aim of this systematic review was to investigate the effects of maternal HFD during pregnancy and/or lactation on these behaviors and on some aspects of the serotonergic system. Criteria for eligibility included studies of offspring of rodents and non-human primates exposed to HFD at least during pregnancy and/or lactation, offspring that showed outcomes related to anxiety-like and depression-like behaviors and to the serotonergic system. The searches were realized in the LILACS, Web of Science, Scopus, and PubMed databases. The systematic review protocol was registered on the CAMARADES website. The internal validity was assessed by the SYRCLE risk of bias tool. The Kappa index was used for analyzing agreement among the reviewers. In addition, the PRISMA statement was used to report this systematic review. Sixteen articles were included in this review. Most of which studied HFD prior to mating and during pregnancy and lactation. All studies analyzed outcomes related to emotional behavior; three analyzed outcomes related to serotonin system compounds. Maternal consumption of HFD was found to be associated with an inconsistent pattern of the expression of TPH2 as well as reduced the immunoreactivity of 5-HT in the prefrontal cortex and increased 5-HT1A receptor expression in the dorsal raphe of offspring. An association between an HFD and alterations in emotional behavior was found in most of the studies selected.
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Affiliation(s)
- Luana Olegário da Silva
- Graduate Program in Nutrition, Physical Activity and Phenotypic Plasticity, Universidade Federal de Pernambuco, Vitória de Santo Antão, Brazil
| | - Raquel da Silva Aragão
- Graduate Program in Nutrition, Physical Activity and Phenotypic Plasticity, Universidade Federal de Pernambuco, Vitória de Santo Antão, Brazil.,Graduate Program in Nutrition, Universidade Federal de Pernambuco, Recife, Brazil.,Physical Education and Sport Sciences Nucleus, Universidade Federal de Pernambuco, Vitória de Santo Antão, Brazil.,Unity of Studies in Nutrition and Phenotypic Plasticity, Department of Nutrition, Universidade Federal de Pernambuco, Recife, Brazil
| | | | - Kelli Nogueira Ferraz-Pereira
- Graduate Program in Nutrition, Physical Activity and Phenotypic Plasticity, Universidade Federal de Pernambuco, Vitória de Santo Antão, Brazil.,Unity of Studies in Nutrition and Phenotypic Plasticity, Department of Nutrition, Universidade Federal de Pernambuco, Recife, Brazil
| | - Isabeli Lins Pinheiro
- Physical Education and Sport Sciences Nucleus, Universidade Federal de Pernambuco, Vitória de Santo Antão, Brazil.,Unity of Studies in Nutrition and Phenotypic Plasticity, Department of Nutrition, Universidade Federal de Pernambuco, Recife, Brazil
| | - Lígia Cristina Monteiro Galindo
- Graduate Program in Nutrition, Physical Activity and Phenotypic Plasticity, Universidade Federal de Pernambuco, Vitória de Santo Antão, Brazil.,Unity of Studies in Nutrition and Phenotypic Plasticity, Department of Nutrition, Universidade Federal de Pernambuco, Recife, Brazil.,Departament of Anatomy, Universidade Federal de Pernambuco, Recife, Brazil
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14
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Martin H, Bullich S, Guiard BP, Fioramonti X. The impact of insulin on the serotonergic system and consequences on diabetes-associated mood disorders. J Neuroendocrinol 2021; 33:e12928. [PMID: 33506507 DOI: 10.1111/jne.12928] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/30/2020] [Revised: 11/20/2020] [Accepted: 12/02/2020] [Indexed: 12/12/2022]
Abstract
The idea that insulin could influence emotional behaviours has long been suggested. However, the underlying mechanisms have yet to be solved and there is no direct and clear-cut evidence demonstrating that such action involves brain serotonergic neurones. Indeed, initial arguments in favour of the association between insulin, serotonin and mood arise from clinical or animal studies showing that impaired insulin action in type 1 or type 2 diabetes causes anxiety- and depressive symptoms along with blunted plasma and brain serotonin levels. The present review synthesises the main mechanistic hypotheses that might explain the comorbidity between diabetes and depression. It also provides a state of knowledge of the direct and indirect experimental evidence that insulin modulates brain serotonergic neurones. Finally, it highlights the literature suggesting that antidiabetic drugs present antidepressant-like effects and, conversely, that serotonergic antidepressants impact glucose homeostasis. Overall, this review provides mechanistic insights into how insulin signalling alters serotonergic neurotransmission and related behaviours bringing new targets for therapeutic options.
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Affiliation(s)
- Hugo Martin
- NutriNeuro, UMR 1286 INRAE, Bordeaux INP, Bordeaux University, Bordeaux, France
| | - Sébastien Bullich
- Centre de Recherches sur la Cognition Animale (CRCA), Centre de Biologie Intégrative (CBI), CNRS UMR5169, UPS, Université de Toulouse, Toulouse, France
| | - Bruno P Guiard
- Centre de Recherches sur la Cognition Animale (CRCA), Centre de Biologie Intégrative (CBI), CNRS UMR5169, UPS, Université de Toulouse, Toulouse, France
| | - Xavier Fioramonti
- NutriNeuro, UMR 1286 INRAE, Bordeaux INP, Bordeaux University, Bordeaux, France
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15
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Lu Y, An T, Tian H, Gao X, Wang F, Wang S, Ma K. Depression with Comorbid Diabetes: What Evidence Exists for Treatments Using Traditional Chinese Medicine and Natural Products? Front Pharmacol 2021; 11:596362. [PMID: 33568996 PMCID: PMC7868339 DOI: 10.3389/fphar.2020.596362] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2020] [Accepted: 12/14/2020] [Indexed: 12/13/2022] Open
Abstract
Comorbidity between diabetes mellitus (DM) and depression, two chronic and devastating diseases spreading worldwide, has been confirmed by a large body of epidemiological and clinical studies. Due to the bidirectional relationship between DM and depression, this comorbidity leads to poorer outcomes in both conditions. Given the adverse effects and limited effectiveness of the existing therapies for depression associated with diabetes, the development of novel therapeutic drugs with more potency and fewer side effects is still the most important goal. Hence, many researchers have made great efforts to investigate the potential usefulness of traditional Chinese medicine (TCM) and natural products, including natural extracts and purified compounds, in the treatment of comorbid depression in diabetes. Here, we reviewed the related literature on TCM and natural products that can remedy the comorbidity of diabetes and depression and presented them on the basis of their mechanism of action, focusing on shared risk factors, including insulin resistance, oxidative stress and inflammation, and nervous disturbances. In short, this review suggests that TCM and natural products could expand the therapeutic alternatives to ameliorate the association between DM and depressive disorders.
