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Liu Y, Gu R, Gao M, Wei Y, Shi Y, Wang X, Gu Y, Gu X, Zhang H. Emerging role of substance and energy metabolism associated with neuroendocrine regulation in tumor cells. Front Endocrinol (Lausanne) 2023; 14:1126271. [PMID: 37051193 PMCID: PMC10084767 DOI: 10.3389/fendo.2023.1126271] [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: 12/17/2022] [Accepted: 02/07/2023] [Indexed: 03/29/2023] Open
Abstract
Cancer is the second most common cause of mortality in the world. One of the unresolved difficult pathological mechanism issues in malignant tumors is the imbalance of substance and energy metabolism of tumor cells. Cells maintain life through energy metabolism, and normal cells provide energy through mitochondrial oxidative phosphorylation to generate ATP, while tumor cells demonstrate different energy metabolism. Neuroendocrine control is crucial for tumor cells' consumption of nutrients and energy. As a result, better combinatorial therapeutic approaches will be made possible by knowing the neuroendocrine regulating mechanism of how the neuroendocrine system can fuel cellular metabolism. Here, the basics of metabolic remodeling in tumor cells for nutrients and metabolites are presented, showing how the neuroendocrine system regulates substance and energy metabolic pathways to satisfy tumor cell proliferation and survival requirements. In this context, targeting neuroendocrine regulatory pathways in tumor cell metabolism can beneficially enhance or temper tumor cell metabolism and serve as promising alternatives to available treatments.
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Affiliation(s)
- Yingying Liu
- Institute for Immunology and School of Medicine, Tsinghua University, Beijing, China
- School of Chinese Medicine and School of Integrated Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Renjun Gu
- School of Chinese Medicine and School of Integrated Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Murong Gao
- Beijing Rehabilitation Hospital Affiliated to Capital Medical University, Beijing, China
| | - Yangwa Wei
- Department of Hepatobiliary Surgery, Hainan Provincial People’s Hospital, Haikou, China
| | - Yu Shi
- Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
| | - Xu Wang
- School of Basic Medical Sciences, Fujian Medical University, Fuzhou, China
| | - Yihuang Gu
- School of Acupuncture and Tuina, School of Regimen and Rehabilitation, Nanjing University of Chinese Medicine, Nanjing, China
- The Second Hospital of Nanjing, Nanjing, China
- *Correspondence: Hongru Zhang, ; Xin Gu, ; Yihuang Gu,
| | - Xin Gu
- School of Chinese Medicine and School of Integrated Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China
- *Correspondence: Hongru Zhang, ; Xin Gu, ; Yihuang Gu,
| | - Hongru Zhang
- School of Chinese Medicine and School of Integrated Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China
- *Correspondence: Hongru Zhang, ; Xin Gu, ; Yihuang Gu,
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2
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Vohra MS, Benchoula K, Serpell CJ, Hwa WE. AgRP/NPY and POMC neurons in the arcuate nucleus and their potential role in treatment of obesity. Eur J Pharmacol 2022; 915:174611. [PMID: 34798121 DOI: 10.1016/j.ejphar.2021.174611] [Citation(s) in RCA: 85] [Impact Index Per Article: 28.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2021] [Revised: 10/27/2021] [Accepted: 10/27/2021] [Indexed: 02/08/2023]
Abstract
Obesity is a major health crisis affecting over a third of the global population. This multifactorial disease is regulated via interoceptive neural circuits in the brain, whose alteration results in excessive body weight. Certain central neuronal populations in the brain are recognised as crucial nodes in energy homeostasis; in particular, the hypothalamic arcuate nucleus (ARC) region contains two peptide microcircuits that control energy balance with antagonistic functions: agouti-related peptide/neuropeptide-Y (AgRP/NPY) signals hunger and stimulates food intake; and pro-opiomelanocortin (POMC) signals satiety and reduces food intake. These neuronal peptides levels react to energy status and integrate signals from peripheral ghrelin, leptin, and insulin to regulate feeding and energy expenditure. To manage obesity comprehensively, it is crucial to understand cellular and molecular mechanisms of information processing in ARC neurons, since these regulate energy homeostasis. Importantly, a specific strategy focusing on ARC circuits needs to be devised to assist in treating obese patients and maintaining weight loss with minimal or no side effects. The aim of this review is to elucidate the recent developments in the study of AgRP-, NPY- and POMC-producing neurons, specific to their role in controlling metabolism. The impact of ghrelin, leptin, and insulin signalling via action of these neurons is also surveyed, since they also impact energy balance through this route. Lastly, we present key proteins, targeted genes, compounds, drugs, and therapies that actively work via these neurons and could potentially be used as therapeutic targets for treating obesity conditions.
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Affiliation(s)
- Muhammad Sufyan Vohra
- School of Medicine, Faculty of Health and Medical Sciences, Taylor's University Lakeside Campus, 47500, Subang Jaya, Selangor Darul Ehsan, Malaysia
| | - Khaled Benchoula
- School of Medicine, Faculty of Health and Medical Sciences, Taylor's University Lakeside Campus, 47500, Subang Jaya, Selangor Darul Ehsan, Malaysia
| | - Christopher J Serpell
- School of Physical Sciences, Ingram Building, University of Kent, Canterbury, Kent, CT2 7NH, United Kingdom
| | - Wong Eng Hwa
- School of Medicine, Faculty of Health and Medical Sciences, Taylor's University Lakeside Campus, 47500, Subang Jaya, Selangor Darul Ehsan, Malaysia.
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Cano G, Hernan SL, Sved AF. Centrally Projecting Edinger-Westphal Nucleus in the Control of Sympathetic Outflow and Energy Homeostasis. Brain Sci 2021; 11:1005. [PMID: 34439626 PMCID: PMC8392615 DOI: 10.3390/brainsci11081005] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2021] [Revised: 07/13/2021] [Accepted: 07/20/2021] [Indexed: 11/16/2022] Open
Abstract
The centrally projecting Edinger-Westphal nucleus (EWcp) is a midbrain neuronal group, adjacent but segregated from the preganglionic Edinger-Westphal nucleus that projects to the ciliary ganglion. The EWcp plays a crucial role in stress responses and in maintaining energy homeostasis under conditions that require an adjustment of energy expenditure, by virtue of modulating heart rate and blood pressure, thermogenesis, food intake, and fat and glucose metabolism. This modulation is ultimately mediated by changes in the sympathetic outflow to several effector organs, including the adrenal gland, heart, kidneys, brown and white adipose tissues and pancreas, in response to environmental conditions and the animal's energy state, providing for appropriate energy utilization. Classic neuroanatomical studies have shown that the EWcp receives inputs from forebrain regions involved in these functions and projects to presympathetic neuronal populations in the brainstem. Transneuronal tracing with pseudorabies virus has demonstrated that the EWcp is connected polysynaptically with central circuits that provide sympathetic innervation to all these effector organs that are critical for stress responses and energy homeostasis. We propose that EWcp integrates multimodal signals (stress, thermal, metabolic, endocrine, etc.) and modulates the sympathetic output simultaneously to multiple effector organs to maintain energy homeostasis under different conditions that require adjustments of energy demands.
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Affiliation(s)
- Georgina Cano
- Department of Neuroscience, A210 Langley Hall, University of Pittsburgh, Pittsburgh, PA 15260, USA; (S.L.H.); (A.F.S.)
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Nilsson IAK, Hökfelt T, Schalling M. The Anorectic Phenotype of the anx/anx Mouse Is Associated with Hypothalamic Dysfunction. NEUROMETHODS 2021:297-317. [DOI: 10.1007/978-1-0716-0924-8_16] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2025]
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Pulver A, Kiive E, Kanarik M, Harro J. Association of orexin/hypocretin receptor gene (HCRTR1) with reward sensitivity, and interaction with gender. Brain Res 2020; 1746:147013. [PMID: 32652147 DOI: 10.1016/j.brainres.2020.147013] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2020] [Revised: 07/02/2020] [Accepted: 07/06/2020] [Indexed: 12/12/2022]
Abstract
Orexins/hypocretins maintain wakefulness, increase appetite and participate in the coordination of stress response. We have recently provided evidence on the role of orexins in aggression, showing the association of the HCRTR1 genotype. (rs2271933 G > A; leading to amino acid substitution Ile408Val) with aggressiveness or breach of law in four independent cohorts. Aggressive behaviour can be reward driven and hence we have examined the association of HCRTR1 rs2271933 genotype with different aspects of reward sensitivity in the birth cohort representative Estonian Children Personality Behaviour and Health Study. HCRTR1 genotype was associated with reward sensitivity in a gender dependent manner. Male HCRTR1 A/A homozygotes had higher Openness to Rewards and the overall reward sensitivity score while, in contrast, female A/A homozygotes scored lower than G-allele carriers in Openness to Rewards. In the total sample, aggressiveness correlated positively with reward sensitivity, but this was on account of Insatiability by Reward. In contrast, the HCRTR1 A/A homozygotes had a positive association of aggressiveness and Openness to Rewards. Experience of stressful life events had a small but significant increasing effect on both aspects of reward sensitivity, and correlated in an anomalous way with reward sensitivity in the HCRTR1 A/A homozygotes. Conclusively, the higher aggressiveness of HCRTR1 A/A homozygotes appears based on a qualitative difference in sensitivity to rewards, in the form that suggests their lower ability to prevent responses to challenges being converted into overt aggression.