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Affiliation(s)
- Yanting Lu
- Shandong Co-Innovation Center of Classic TCM Formula, Shandong University of Traditional Chinese Medicine, Jinan, China
- College of TCM, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Tao An
- School of Pharmaceutical Sciences, Qilu University of Technology (Shandong Academy of Sciences), Jinan, China
| | - Hu Tian
- College of TCM, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Xueqin Gao
- College of TCM, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Furong Wang
- College of TCM, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Shijun Wang
- Shandong Co-Innovation Center of Classic TCM Formula, Shandong University of Traditional Chinese Medicine, Jinan, China
- College of TCM, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Ke Ma
- Shandong Co-Innovation Center of Classic TCM Formula, Shandong University of Traditional Chinese Medicine, Jinan, China
- College of TCM, Shandong University of Traditional Chinese Medicine, Jinan, China
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16
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Sinet F, Soty M, Zemdegs J, Guiard B, Estrada J, Malleret G, Silva M, Mithieux G, Gautier-Stein A. Dietary Fibers and Proteins Modulate Behavior via the Activation of Intestinal Gluconeogenesis. Neuroendocrinology 2021; 111:1249-1265. [PMID: 33429400 DOI: 10.1159/000514289] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/07/2020] [Accepted: 01/07/2021] [Indexed: 11/19/2022]
Abstract
INTRODUCTION Several studies have suggested that diet, especially the one enriched in microbiota-fermented fibers or fat, regulates behavior. The underlying mechanisms are currently unknown. We previously reported that certain macronutrients (fermentable fiber and protein) regulate energy homeostasis via the activation of intestinal gluconeogenesis (IGN), which generates a neural signal to the brain. We hypothesized that these nutriments might control behavior using the same gut-brain circuit. METHODS Wild-type and IGN-deficient mice were fed chow or diets enriched in protein or fiber. Changes in their behavior were assessed using suited tests. Hippocampal neurogenesis, extracellular levels of serotonin, and protein expression levels were assessed by immunofluorescence, in vivo dialysis, and Western blotting, respectively. IGN was rescued by infusing glucose into the portal vein of IGN-deficient mice. RESULTS We show here that both fiber- and protein-enriched diets exert beneficial actions on anxiety-like and depressive-like behaviors. These benefits do not occur in mice lacking IGN. Consistently, IGN-deficient mice display hallmarks of depressive-like disorders, including decreased hippocampal neurogenesis, basal hyperactivity, and deregulation of the hypothalamic-pituitary-adrenal axis, which are associated with increased expression of the precursor of corticotropin-releasing hormone in the hypothalamus and decreased expression of the glucocorticoid receptor in the hippocampus. These neurobiological alterations are corrected by portal glucose infusion mimicking IGN. CONCLUSION IGN translates nutritional information, allowing the brain to finely coordinate energy metabolism and behavior.
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Affiliation(s)
- Flore Sinet
- INSERM UMR-S1213, Université Claude Bernard Lyon 1, Université de Lyon, Lyon, France
| | - Maud Soty
- INSERM UMR-S1213, Université Claude Bernard Lyon 1, Université de Lyon, Lyon, France
| | - Juliane Zemdegs
- CRCA - UMR 5169 - Université Paul Sabatier, Toulouse, France
| | - Bruno Guiard
- CRCA - UMR 5169 - Université Paul Sabatier, Toulouse, France
| | - Judith Estrada
- INSERM UMR-S1213, Université Claude Bernard Lyon 1, Université de Lyon, Lyon, France
| | - Gaël Malleret
- Forgetting and Cortical Dynamics, Lyon Neuroscience Research Center, Université de Lyon, Lyon, France
| | - Marine Silva
- INSERM UMR-S1213, Université Claude Bernard Lyon 1, Université de Lyon, Lyon, France
| | - Gilles Mithieux
- INSERM UMR-S1213, Université Claude Bernard Lyon 1, Université de Lyon, Lyon, France
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17
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Downregulation of hippocampal SIRT6 activates AKT/CRMP2 signaling and ameliorates chronic stress-induced depression-like behavior in mice. Acta Pharmacol Sin 2020; 41:1557-1567. [PMID: 32265492 DOI: 10.1038/s41401-020-0387-5] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/18/2019] [Accepted: 02/19/2020] [Indexed: 12/15/2022]
Abstract
Sirtuin 6 (SIRT6) has been reported to play a key role in cognitive function and mood regulation, yet its role in mood disorders is not completely understood. Here, we confirmed that knockdown of hippocampal SIRT6 alleviated depression-like behaviors induced by chronic unpredictable stress (CUS) in mice. Our in vitro data showed that SIRT6 negatively regulated protein kinase B (AKT) signaling by deacetylating histone 3 at Lys9 and Lys56. Knockdown of SIRT6 significantly increased AKT phosphorylation activity, while decreased collapsin response mediator protein 2 (CRMP2) phosphorylation activity. Furthermore, pharmacologic inhibition of SIRT6 by ferulic acid (FA) (40 or 80 mg· kg-1 per day, i.g.) could activate AKT/CRMP2 pathway in vitro, which has been proved to exert an antidepressant-like effect on CUS-induced depressive models. In conclusion, our study suggested that hippocampal SIRT6 contributes to the performance of depression-like behaviors by suppressing AKT/CRMP2 signaling, and FA ameliorates CUS-induced depression-like behaviors in mice as a potential pharmacologic inhibitor of SIRT6.
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18
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Li J, Ma S, Chen J, Hu K, Li Y, Zhang Z, Su Z, Woodgett JR, Li M, Huang Q. GSK-3β Contributes to Parkinsonian Dopaminergic Neuron Death: Evidence From Conditional Knockout Mice and Tideglusib. Front Mol Neurosci 2020; 13:81. [PMID: 32581704 PMCID: PMC7283909 DOI: 10.3389/fnmol.2020.00081] [Citation(s) in RCA: 42] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2020] [Accepted: 04/23/2020] [Indexed: 12/22/2022] Open
Abstract
Glycogen synthase kinase-3 (GSK-3) dysregulation has been implicated in nigral dopaminergic neurodegeneration, one of the main pathological features of Parkinson’s disease (PD). The two isoforms, GSK-3α and GSK-3β, have both been suggested to play a detrimental role in neuronal death. To date, several studies have focused on the role of GSK-3β on PD pathogenesis, while the role of GSK-3α has been largely overlooked. Here, we report in situ observations that both GSK-3α and GSK-3β are dephosphorylated at a negatively acting regulatory serine, indicating kinase activation, selectively in nigral dopaminergic neurons following exposure of mice to 1-methyl-4-pheny-1,2,3,6-tetrahydropyridine (MPTP). To identify whether GSK-3α and GSK-3β display functional redundancy in regulating parkinsonian dopaminergic cell death, we analysed dopaminergic neuron-specific Gsk3a null (Gsk3aΔDat) and Gsk3b null (Gsk3bΔDat) mice, respectively. We found that Gsk3bΔDat, but not Gsk3aΔDat, showed significant resistance to MPTP insult, revealing non-redundancy of GSK-3α and GSK-3β in PD pathogenesis. In addition, we tested the neuroprotective effect of tideglusib, the most clinically advanced inhibitor of GSK-3, in the MPTP model of PD. Administration of higher doses (200 mg/kg and 500 mg/kg) of tideglusib exhibited significant neuroprotection, whereas 50 mg/kg tideglusib failed to prevent dopaminergic neurodegeneration from MPTP toxicity. Administration of 200 mg/kg tideglusib improved motor symptoms of MPTP-treated mice. Together, these data demonstrate GSK-3β and not GSK-3α is critical for parkinsonian neurodegeneration. Our data support the view that GSK-3β acts as a potential therapeutic target in PD and tideglusib would be a candidate drug for PD neuroprotective therapy.