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Affiliation(s)
- Aleksander Pulver
- School of Natural Sciences and Health, Tallinn University, Narva Road 29, Astra Building, 10120 Tallinn, Estonia
| | - Evelyn Kiive
- Division of Special Education, Department of Education, University of Tartu, Näituse 2, 50409 Tartu, Estonia
| | - Margus Kanarik
- Division of Neuropsychopharmacology, Department of Psychology, University of Tartu, Ravila 14A Chemicum, 50411 Tartu, Estonia
| | - Jaanus Harro
- School of Natural Sciences and Health, Tallinn University, Narva Road 29, Astra Building, 10120 Tallinn, Estonia; Division of Neuropsychopharmacology, Department of Psychology, University of Tartu, Ravila 14A Chemicum, 50411 Tartu, Estonia.
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Sato T, Nemoto T, Hasegawa K, Ida T, Kojima M. A new action of peptide hormones for survival in a low-nutrient environment. Endocr J 2019; 66:943-952. [PMID: 31564683 DOI: 10.1507/endocrj.ej19-0274] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
Abstract
Malnutrition occurs when nutrient intake is too low for any reason and occurs regardless of gender or age. Therefore, besides loss of eating or digestive functionality due to illness, malnutrition can occur when a healthy individual undergoes an extreme diet and biases their nutrition, or when athletes exerts more energy than they can replenish through food. It has recently been reported that in Japan, the mortality rate of leaner individuals is equal to or higher than that of obese people. It is important to understand what homeostatic maintenance mechanism is behind this when the body is under hypotrophic conditions. Such mechanisms are generally endocranially controlled. We address this fundamental concern in this paper by focusing on peptide hormones. We introduce a mechanism for survival in a malnourished state via the regulation of food intake and temperature. Additionally, we will discuss the latest findings and future prospects for research on changes in the endocrine environment associated with malnutrition associated with exercise. We also review changes in next-generation endocrine environments when caused by malnutrition brought on by dieting.
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Affiliation(s)
- Takahiro Sato
- Division of Molecular Genetics, Institute of Life Science, Kurume University, Kurume, Fukuoka 830-0011, Japan
| | - Takahiro Nemoto
- Department of Physiology, Nippon Medical School, Bunkyo-ku, Tokyo 113-8602, Japan
| | - Kazuya Hasegawa
- Faculty of Nutritional Science, The University of Morioka, Takizawa, Iwate 020-0694, Japan
| | - Takanori Ida
- Division for Searching and Identification of Bioactive Peptides, Department of Bioactive Peptides, Frontier Science Research Center, University of Miyazaki, Kiyotake, Miyazaki 889-1692, Japan
| | - Masayasu Kojima
- Division of Molecular Genetics, Institute of Life Science, Kurume University, Kurume, Fukuoka 830-0011, Japan
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Harro J, Laas K, Eensoo D, Kurrikoff T, Sakala K, Vaht M, Parik J, Mäestu J, Veidebaum T. Orexin/hypocretin receptor gene (HCRTR1) variation is associated with aggressive behaviour. Neuropharmacology 2019; 156:107527. [DOI: 10.1016/j.neuropharm.2019.02.009] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2018] [Revised: 01/11/2019] [Accepted: 02/06/2019] [Indexed: 12/01/2022]
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Wijdicks EFM. Stomaching Acute Brain Injury. Neurocrit Care 2019; 30:542-545. [PMID: 30771087 DOI: 10.1007/s12028-019-00685-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/01/2022]
Abstract
Gastrointestinal complications, including hemorrhage, can occur with intracranial lesions and after craniotomy. As early as the 19th century, surgeons were aware that brain tumors could cause gastric ulcers and acute perforations. Investigators used animal experiments both to reproduce these clinical observations and to seek ways to block the effects. Gastrointestinal lesions were seen as a result of the stress of acute brain injury or as a direct consequence of brain surgery. The thinking at the time was markedly influenced by the presumed stress and psychic factors proposed by Cannon. This historical vignette summarizes the major experimental works linking the brain with the stomach.
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Affiliation(s)
- Eelco F M Wijdicks
- Department of Neurology, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA.
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Güemes A, Georgiou P. Review of the role of the nervous system in glucose homoeostasis and future perspectives towards the management of diabetes. Bioelectron Med 2018; 4:9. [PMID: 32232085 PMCID: PMC7098234 DOI: 10.1186/s42234-018-0009-4] [Citation(s) in RCA: 38] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2018] [Accepted: 06/10/2018] [Indexed: 12/16/2022] Open
Abstract
Diabetes is a disease caused by a breakdown in the glucose metabolic process resulting in abnormal blood glucose fluctuations. Traditionally, control has involved external insulin injection in response to elevated blood glucose to substitute the role of the beta cells in the pancreas which would otherwise perform this function in a healthy individual. The central nervous system (CNS), however, also plays a vital role in glucose homoeostasis through the control of pancreatic secretion and insulin sensitivity which could potentially be used as a pathway for enhancing glucose control. In this review, we present an overview of the brain regions, peripheral nerves and molecular mechanisms by which the CNS regulates glucose metabolism and the potential benefits of modulating them for diabetes management. Development of technologies to interface to the nervous system will soon become a reality through bioelectronic medicine and we present the emerging opportunities for the treatment of type 1 and type 2 diabetes.
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Affiliation(s)
- Amparo Güemes
- Centre for Bio-Inspired Technology, Department of Electrical and Electronic Engineering, Imperial College London, South Kensington Campus, London, UK
| | - Pantelis Georgiou
- Centre for Bio-Inspired Technology, Department of Electrical and Electronic Engineering, Imperial College London, South Kensington Campus, London, UK
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Anandhakrishnan A, Korbonits M. Glucagon-like peptide 1 in the pathophysiology and pharmacotherapy of clinical obesity. World J Diabetes 2016; 7:572-598. [PMID: 28031776 PMCID: PMC5155232 DOI: 10.4239/wjd.v7.i20.572] [Citation(s) in RCA: 49] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/14/2016] [Revised: 09/26/2016] [Accepted: 10/18/2016] [Indexed: 02/05/2023] Open
Abstract
Though the pathophysiology of clinical obesity is undoubtedly multifaceted, several lines of clinical evidence implicate an important functional role for glucagon-like peptide 1 (GLP-1) signalling. Clinical studies assessing GLP-1 responses in normal weight and obese subjects suggest that weight gain may induce functional deficits in GLP-1 signalling that facilitates maintenance of the obesity phenotype. In addition, genetic studies implicate a possible role for altered GLP-1 signalling as a risk factor towards the development of obesity. As reductions in functional GLP-1 signalling seem to play a role in clinical obesity, the pharmacological replenishment seems a promising target for the medical management of obesity in clinical practice. GLP-1 analogue liraglutide at a high dose (3 mg/d) has shown promising results in achieving and maintaining greater weight loss in obese individuals compared to placebo control, and currently licensed anti-obesity medications. Generally well tolerated, provided that longer-term data in clinical practice supports the currently available evidence of superior short- and long-term weight loss efficacy, GLP-1 analogues provide promise towards achieving the successful, sustainable medical management of obesity that remains as yet, an unmet clinical need.
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11
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Bean TG, Boxall ABA, Lane J, Herborn KA, Pietravalle S, Arnold KE. Behavioural and physiological responses of birds to environmentally relevant concentrations of an antidepressant. Philos Trans R Soc Lond B Biol Sci 2015; 369:rstb.2013.0575. [PMID: 25405964 DOI: 10.1098/rstb.2013.0575] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
Many wildlife species forage on sewage-contaminated food, for example, at wastewater treatment plants and on fields fertilized with sewage sludge. The resultant exposure to human pharmaceuticals remains poorly studied for terrestrial species. On the basis of predicted exposure levels in the wild, we administered the common antidepressant fluoxetine (FLUOX) or control treatment via prey to wild-caught starlings (Sturnus vulgaris) for 22 weeks over winter. To investigate responses to fluoxetine, birds were moved from their group aviaries into individual cages for 2 days. Boldness, exploration and activity levels showed no treatment effects but controls and FLUOX birds habituated differently to isolation in terms of the concentration of corticosterone (CORT) metabolites in faeces. The controls that excreted higher concentrations of CORT metabolites on day 1 lost more body mass by day 2 of isolation than those which excreted lower levels of CORT metabolites. CORT metabolites and mass loss were unrelated in FLUOX birds. When we investigated the movements of birds in their group aviaries, we found the controls made a higher frequency of visits to food trays than FLUOX birds around the important foraging periods of sunrise and sunset, as is optimal for wintering birds. Although individual variability makes interpreting the sub-lethal endpoints measured challenging, our data suggest that fluoxetine at environmentally relevant concentrations can significantly alter behaviour and physiology.
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Affiliation(s)
- Tom G Bean
- Environment Department, University of York, York YO10 5DD, UK
| | | | - Julie Lane
- National Wildlife Management Centre, Animal Health and Veterinary Laboratories Agency, York YO41 1LZ, UK
| | - Katherine A Herborn
- Institute of Biodiversity, Animal Health and Comparative Medicine, University of Glasgow, Glasgow G12 8QQ, UK
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Joly-Amado A, Cansell C, Denis RGP, Delbes AS, Castel J, Martinez S, Luquet S. The hypothalamic arcuate nucleus and the control of peripheral substrates. Best Pract Res Clin Endocrinol Metab 2014; 28:725-37. [PMID: 25256767 DOI: 10.1016/j.beem.2014.03.003] [Citation(s) in RCA: 102] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/25/2022]
Abstract
The arcuate nucleus (ARC) of the hypothalamus is particularly regarded as a critical platform that integrates circulating signals of hunger and satiety reflecting energy stores and nutrient availability. Among ARC neurons, pro-opiomelanocortin (POMC) and agouti-related protein and neuropeptide Y (NPY/AgRP neurons) are considered as two opposing branches of the melanocortin signaling pathway. Integration of circulating signals of hunger and satiety results in the release of the melanocortin receptor ligand α-melanocyte-stimulating hormone (αMSH) by the POMC neurons system and decreases feeding and increases energy expenditure. The orexigenic/anabolic action of NPY/AgRP neurons is believed to rely essentially on their inhibitory input onto POMC neurons and second-orders targets. Recent updates in the field have casted a new light on the role of the ARC neurons in the coordinated regulation of peripheral organs involved in the control of nutrient storage, transformation and substrate utilization independent of food intake.