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Affiliation(s)
- Junyu Li
- Guangdong Provincial Key Laboratory of Brain Function and Disease, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.,Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
| | - Shanshan Ma
- Guangdong Provincial Key Laboratory of Brain Function and Disease, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.,Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
| | | | - Kunhua Hu
- Guangdong Provincial Key Laboratory of Brain Function and Disease, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.,Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
| | - Yongyi Li
- Guangdong Provincial Key Laboratory of Brain Function and Disease, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.,Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
| | - Zeyu Zhang
- Guangdong Provincial Key Laboratory of Brain Function and Disease, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.,Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
| | - Zixiang Su
- Guangdong Provincial Key Laboratory of Brain Function and Disease, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.,Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
| | - James R Woodgett
- Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, ON, Canada
| | - Mingtao Li
- Guangdong Provincial Key Laboratory of Brain Function and Disease, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.,Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
| | - Qiaoying Huang
- Guangdong Provincial Key Laboratory of Brain Function and Disease, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.,Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
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19
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Haleem DJ, Gul S. Circulating leptin, cortisol and gender differences associated with anorexia or obesity in depression. World J Biol Psychiatry 2020; 21:195-202. [PMID: 31347937 DOI: 10.1080/15622975.2019.1648870] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Objectives: To assess the role of circulating cortisol and leptin in depression associated with anorexia or obesity.Methods: Two hundred and fifty depressed patients presenting to the outpatient clinic of a psychiatric hospital and 250 non-depressed healthy volunteers were included in the study. The subjects of both groups were sub-grouped based upon their gender and BMI. Serum cortisol and leptin were determined by using respective ELISA kits.Results: The number of depressed than non-depressed subjects was three-fold higher in obese BMI groups of both genders. There were more depressed than non-depressed subjects in the underweight male BMI groups and in the overweight female BMI groups. There was a BMI-related increase in serum leptin and a decrease in serum cortisol in both genders. Depression in underweight BMI groups of both genders was associated with a decrease in serum leptin and an increase in cortisol. Higher serum leptin in obese BMI group was associated with a decrease in serum cortisol.Conclusions: Obesity is a risk factor for depression. The shift from typical to atypical depression is due to an inhibitory effect of higher circulating leptin on HPA axis activity and subsequent decrease in the lipolytic effects of cortisol.
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Affiliation(s)
- Darakhshan Jabeen Haleem
- Neuroscience Research Laboratory, Dr Panjwani Center for Molecular Medicine & Drug Research (PCMD), International Center for Chemical and Biological Science (ICCBS), University of Karachi, Karachi, Pakistan
| | - Sumera Gul
- Neuroscience Research Laboratory, Dr Panjwani Center for Molecular Medicine & Drug Research (PCMD), International Center for Chemical and Biological Science (ICCBS), University of Karachi, Karachi, Pakistan
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Karth MM, Baugher BJ, Daly N, Karth MD, Gironda SC, Sachs BD. Brain 5-HT Deficiency Prevents Antidepressant-Like Effects of High-Fat-Diet and Blocks High-Fat-Diet-Induced GSK3β Phosphorylation in the Hippocampus. Front Mol Neurosci 2019; 12:298. [PMID: 31920532 PMCID: PMC6917648 DOI: 10.3389/fnmol.2019.00298] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2019] [Accepted: 11/20/2019] [Indexed: 02/06/2023] Open
Abstract
Obesity is associated with an increased risk of depression and anxiety disorders, but the nature of the relationship(s) between obesity and mental illness remains highly controversial. Some argue that depression and anxiety lead to increased consumption of "comfort foods," the intake of which reduces negative affect and promotes obesity. In contrast, others have theorized that negative affect results from chronic excessive consumption of highly palatable foods. The brain serotonin (5-HT) system has long been implicated in both the development and treatment of mental illness. Preclinical studies have shown that low brain 5-HT exacerbates depression- and anxiety-like behaviors induced by stress and blocks reductions in depression-like behavior induced by antidepressants, but the effects of brain 5-HT deficiency on responses to high-fat diet (HFD) have not been explored. The current work used genetically modified mice to evaluate the effects of low 5-HT on behavioral and molecular alterations induced by chronic exposure to HFD. Our results reveal that HFD decreases depression-like behavior and increases some anxiety-like behaviors in wild-type (WT) mice. However, genetic brain 5-HT deficiency blocks HFD-induced reductions in forced swim immobility and prevents HFD-induced increases in hippocampal GSK3β phosphorylation despite having no significant effects on HFD-induced changes in body weight or anxiety-like behavior. Together, our results suggest that brain 5-HT deficiency significantly impacts a subset of behavioral and molecular responses to HFD, a finding that could help explain the complex relationships between obesity and mental illness.
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Affiliation(s)
- Michelle M Karth
- Department of Psychological and Brain Sciences, College of Liberal Arts and Sciences, Villanova University, Villanova, PA, United States
| | - Brittany J Baugher
- Department of Psychological and Brain Sciences, College of Liberal Arts and Sciences, Villanova University, Villanova, PA, United States
| | - Nicole Daly
- Department of Psychological and Brain Sciences, College of Liberal Arts and Sciences, Villanova University, Villanova, PA, United States
| | - Melinda D Karth
- Department of Psychological and Brain Sciences, College of Liberal Arts and Sciences, Villanova University, Villanova, PA, United States
| | - Stephen C Gironda
- Department of Psychological and Brain Sciences, College of Liberal Arts and Sciences, Villanova University, Villanova, PA, United States
| | - Benjamin D Sachs
- Department of Psychological and Brain Sciences, College of Liberal Arts and Sciences, Villanova University, Villanova, PA, United States
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Metformin Promotes Anxiolytic and Antidepressant-Like Responses in Insulin-Resistant Mice by Decreasing Circulating Branched-Chain Amino Acids. J Neurosci 2019; 39:5935-5948. [PMID: 31160539 DOI: 10.1523/jneurosci.2904-18.2019] [Citation(s) in RCA: 98] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2018] [Revised: 05/07/2019] [Accepted: 05/15/2019] [Indexed: 12/27/2022] Open
Abstract
Epidemiological studies indicate that insulin resistance (IR), a hallmark of type 2 diabetes, is associated with an increased risk of major depression. Here, we demonstrated that male mice fed a high-fat diet (HFD) exhibited peripheral metabolic impairments reminiscent of IR accompanied by elevated circulating levels of branched-chain amino acids (BCAAs), whereas both parameters were normalized by chronic treatment with metformin (Met). Given the role of BCAAs in the regulation of tryptophan influx into the brain, we then explored the activity of the serotonin (5-HT) system. Our results indicated that HFD-fed mice displayed impairment in the electrical activity of dorsal raphe 5-HT neurons, attenuated hippocampal extracellular 5-HT concentrations and anxiety, one of the most visible and early symptoms of depression. On the contrary, Met stimulated 5-HT neurons excitability and 5-HT neurotransmission while hindering HFD-induced anxiety. Met also promoted antidepressant-like activities as observed with fluoxetine. In light of these data, we designed a modified HFD in which BCAA dietary supply was reduced by half. Deficiency in BCAAs failed to reverse HFD-induced metabolic impairments while producing antidepressant-like activity and enhancing the behavioral response to fluoxetine. Our results suggest that Met may act by decreasing circulating BCAAs levels to favor serotonergic neurotransmission in the hippocampus and promote antidepressant-like effects in mice fed an HFD. These findings also lead us to envision that a diet poor in BCAAs, provided either alone or as add-on therapy to conventional antidepressant drugs, could help to relieve depressive symptoms in patients with metabolic comorbidities.SIGNIFICANCE STATEMENT Insulin resistance in humans is associated with increased risk of anxiodepressive disorders. Such a relationship has been also found in rodents fed a high-fat diet (HFD). To determine whether insulin-sensitizing strategies induce anxiolytic- and/or antidepressant-like activities and to investigate the underlying mechanisms, we tested the effects of metformin, an oral antidiabetic drug, in mice fed an HFD. Metformin reduced levels of circulating branched-chain amino acids, which regulate tryptophan uptake within the brain. Moreover, metformin increased hippocampal serotonergic neurotransmission while promoting anxiolytic- and antidepressant-like effects. Moreover, a diet poor in these amino acids produced similar beneficial behavioral property. Collectively, these results suggest that metformin could be used as add-on therapy to a conventional antidepressant for the comorbidity between metabolic and mental disorders.