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Affiliation(s)
- Aurélie Joly-Amado
- Univ Paris Diderot, Sorbonne Paris Cité, Unité de Biologie Fonctionnelle et Adaptative (BFA) UMR 8251 CNRS, F-75205 Paris, France
| | - Céline Cansell
- Univ Paris Diderot, Sorbonne Paris Cité, Unité de Biologie Fonctionnelle et Adaptative (BFA) UMR 8251 CNRS, F-75205 Paris, France
| | - Raphaël G P Denis
- Univ Paris Diderot, Sorbonne Paris Cité, Unité de Biologie Fonctionnelle et Adaptative (BFA) UMR 8251 CNRS, F-75205 Paris, France
| | - Anne-Sophie Delbes
- Univ Paris Diderot, Sorbonne Paris Cité, Unité de Biologie Fonctionnelle et Adaptative (BFA) UMR 8251 CNRS, F-75205 Paris, France
| | - Julien Castel
- Univ Paris Diderot, Sorbonne Paris Cité, Unité de Biologie Fonctionnelle et Adaptative (BFA) UMR 8251 CNRS, F-75205 Paris, France
| | - Sarah Martinez
- Univ Paris Diderot, Sorbonne Paris Cité, Unité de Biologie Fonctionnelle et Adaptative (BFA) UMR 8251 CNRS, F-75205 Paris, France
| | - Serge Luquet
- Univ Paris Diderot, Sorbonne Paris Cité, Unité de Biologie Fonctionnelle et Adaptative (BFA) UMR 8251 CNRS, F-75205 Paris, France.
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Vogt MC, Paeger L, Hess S, Steculorum SM, Awazawa M, Hampel B, Neupert S, Nicholls HT, Mauer J, Hausen AC, Predel R, Kloppenburg P, Horvath TL, Brüning JC. Neonatal insulin action impairs hypothalamic neurocircuit formation in response to maternal high-fat feeding. Cell 2014; 156:495-509. [PMID: 24462248 DOI: 10.1016/j.cell.2014.01.008] [Citation(s) in RCA: 271] [Impact Index Per Article: 24.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2013] [Revised: 12/04/2013] [Accepted: 01/06/2014] [Indexed: 11/17/2022]
Abstract
Maternal metabolic homeostasis exerts long-term effects on the offspring's health outcomes. Here, we demonstrate that maternal high-fat diet (HFD) feeding during lactation predisposes the offspring for obesity and impaired glucose homeostasis in mice, which is associated with an impairment of the hypothalamic melanocortin circuitry. Whereas the number and neuropeptide expression of anorexigenic proopiomelanocortin (POMC) and orexigenic agouti-related peptide (AgRP) neurons, electrophysiological properties of POMC neurons, and posttranslational processing of POMC remain unaffected in response to maternal HFD feeding during lactation, the formation of POMC and AgRP projections to hypothalamic target sites is severely impaired. Abrogating insulin action in POMC neurons of the offspring prevents altered POMC projections to the preautonomic paraventricular nucleus of the hypothalamus (PVH), pancreatic parasympathetic innervation, and impaired glucose-stimulated insulin secretion in response to maternal overnutrition. These experiments reveal a critical timing, when altered maternal metabolism disrupts metabolic homeostasis in the offspring via impairing neuronal projections, and show that abnormal insulin signaling contributes to this effect.