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22
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Pan Q, Liu Q, Wan R, Kalavagunta PK, Liu L, Lv W, Qiao T, Shang J, Wu H. Selective inhibition of intestinal 5-HT improves neurobehavioral abnormalities caused by high-fat diet mice. Metab Brain Dis 2019; 34:747-761. [PMID: 30931486 DOI: 10.1007/s11011-019-0392-x] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/22/2018] [Accepted: 01/28/2019] [Indexed: 12/16/2022]
Abstract
Recent literature reported the adverse effects of high-fat diet (HFD) on animal's emotional and cognitive function. An HFD-induced obesity/hyperlipidemia is accompanied by hormonal and neurochemical changes that can lead to depression. The important roles of gut-derived serotonin (5-Hydroxytryptamine, 5-HT) during this processing have been increasingly focused. Hence, to determine the potential role of gut-derived serotonin, HFD model was established in C57BL/6 mice. At the 4th week of feeding, a pharmacologic inhibitor of gut-derived 5-HT synthesis LP533401 (12.5 mg/kg/day), simvastatin (SIM) (5 mg/kg/day) and benzafibrate (BZ) (75 mg/kg/day) were administered for two weeks by oral gavage. Then, intraperitoneal glucose tolerance test (IPGTT), open field test (OFT), tail suspension test (TST), forced swim test (FST), sucrose preference test (SPT) were used to evaluate metabolic and neurobehavioral performances. Immunohistochemical staining, real-time quantitative PCR and other methods were to explore possible mechanisms. It was found that HFD feeding and drug treatments had some significant effects on neurobehaviors and brain: (1) All administrations reduced the total cholesterol (TC) and triglyceride (TG) parametric abnormality caused by HFD. LP533401 and SIM could significantly improve the impaired glucose tolerance, while BZ had no significant effect. (2) LP533401, SIM and BZ alleviated depression-like behavior of HFD mice in OFT, TST, FST and SPT. (3) LP533401 and SIM reversed the inhibition of Tryptophan Hydroxylase 2, Tph2 gene expression and the activation of Indoleamine 2,3-dioxy-Genase, IDO expression in HFD-treated brain, whereas BZ did not. (4) LP533401, SIM and BZ restored the inhibitory expression of 5-HT1A receptor in HFD hippocampus. Conclusions: Selective inhibition of intestinal 5-HT can attenuate depressive-like behavior, reduce 5-HT1AR impairment in hippocampus and correct abnormal 5-HT pathway in brain while ameliorating HFD-induced glucose intolerance. Further experiments are warranted to define the adequate strategy of targeting peripheral 5-HT for the treatment of such co-morbidity.
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Affiliation(s)
- Qi Pan
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 210009, China
- Jiangsu Key Laboratory of TCM Evaluation and Translational Research, China Pharmaceutical University, Nanjing, 211198, China
- School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, 211198, China
| | - Qiongzhen Liu
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 210009, China
- Jiangsu Key Laboratory of TCM Evaluation and Translational Research, China Pharmaceutical University, Nanjing, 211198, China
| | - Renling Wan
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 210009, China
- Jiangsu Key Laboratory of TCM Evaluation and Translational Research, China Pharmaceutical University, Nanjing, 211198, China
- School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, 211198, China
| | - Praveen Kumar Kalavagunta
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 210009, China
- Jiangsu Key Laboratory of TCM Evaluation and Translational Research, China Pharmaceutical University, Nanjing, 211198, China
- School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, 211198, China
| | - Li Liu
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 210009, China
- Jiangsu Key Laboratory of TCM Evaluation and Translational Research, China Pharmaceutical University, Nanjing, 211198, China
- School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, 211198, China
| | - Wenting Lv
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 210009, China
- Jiangsu Key Laboratory of TCM Evaluation and Translational Research, China Pharmaceutical University, Nanjing, 211198, China
- School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, 211198, China
| | - Tong Qiao
- Vascular Surgery Department, Nanjing Drum Tower Hospital, Nanjing, 210008, China
| | - Jing Shang
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 210009, China.
- Jiangsu Key Laboratory of TCM Evaluation and Translational Research, China Pharmaceutical University, Nanjing, 211198, China.
- School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, 211198, China.
- Qinghai Key Laboratory of Tibetan Medicine Pharmacology and Safety Evaluation, Northwest, Xining, Qinghai, China.
| | - Huali Wu
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 210009, China.
- Department of Pharmacology, China Pharmaceutical University, Nanjing, 210009, China.
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23
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Steardo L, Fabrazzo M, Sampogna G, Monteleone AM, D'Agostino G, Monteleone P, Maj M. Impaired glucose metabolism in bipolar patients and response to mood stabilizer treatments. J Affect Disord 2019; 245:174-179. [PMID: 30391773 DOI: 10.1016/j.jad.2018.10.360] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/24/2018] [Revised: 10/15/2018] [Accepted: 10/27/2018] [Indexed: 12/27/2022]
Abstract
BACKGROUND Metabolic dysfunctions in patients with bipolar disorder (BD) are critical factors that interfere with outcome, but only one study evaluated the influence of glucose dysmetabolism on the response to treatment with lithium. We aimed to investigate the potential impact of glucose metabolic status on clinical characteristics of BD patients and their response to treatment with different mood stabilizers in monotherapy or in combination. METHODS 45 BD patients with insulin resistance (IR) or type 2 diabetes mellitus (DM2) and 46 patients with normal glucose metabolism, treated with mood stabilizers for at least one year were assessed by diagnostic and rating instruments. Their clinical characteristics were compared and an ordinal logistic regression model was adopted to identify possible predictors of response to mood stabilizer treatments. RESULTS Compared to patients with normal glucose metabolism, BD patients with impaired glucose metabolism showed a worse clinical presentation of their psychiatric illness and a worse response to mood stabilizers. Ordinal logistic regression analysis evidenced that impaired glucose metabolism was the only predictor of poor response to mood stabilizers (OR 4.3; 95% CI: 1.7-11.1; p < 0.002). LIMITATIONS Cross-sectional design and the relatively small sample size, are the main limitations of our study. CONCLUSIONS Our findings expand literature data suggesting that BD patients with impaired glucose metabolism are at a greater risk of not responding to lithium as well as to different mood stabilizer treatments.
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Affiliation(s)
- Luca Steardo
- Department of Psychiatry, University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Michele Fabrazzo
- Department of Psychiatry, University of Campania "Luigi Vanvitelli", Naples, Italy.
| | - Gaia Sampogna
- Department of Psychiatry, University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Alessio M Monteleone
- Department of Psychiatry, University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Giulia D'Agostino
- Department of Medicine, Surgery and Dentistry "Scuola Medica Salernitana", University of Salerno, Salerno, Italy
| | - Palmiero Monteleone
- Department of Medicine, Surgery and Dentistry "Scuola Medica Salernitana", University of Salerno, Salerno, Italy
| | - Mario Maj
- Department of Psychiatry, University of Campania "Luigi Vanvitelli", Naples, Italy
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24
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Lyra E Silva NDM, Lam MP, Soares CN, Munoz DP, Milev R, De Felice FG. Insulin Resistance as a Shared Pathogenic Mechanism Between Depression and Type 2 Diabetes. Front Psychiatry 2019; 10:57. [PMID: 30837902 PMCID: PMC6382695 DOI: 10.3389/fpsyt.2019.00057] [Citation(s) in RCA: 95] [Impact Index Per Article: 15.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/21/2018] [Accepted: 01/25/2019] [Indexed: 12/28/2022] Open
Abstract
Neuropsychiatric disorders and type 2 diabetes (T2D) are major public health concerns proposed to be intimately connected. T2D is associated with increased risk of dementia, neuropsychiatric and mood disorders. Evidences of the involvement of insulin signaling on brain mechanisms related to depression indicate that insulin resistance, a hallmark of type 2 diabetes, could develop in the brains of depressive patients. In this article, we briefly review possible molecular mechanisms associating defective brain insulin signaling with reward system, neurogenesis, synaptic plasticity and hypothalamic-pituitary-adrenal (HPA) stress axis in depression. We further discuss the involvement of tumor necrosis factor α (TNFα) promoting defective insulin signaling and depressive-like behavior in rodent models. Finally, due to the high resistant rate of anti-depressants, novel insights into the link between insulin resistance and depression may advance the development of alternative treatments for this disease.
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Affiliation(s)
| | - Minh P Lam
- Department of Psychiatry, Queen's University, Kingston, ON, Canada
| | - Claudio N Soares
- Centre for Neuroscience Studies, Queen's University, Kingston, ON, Canada.,Department of Psychiatry, Queen's University, Kingston, ON, Canada
| | - Douglas P Munoz
- Centre for Neuroscience Studies, Queen's University, Kingston, ON, Canada
| | - Roumen Milev
- Centre for Neuroscience Studies, Queen's University, Kingston, ON, Canada.,Department of Psychiatry, Queen's University, Kingston, ON, Canada
| | - Fernanda G De Felice
- Centre for Neuroscience Studies, Queen's University, Kingston, ON, Canada.,Department of Psychiatry, Queen's University, Kingston, ON, Canada.,Institute of Medical Biochemistry Leopoldo De Meis, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
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25
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Chen WG, Zheng JX, Xu X, Hu YM, Ma YM. Hippocampal FXR plays a role in the pathogenesis of depression: A preliminary study based on lentiviral gene modulation. Psychiatry Res 2018; 264:374-379. [PMID: 29677620 DOI: 10.1016/j.psychres.2018.04.025] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/09/2018] [Revised: 03/29/2018] [Accepted: 04/10/2018] [Indexed: 01/23/2023]
Abstract
As a well-known bile acid receptor, the role of Farnesoid X receptor (FXR) in the digestive system and cardiovascular system has been widely explored. However, there are very few studies involving FXR in the central nervous system. In this study, we explored the role of FXR in the pathogenesis of depression, a serious and worldwide neuropsychiatric disease. It was found that chronic unpredictable mild stress (CUMS) fully enhanced the protein and mRNA expressions of FXR in hippocampus, but not medial prefrontal cortex (mPFC). Overexpression of hippocampal FXR induced notable depressive-like behaviors and decreased expression of brain-derived neurotrophic factor (BDNF) in naïve rats, while knockdown of hippocampal FXR fully prevented the effects of CUMS on rat behaviors and hippocampal BDNF expression. Taken together, our research extends the knowledge of FXR's role in the central nervous system, and may provide a potential and novel therapeutic target for treating depression.
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Affiliation(s)
- Wei-Guan Chen
- Department of Rehabilitation Medicine, The Affiliated Hospital of Nantong University, Nantong, Jiangsu 226001, PR China
| | - Jia-Xuan Zheng
- Department of Rehabilitation Medicine, The Affiliated Hospital of Nantong University, Nantong, Jiangsu 226001, PR China
| | - Xi Xu
- Department of Rehabilitation Medicine, The Affiliated Hospital of Nantong University, Nantong, Jiangsu 226001, PR China
| | - Yu-Ming Hu
- Department of Rehabilitation Medicine, The Affiliated Hospital of Nantong University, Nantong, Jiangsu 226001, PR China
| | - Yu-Min Ma
- Department of Internal Medicine, The Second Peoples Hospital of Nantong, No. 43, XingRong Street, Tangzha Town, Nantong, Jiangsu 226002, PR China.