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Affiliation(s)
- Merly C Vogt
- Max Planck Institute for Neurological Research, 50931 Cologne, Germany; Department of Mouse Genetics and Metabolism, Institute for Genetics, University of Cologne, 50674 Cologne, Germany; Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases (CECAD) and Center of Molecular Medicine Cologne (CMMC), University of Cologne, 50674 Cologne, Germany
| | - Lars Paeger
- Biocenter, Institute for Zoology, University of Cologne, 50674 Cologne, Germany; Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases (CECAD) and Center of Molecular Medicine Cologne (CMMC), University of Cologne, 50674 Cologne, Germany
| | - Simon Hess
- Biocenter, Institute for Zoology, University of Cologne, 50674 Cologne, Germany; Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases (CECAD) and Center of Molecular Medicine Cologne (CMMC), University of Cologne, 50674 Cologne, Germany
| | - Sophie M Steculorum
- Max Planck Institute for Neurological Research, 50931 Cologne, Germany; Department of Mouse Genetics and Metabolism, Institute for Genetics, University of Cologne, 50674 Cologne, Germany; Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases (CECAD) and Center of Molecular Medicine Cologne (CMMC), University of Cologne, 50674 Cologne, Germany
| | - Motoharu Awazawa
- Max Planck Institute for Neurological Research, 50931 Cologne, Germany; Department of Mouse Genetics and Metabolism, Institute for Genetics, University of Cologne, 50674 Cologne, Germany; Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases (CECAD) and Center of Molecular Medicine Cologne (CMMC), University of Cologne, 50674 Cologne, Germany
| | - Brigitte Hampel
- Max Planck Institute for Neurological Research, 50931 Cologne, Germany; Department of Mouse Genetics and Metabolism, Institute for Genetics, University of Cologne, 50674 Cologne, Germany; Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases (CECAD) and Center of Molecular Medicine Cologne (CMMC), University of Cologne, 50674 Cologne, Germany
| | - Susanne Neupert
- Biocenter, Institute for Zoology, University of Cologne, 50674 Cologne, Germany
| | - Hayley T Nicholls
- Max Planck Institute for Neurological Research, 50931 Cologne, Germany; Department of Mouse Genetics and Metabolism, Institute for Genetics, University of Cologne, 50674 Cologne, Germany; Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases (CECAD) and Center of Molecular Medicine Cologne (CMMC), University of Cologne, 50674 Cologne, Germany
| | - Jan Mauer
- Max Planck Institute for Neurological Research, 50931 Cologne, Germany; Department of Mouse Genetics and Metabolism, Institute for Genetics, University of Cologne, 50674 Cologne, Germany; Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases (CECAD) and Center of Molecular Medicine Cologne (CMMC), University of Cologne, 50674 Cologne, Germany
| | - A Christine Hausen
- Max Planck Institute for Neurological Research, 50931 Cologne, Germany; Department of Mouse Genetics and Metabolism, Institute for Genetics, University of Cologne, 50674 Cologne, Germany; Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases (CECAD) and Center of Molecular Medicine Cologne (CMMC), University of Cologne, 50674 Cologne, Germany
| | - Reinhard Predel
- Biocenter, Institute for Zoology, University of Cologne, 50674 Cologne, Germany
| | - Peter Kloppenburg
- Biocenter, Institute for Zoology, University of Cologne, 50674 Cologne, Germany; Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases (CECAD) and Center of Molecular Medicine Cologne (CMMC), University of Cologne, 50674 Cologne, Germany
| | - Tamas L Horvath
- Program in Integrative Cell Signaling and Neurobiology of Metabolism, Section of Comparative Medicine, Department of Obstetrics/Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06510, USA.
| | - Jens C Brüning
- Max Planck Institute for Neurological Research, 50931 Cologne, Germany; Department of Mouse Genetics and Metabolism, Institute for Genetics, University of Cologne, 50674 Cologne, Germany; Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases (CECAD) and Center of Molecular Medicine Cologne (CMMC), University of Cologne, 50674 Cologne, Germany; Center for Endocrinology, Diabetes and Preventive Medicine (CEDP), University Hospital Cologne, 50924 Cologne, Germany.
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Denis RGP, Joly-Amado A, Cansell C, Castel J, Martinez S, Delbes AS, Luquet S. Central orchestration of peripheral nutrient partitioning and substrate utilization: implications for the metabolic syndrome. DIABETES & METABOLISM 2013; 40:191-7. [PMID: 24332017 DOI: 10.1016/j.diabet.2013.11.002] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/18/2013] [Accepted: 11/11/2013] [Indexed: 12/24/2022]
Abstract
Energy homoeostasis is maintained through a complex interplay of nutrient intake and energy expenditure. The central nervous system is an essential component of this regulation, as it integrates circulating signals of hunger and satiety to develop adaptive responses at the behavioural and metabolic levels, while the hypothalamus is regarded as a particularly crucial structure in the brain in terms of energy homoeostasis. The arcuate nucleus (ARC) of the hypothalamus contains at least two intermingled neuronal populations: the neurons that produce neuropeptide Y (NPY); and the Agouti-related protein (AgRP) produced by AgRP/NPY neurons situated below the third ventricle in close proximity to proopiomelanocortin (POMC)-producing neurons. POMC neurons exert their catabolic and anorectic actions by releasing α-melanocyte-stimulating hormone (α-MSH), while AgRP neurons oppose this action by exerting tonic GABAergic inhibition of POMC neurons and releasing the melanocortin receptor inverse agonist AgRP. The release of neurotransmitters and neuropeptides by second-order AgRP neurons appears to take place on a multiple time scale, thereby allowing neuromodulation of preganglionic neuronal activity and subsequent control of nutrient partitioning - in other words, the coordinated regulation of conversion, storage and utilization of carbohydrates vs. lipids. This suggests that the function of AgRP neurons extends beyond the strict regulation of feeding to the regulation of efferent organ activity, such that AgRP neurons may now be viewed as an important bridge between central detection of nutrient availability and peripheral nutrient partitioning, thus providing a mechanistic link between obesity and obesity-related disorders.