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26
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Hippocampal mTOR signaling is required for the antidepressant effects of paroxetine. Neuropharmacology 2018; 128:181-195. [DOI: 10.1016/j.neuropharm.2017.10.008] [Citation(s) in RCA: 38] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2017] [Revised: 09/07/2017] [Accepted: 10/07/2017] [Indexed: 02/04/2023]
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27
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Mazur-Bialy AI, Pocheć E. Vitamin B2 deficiency enhances the pro-inflammatory activity of adipocyte, consequences for insulin resistance and metabolic syndrome development. Life Sci 2017; 178:9-16. [DOI: 10.1016/j.lfs.2017.04.010] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2017] [Revised: 04/12/2017] [Accepted: 04/13/2017] [Indexed: 12/24/2022]
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28
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Kokras N, Baltas D, Theocharis F, Dalla C. Kinoscope: An Open-Source Computer Program for Behavioral Pharmacologists. Front Behav Neurosci 2017; 11:88. [PMID: 28553211 PMCID: PMC5427106 DOI: 10.3389/fnbeh.2017.00088] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2016] [Accepted: 04/25/2017] [Indexed: 11/25/2022] Open
Abstract
Behavioral analysis in preclinical neuropsychopharmacology relies on the accurate measurement of animal behavior. Several excellent solutions for computer-assisted behavioral analysis are available for specialized behavioral laboratories wishing to invest significant resources. Herein, we present an open source straightforward software solution aiming at the rapid and easy introduction to an experimental workflow, and at the improvement of training staff members in a better and more reproducible manual scoring of behavioral experiments with the use of visual aids-maps. Currently the program readily supports the Forced Swim Test, Novel Object Recognition test and the Elevated Plus maze test, but with minor modifications can be used for scoring virtually any behavioral test. Additional modules, with predefined templates and scoring parameters, are continuously added. Importantly, the prominent use of visual maps has been shown to improve, in a student-engaging manner, the training and auditing of scoring in behavioral rodent experiments.
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Affiliation(s)
- Nikolaos Kokras
- Department of Pharmacology, Medical School, National and Kapodistrian University of AthensAthens, Greece.,First Department of Psychiatry, Medical School, National and Kapodistrian University of AthensAthens, Greece
| | - Dimitrios Baltas
- Department of Pharmacology, Medical School, National and Kapodistrian University of AthensAthens, Greece
| | - Foivos Theocharis
- Department of Pharmacology, Medical School, National and Kapodistrian University of AthensAthens, Greece
| | - Christina Dalla
- Department of Pharmacology, Medical School, National and Kapodistrian University of AthensAthens, Greece
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29
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Liu W, Liu J, Xia J, Xue X, Wang H, Qi Z, Ji L. Leptin receptor knockout-induced depression-like behaviors and attenuated antidepressant effects of exercise are associated with STAT3/SOCS3 signaling. Brain Behav Immun 2017; 61:297-305. [PMID: 28069387 DOI: 10.1016/j.bbi.2017.01.001] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/24/2016] [Revised: 12/24/2016] [Accepted: 01/05/2017] [Indexed: 01/16/2023] Open
Abstract
Relatively little has been known about pathophysiological mechanisms contributing to the development of neuropsychiatric symptoms in the context of metabolic syndrome. Impaired leptin signaling activation in db/db mice has been proposed as a potential link between behavioral and metabolic disorders. Our previous studies have shown that exercise has the beneficial effects on a depression-like and insulin-resistant state in mice. The present study aimed to determine whether and how leptin receptor knockout (db/db) induces depression-like behaviors, and to identify the antidepressant effects of swimming exercise in db/db mice. Our results support the validity of db/db mice as an animal model to study depression with metabolic abnormalities, but fail to confirm the improvement of exercise on depression. LepRb knockout-induced depression-like behaviors are associated with STAT3/SOCS3 signaling but independent of IKKβ/NFκB signaling. Our findings suggest the potential importance of LepRb as an exercise-regulated target for depression, also representing a new target underlying treatment-resistant depression.
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Affiliation(s)
- Weina Liu
- Key Laboratory of Adolescent Health Assessment and Exercise Intervention of Ministry of Education, East China Normal University, Shanghai 200241, China; School of Physical Education & Health Care, East China Normal University, Shanghai 200241, China
| | - Jiatong Liu
- Key Laboratory of Adolescent Health Assessment and Exercise Intervention of Ministry of Education, East China Normal University, Shanghai 200241, China; School of Physical Education & Health Care, East China Normal University, Shanghai 200241, China
| | - Jie Xia
- Key Laboratory of Adolescent Health Assessment and Exercise Intervention of Ministry of Education, East China Normal University, Shanghai 200241, China; School of Physical Education & Health Care, East China Normal University, Shanghai 200241, China
| | - Xiangli Xue
- Key Laboratory of Adolescent Health Assessment and Exercise Intervention of Ministry of Education, East China Normal University, Shanghai 200241, China; School of Physical Education & Health Care, East China Normal University, Shanghai 200241, China
| | - Hongmei Wang
- Key Laboratory of Adolescent Health Assessment and Exercise Intervention of Ministry of Education, East China Normal University, Shanghai 200241, China; School of Physical Education & Health Care, East China Normal University, Shanghai 200241, China
| | - Zhengtang Qi
- Key Laboratory of Adolescent Health Assessment and Exercise Intervention of Ministry of Education, East China Normal University, Shanghai 200241, China; School of Physical Education & Health Care, East China Normal University, Shanghai 200241, China.
| | - Liu Ji
- Key Laboratory of Adolescent Health Assessment and Exercise Intervention of Ministry of Education, East China Normal University, Shanghai 200241, China; School of Physical Education & Health Care, East China Normal University, Shanghai 200241, China.
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30
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Guo J, Chang L, Li C, Li M, Yan P, Guo Z, Wang C, Zha Q, Wang Q. SB203580 reverses memory deficits and depression-like behavior induced by microinjection of Aβ 1-42 into hippocampus of mice. Metab Brain Dis 2017; 32:57-68. [PMID: 27488110 DOI: 10.1007/s11011-016-9880-4] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/07/2016] [Accepted: 07/19/2016] [Indexed: 11/26/2022]
Abstract
A high co-morbidity between Alzheimer's disease (AD) and depression suggests there might be similar mechanisms underlying the course of these diseases. Previous studies have shown that p38MAPK plays a critical role in the pathophysiology of AD and depression. However, little is known about whether SB203580, a selective inhibitor of p38MAPK, may protect against AD-associated cognitive impairments and depression-like behavior, simultaneously. Herein, we have shown, for the first time, that SB203580 may reverse memory impairments and depression-like behavior induced by hippocampal infusion of β-amyloid 1-42 (Aβ1-42), as measured by novel object recognition, Morris water maze, tail-suspension and forced-swimming tests. In addition, phorbol 12-myristate 13-acetate (PMA), a PKC activator which also activates p38MAPK, significantly abolished the effects of SB203580. Moreover, Aβ1-42 causes increased phosphorylation of p38MAPK and decreased phosphorylation of Ser9-glycogen synthase kinase 3β (GSK3β) and cAMP-response element binding protein (CREB) in the hippocampus of mice, which could be significantly reversed by SB203580. Our results suggest that SB203580 reversed Aβ1-42-induced cognitive impairments and depression-like behavior via inhibiting p38MAPK signaling pathway, which not only supports p38MAPK as a therapeutic target for AD-associated cognitive dysfunction and depression-like behavior, but also provides experimental basis for the use of SB203580 in co-morbidity of AD and depression.
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Affiliation(s)
- Jiejie Guo
- Ningbo Key Laboratory of Behavioral Neuroscience, Zhejiang Provincial Key Laboratory of Pathophysiology, School of Medicine, Ningbo University, 818 Fenghua Road, Ningbo, Zhejiang, 315211, People's Republic of China
| | - Lan Chang
- Ningbo Key Laboratory of Behavioral Neuroscience, Zhejiang Provincial Key Laboratory of Pathophysiology, School of Medicine, Ningbo University, 818 Fenghua Road, Ningbo, Zhejiang, 315211, People's Republic of China
| | - Chenli Li
- Ningbo Key Laboratory of Behavioral Neuroscience, Zhejiang Provincial Key Laboratory of Pathophysiology, School of Medicine, Ningbo University, 818 Fenghua Road, Ningbo, Zhejiang, 315211, People's Republic of China
| | - Mengmeng Li
- Ningbo Key Laboratory of Behavioral Neuroscience, Zhejiang Provincial Key Laboratory of Pathophysiology, School of Medicine, Ningbo University, 818 Fenghua Road, Ningbo, Zhejiang, 315211, People's Republic of China
| | - Peiyun Yan
- Ningbo Key Laboratory of Behavioral Neuroscience, Zhejiang Provincial Key Laboratory of Pathophysiology, School of Medicine, Ningbo University, 818 Fenghua Road, Ningbo, Zhejiang, 315211, People's Republic of China
| | - Zhiping Guo
- School of Medicine, Lishui University, Lishui, Zhejiang, 323000, People's Republic of China
| | - Chuang Wang
- Ningbo Key Laboratory of Behavioral Neuroscience, Zhejiang Provincial Key Laboratory of Pathophysiology, School of Medicine, Ningbo University, 818 Fenghua Road, Ningbo, Zhejiang, 315211, People's Republic of China.
| | - Qin Zha
- The Affiliated Hospital of School of Medicine, Ningbo University, Ningbo, Zhejiang, 315200, China.
| | - Qinwen Wang
- Ningbo Key Laboratory of Behavioral Neuroscience, Zhejiang Provincial Key Laboratory of Pathophysiology, School of Medicine, Ningbo University, 818 Fenghua Road, Ningbo, Zhejiang, 315211, People's Republic of China.
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31
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Vinuesa A, Pomilio C, Menafra M, Bonaventura MM, Garay L, Mercogliano MF, Schillaci R, Lux Lantos V, Brites F, Beauquis J, Saravia F. Juvenile exposure to a high fat diet promotes behavioral and limbic alterations in the absence of obesity. Psychoneuroendocrinology 2016; 72:22-33. [PMID: 27337091 DOI: 10.1016/j.psyneuen.2016.06.004] [Citation(s) in RCA: 48] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/27/2016] [Revised: 06/03/2016] [Accepted: 06/04/2016] [Indexed: 01/09/2023]
Abstract
The incidence of metabolic disorders including obesity, type 2 diabetes and metabolic syndrome have seriously increased in the last decades. These diseases - with growing impact in modern societies - constitute major risk factors for neurodegenerative disorders such as Alzheimer's disease (AD), sharing insulin resistance, inflammation and associated cognitive impairment. However, cerebral cellular and molecular pathways involved are not yet clearly understood. Thus, our aim was to study the impact of a non-severe high fat diet (HFD) that resembles western-like alimentary habits, particularly involving juvenile stages where the brain physiology and connectivity are in plain maturation. To this end, one-month-old C57BL/6J male mice were given either a control diet or HFD during 4 months. Exposure to HFD produced metabolic alterations along with changes in behavioral and central parameters, in the absence of obesity. Two-month-old HFD mice showed increased glycemia and plasmatic IL1β but these values normalized at the end of the HFD protocol at 5 months of age, probably representing an acute response that is compensated at later stages. After four months of HFD exposure, mice presented dyslipidemia, increased Lipoprotein-associated phospholipase A2 (Lp-PLA2) activity, hepatic insulin resistance and inflammation. Alterations in the behavioral profile of the HFD group were shown by the impediment in nest building behavior, deficiencies in short and mid-term spatial memories, anxious and depressive- like behavior. Regarding the latter disruptions in emotional processing, we found an increased neural activity in the amygdala, shown by a greater number of c-Fos+ nuclei. We found that hippocampal adult neurogenesis was decreased in HFD mice, showing diminished cell proliferation measured as Ki67+ cells and neuronal differentiation in SGZ by doublecortin labeling. These phenomena were accompanied by a neuroinflammatory and insulin-resistant state in the hippocampus, depicted by a reactive phenotype in Iba1+ microglia cells (increased in number and soma size) and an impaired response to insulin given by decreased phosphorylated Akt levels and increased levels of inhibitory phosphorylation of IRS1. Our data portray a set of alterations in behavioral and neural parameters as a consequence of an early-life exposure to a quite moderate high fat diet, many of which can resemble AD-related features. These results highly emphasize the need to study how metabolic and neurodegenerative disorders are interrelated in deep, thus allowing the finding of successful preventive and therapeutic approaches.
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Affiliation(s)
- Angeles Vinuesa
- Neurobiology of Aging, Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Argentina; Instituto de Biología y Medicina Experimental, CONICET, Buenos Aires, Argentina
| | - Carlos Pomilio
- Neurobiology of Aging, Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Argentina; Instituto de Biología y Medicina Experimental, CONICET, Buenos Aires, Argentina
| | - Martin Menafra
- Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Buenos Aires, Argentina
| | | | - Laura Garay
- Instituto de Biología y Medicina Experimental, CONICET, Buenos Aires, Argentina
| | | | - Roxana Schillaci
- Instituto de Biología y Medicina Experimental, CONICET, Buenos Aires, Argentina
| | - Victoria Lux Lantos
- Instituto de Biología y Medicina Experimental, CONICET, Buenos Aires, Argentina
| | - Fernando Brites
- Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Buenos Aires, Argentina
| | - Juan Beauquis
- Neurobiology of Aging, Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Argentina; Instituto de Biología y Medicina Experimental, CONICET, Buenos Aires, Argentina
| | - Flavia Saravia
- Neurobiology of Aging, Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Argentina; Instituto de Biología y Medicina Experimental, CONICET, Buenos Aires, Argentina.
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Shahjouei S, Ansari S, Pourmotabbed T, Zand R. Potential Roles of Adropin in Central Nervous System: Review of Current Literature. Front Mol Biosci 2016; 3:25. [PMID: 27446928 PMCID: PMC4921473 DOI: 10.3389/fmolb.2016.00025] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2016] [Accepted: 05/27/2016] [Indexed: 01/04/2023] Open
Abstract
Adropin is a 4.9 kDa peptide that is important for maintenance of metabolic and non-metabolic homeostasis. It regulates glucose and fatty acid metabolism and is involved in endothelial cell function and endothelial nitric oxide (NO) synthase bioactivity as well as physical activity and motor coordination. Adropin is expressed in many tissues and organs including central nervous system (CNS). This peptide plays a crucial role in the development of various CNS disorders such as stroke, schizophrenia, bipolar disorder as well as Alzheimer's, Parkinson's, and Huntington's diseases. In this comprehensive review, the potential roles of adropin in cellular signaling pathways that lead to pathogenesis and/or treatment of CNS disorders will be discussed.