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Affiliation(s)
- R G P Denis
- Unité « biologie fonctionnelle et adaptative » (BFA), université Paris Diderot-Paris 7, CNRS EAC 4413, 4, rue Marie-Andrée-Lagroua-Weill-Hallé, bâtiment Buffon, case courrier 7126, 75205 Paris cedex 13, France
| | - A Joly-Amado
- Unité « biologie fonctionnelle et adaptative » (BFA), université Paris Diderot-Paris 7, CNRS EAC 4413, 4, rue Marie-Andrée-Lagroua-Weill-Hallé, bâtiment Buffon, case courrier 7126, 75205 Paris cedex 13, France
| | - C Cansell
- Unité « biologie fonctionnelle et adaptative » (BFA), université Paris Diderot-Paris 7, CNRS EAC 4413, 4, rue Marie-Andrée-Lagroua-Weill-Hallé, bâtiment Buffon, case courrier 7126, 75205 Paris cedex 13, France
| | - J Castel
- Unité « biologie fonctionnelle et adaptative » (BFA), université Paris Diderot-Paris 7, CNRS EAC 4413, 4, rue Marie-Andrée-Lagroua-Weill-Hallé, bâtiment Buffon, case courrier 7126, 75205 Paris cedex 13, France; Centre national de la recherche scientifique-CNRS, EAC 4413, 75205 Paris, France
| | - S Martinez
- Unité « biologie fonctionnelle et adaptative » (BFA), université Paris Diderot-Paris 7, CNRS EAC 4413, 4, rue Marie-Andrée-Lagroua-Weill-Hallé, bâtiment Buffon, case courrier 7126, 75205 Paris cedex 13, France; Centre national de la recherche scientifique-CNRS, EAC 4413, 75205 Paris, France
| | - A S Delbes
- Unité « biologie fonctionnelle et adaptative » (BFA), université Paris Diderot-Paris 7, CNRS EAC 4413, 4, rue Marie-Andrée-Lagroua-Weill-Hallé, bâtiment Buffon, case courrier 7126, 75205 Paris cedex 13, France; Centre national de la recherche scientifique-CNRS, EAC 4413, 75205 Paris, France
| | - S Luquet
- Unité « biologie fonctionnelle et adaptative » (BFA), université Paris Diderot-Paris 7, CNRS EAC 4413, 4, rue Marie-Andrée-Lagroua-Weill-Hallé, bâtiment Buffon, case courrier 7126, 75205 Paris cedex 13, France; Centre national de la recherche scientifique-CNRS, EAC 4413, 75205 Paris, France.
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15
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Avraham Y, Katzhendler J, Vorobeiv L, Merchavia S, Listman C, Kunkes E, Harfoush F, Salameh S, Ezra AF, Grigoriadis NC, Berry EM, Najajreh Y. Novel Acylethanolamide Derivatives That Modulate Body Weight through Enhancement of Hypothalamic Pro-Opiomelanocortin (POMC) and/or Decreased Neuropeptide Y (NPY). J Med Chem 2013; 56:1811-29. [DOI: 10.1021/jm300484d] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Affiliation(s)
- Yosefa Avraham
- Department of Human Nutrition
and Metabolism, Braun School of Public Health, Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel
| | - Jehoshua Katzhendler
- Institute of Drug Research,
School of Pharmacy, Faculty of Medicine, Hebrew University of Jerusalem, 91120 Jerusalem, Israel
| | - Lia Vorobeiv
- Department of Human Nutrition
and Metabolism, Braun School of Public Health, Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel
| | - Shira Merchavia
- Department of Human Nutrition
and Metabolism, Braun School of Public Health, Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel
| | - Chana Listman
- Department of Human Nutrition
and Metabolism, Braun School of Public Health, Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel
| | - Eithan Kunkes
- Department of Human Nutrition
and Metabolism, Braun School of Public Health, Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel
| | - Fida’ Harfoush
- Anticancer Drugs Research Lab,
Faculty of Pharmacy, Al-Quds University, Abu-Dies, P.O. Box 20002, Jerusalem, Palestinian Authority
| | - Sawsan Salameh
- Anticancer Drugs Research Lab,
Faculty of Pharmacy, Al-Quds University, Abu-Dies, P.O. Box 20002, Jerusalem, Palestinian Authority
| | - Aviva F. Ezra
- Institute of Drug Research,
School of Pharmacy, Faculty of Medicine, Hebrew University of Jerusalem, 91120 Jerusalem, Israel
| | - Nikolaos C. Grigoriadis
- Department of Neurology, AHEPA University Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Elliot M. Berry
- Department of Human Nutrition
and Metabolism, Braun School of Public Health, Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel
| | - Yousef Najajreh
- Anticancer Drugs Research Lab,
Faculty of Pharmacy, Al-Quds University, Abu-Dies, P.O. Box 20002, Jerusalem, Palestinian Authority
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16
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17
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18
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Hypothalamic AgRP-neurons control peripheral substrate utilization and nutrient partitioning. EMBO J 2012; 31:4276-88. [PMID: 22990237 DOI: 10.1038/emboj.2012.250] [Citation(s) in RCA: 101] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2012] [Accepted: 08/16/2012] [Indexed: 12/11/2022] Open
Abstract