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Affiliation(s)
- Shima Shahjouei
- Department of Neurosurgery, Tehran University of Medical Sciences Tehran, Iran
| | - Saeed Ansari
- Department of Neurology, University of Tennessee Health Science Center Memphis, TN, USA
| | - Tayebeh Pourmotabbed
- Department of Microbiology, Immunology, and Biochemistry, University of Tennessee Health Science Center Memphis, TN, USA
| | - Ramin Zand
- Department of Neurology, University of Tennessee Health Science CenterMemphis, TN, USA; Biocomplexity Institute, Virginia Polytechnic Institute and State UniversityBlacksburg, VA, USA
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Veniaminova EA, Strekalova TV. Increased intake of fat and cholesterol as a pathogenetic factor of depression: A possible molecular mechanism. NEUROCHEM J+ 2016. [DOI: 10.1134/s1819712416010153] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
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Woo YS, Seo HJ, McIntyre RS, Bahk WM. Obesity and Its Potential Effects on Antidepressant Treatment Outcomes in Patients with Depressive Disorders: A Literature Review. Int J Mol Sci 2016; 17:ijms17010080. [PMID: 26771598 PMCID: PMC4730324 DOI: 10.3390/ijms17010080] [Citation(s) in RCA: 47] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2015] [Accepted: 01/04/2016] [Indexed: 02/07/2023] Open
Abstract
Accumulating evidence regarding clinical, neurobiological, genetic, and environmental factors suggests a bidirectional link between obesity and depressive disorders. Although a few studies have investigated the link between obesity/excess body weight and the response to antidepressants in depressive disorders, the effect of weight on treatment response remains poorly understood. In this review, we summarized recent data regarding the relationship between the response to antidepressants and obesity/excess body weight in clinical studies of patients with depressive disorders. Although several studies indicated an association between obesity/excess body weight and poor antidepressant responses, it is difficult to draw definitive conclusions due to the variability of subject composition and methodological differences among studies. Especially, differences in sex, age and menopausal status, depressive symptom subtypes, and antidepressants administered may have caused inconsistencies in the results among studies. The relationship between obesity/excess body weight and antidepressant responses should be investigated further in high-powered studies addressing the differential effects on subject characteristics and treatment. Moreover, future research should focus on the roles of mediating factors, such as inflammatory markers and neurocognitive performance, which may alter the antidepressant treatment outcome in patients with comorbid obesity and depressive disorder.
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Affiliation(s)
- Young Sup Woo
- Department of Psychiatry, College of Medicine, the Catholic University of Korea, Seoul 07345, Korea.
- Mood Disorders Psychopharmacology Unit, University Health Network, Toronto, ON M5T 2S8, Canada.
| | - Hye-Jin Seo
- Department of Psychiatry, College of Medicine, the Catholic University of Korea, Seoul 07345, Korea.
| | - Roger S McIntyre
- Mood Disorders Psychopharmacology Unit, University Health Network, Toronto, ON M5T 2S8, Canada.
- Department of Psychiatry, University of Toronto, Toronto, ON M5T 2S8, Canada.
| | - Won-Myong Bahk
- Department of Psychiatry, College of Medicine, the Catholic University of Korea, Seoul 07345, Korea.
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Zemdegs J, Quesseveur G, Jarriault D, Pénicaud L, Fioramonti X, Guiard BP. High-fat diet-induced metabolic disorders impairs 5-HT function and anxiety-like behavior in mice. Br J Pharmacol 2015; 173:2095-110. [PMID: 26472268 DOI: 10.1111/bph.13343] [Citation(s) in RCA: 125] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2015] [Revised: 09/03/2015] [Accepted: 09/09/2015] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND AND PURPOSE The link between type 2 diabetes mellitus (T2DM) and depression is bidirectional. However, the possibility that metabolic disorders may elicit anxiogenic-like/depressive-like symptoms or alter the efficacy of antidepressant drugs remains poorly documented. This study explored the influence of T2DM on emotionality and proposed a therapeutic strategy that might be used in depressed diabetic patients. EXPERIMENTAL APPROACH Mice were fed a high-fat diet (HFD) and subjected to a full comprehensive metabolic and behavioural analysis to establish correlations between metabolic and psychiatric disorders. In vivo intra-hippocampal microdialysis was also applied to propose a mechanism underpinning the phenotype of mice fed the HFD. Finally, we tested whether chronic administration of the selective 5-HT reuptake inhibitor escitalopram or HFD withdrawal could reverse HFD-induced metabolic and behavioural anomalies. KEY RESULTS The increased body weight, hyperglycaemia and impaired glucose tolerance in response to HFD were correlated with anxiogenic-like/depressive-like symptoms. Moreover, this phenotype was associated with decreased extracellular 5-HT levels in the hippocampus which may result from increased sensitivity of the dorsal raphe 5-HT1A autoreceptor. Interestingly, the beneficial effect of prolonged administration of escitalopram was abolished in HFD-fed mice. On the contrary, HFD withdrawal completely reversed metabolic impairments and positively changed symptoms of anxiety, although some behavioural anomalies persisted. CONCLUSIONS AND IMPLICATIONS Our data provide clear-cut evidence that both pathologies are finely correlated and associated with impaired 5-HT mediated neurotransmission in the hippocampus. Further experiments are warranted to define the most adequate strategy for the treatment of such co-morbidity. LINKED ARTICLES This article is part of a themed section on Updating Neuropathology and Neuropharmacology of Monoaminergic Systems. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v173.13/issuetoc.
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Affiliation(s)
- Juliane Zemdegs
- Faculté de Pharmacie, Université Paris Sud XI, Châtenay-Malabry, Cedex, France.,Centre National de la Recherche Scientifique (CNRS), Centre de Recherches sur la Cognition Animale (CRCA) UMR5169, Toulouse, France.,UPS CRCA UMR5169, Université de Toulouse, Toulouse, France.,Center des Sciences du Goût et de l'Alimentation, UMR 6265 CNRS 1324 INRA, Université de Bourgogne Franche-Comté, Dijon, France
| | - Gaël Quesseveur
- Faculté de Pharmacie, Université Paris Sud XI, Châtenay-Malabry, Cedex, France
| | - David Jarriault
- Center des Sciences du Goût et de l'Alimentation, UMR 6265 CNRS 1324 INRA, Université de Bourgogne Franche-Comté, Dijon, France
| | - Luc Pénicaud
- Center des Sciences du Goût et de l'Alimentation, UMR 6265 CNRS 1324 INRA, Université de Bourgogne Franche-Comté, Dijon, France
| | - Xavier Fioramonti
- Center des Sciences du Goût et de l'Alimentation, UMR 6265 CNRS 1324 INRA, Université de Bourgogne Franche-Comté, Dijon, France
| | - Bruno P Guiard
- Faculté de Pharmacie, Université Paris Sud XI, Châtenay-Malabry, Cedex, France.,Centre National de la Recherche Scientifique (CNRS), Centre de Recherches sur la Cognition Animale (CRCA) UMR5169, Toulouse, France.,UPS CRCA UMR5169, Université de Toulouse, Toulouse, France
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