Obesity-related diseases such as diabetes and dyslipidemia result from metabolic alterations including the defective conversion, storage and utilization of nutrients, but the central mechanisms that regulate this process of nutrient partitioning remain elusive. As positive regulators of feeding behaviour, agouti-related protein (AgRP) producing neurons are indispensible for the hypothalamic integration of energy balance. Here, we demonstrate a role for AgRP-neurons in the control of nutrient partitioning. We report that ablation of AgRP-neurons leads to a change in autonomic output onto liver, muscle and pancreas affecting the relative balance between lipids and carbohydrates metabolism. As a consequence, mice lacking AgRP-neurons become obese and hyperinsulinemic on regular chow but display reduced body weight gain and paradoxical improvement in glucose tolerance on high-fat diet. These results provide a direct demonstration of a role for AgRP-neurons in the coordination of efferent organ activity and nutrient partitioning, providing a mechanistic link between obesity and obesity-related disorders.
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19
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Fu RG, Wang L, Yao GL, Xue RL, Ge H, Ren ST, Ma LQ, Jiang HL, Liu X. Chronic Renal Failure Impacts the Expression of Ghrelin and Its Receptor in Hypothalamus and Hippocampus. Ren Fail 2012; 34:1027-32. [DOI: 10.3109/0886022x.2012.708379] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
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20
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Weaver C, Turner N, Hall J. Review of the neuroanatomic landscape implicated in glucose sensing and regulation of nutrient signaling: immunophenotypic localization of diabetes gene Tcf7l2 in the developing murine brain. J Chem Neuroanat 2012; 45:1-17. [PMID: 22796301 DOI: 10.1016/j.jchemneu.2012.06.002] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2012] [Revised: 06/12/2012] [Accepted: 06/19/2012] [Indexed: 01/25/2023]
Abstract
Genetic variants in the transcription factor 7-like 2(Tcf7l2) gene have been found to confer a significant risk of type 2 diabetes and attenuated insulin secretion. Based on its genomic wide association Tcf7l2 is considered the single most important predictor of diabetes to date. Previous studies of Tcf7l2 mRNA localization in the adult brain suggest a putative role of Tcf7l2 in the CNS regulation of energy homeostasis. The present study further characterizes the immunophenotypic distribution of peptide expression in the brains of Tcf7l2 progeny during developmental time periods between E12.5 and P1. Tcf7l2(-/-) is lethal beyond P1. Results show that while negligible TCF7L2 expression is found in the developing brains of Tcf7l2(-/-)mice, TCF7L2 protein is relatively widespread and robustly expressed in the brain by E18.5 and exhibits specific expression within neuronal populations and regions of the brain in Tcf7l2(+/-) and Tcf7l2(+/+) progeny. Strong immunophenotypic labeling was found in the diencephalic structure of the thalamus that suggests a role of Tcf7l2 in the development and maintenance of thalamic activity. Strongly expressed TCF7L2 was localized in select hypothalamic and preoptic nuclei indicative of Tcf7l2 function within neurons controlling energy balance. Definitive neuronal staining for TCF7L2 within nuclei of the brain stem and circumventricular organs extends TCF7L2 localization within autonomic neurons and its potential integration with autonomic function. In addition robust TCF7L2 expression was found in the tectal and tegmental structures of the superior and inferior colliculi as well as transient expression in neuroepithelium of the cerebral and hippocampal cortices of E16 and E18.5. Patterns of TCF7L2 peptide localization when compared to the adult protein synthetic chemical/anatomical landscape of glucose sensing exhibit a good correlational fit between its expression and regions, nuclei, and pathways regulating energy homeostasis via integration and response to peripheral endocrine, metabolic and neuronal signaling. TCF was also found co-localized with peptides that regulate energy homeostasis including AgRP, POMC and NPY. TCF7l2, some variants of which have been shown to impair GLP-1-induced insulin secretion, was also found co-localize with GLP-1 in adult TCF wild type progeny. Impaired Tcf7l2-mediated neural regulation may contribute to the risk and/or underlying pathophysiology of type 2 diabetes that has found high expression in genomic studies of Tcf7l2 variants.
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Affiliation(s)
- Cyprian Weaver
- Department of Medicine, University of Minnesota, Minneapolis, MN 55455, USA.
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21
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Bantubungi K, Prawitt J, Staels B. Control of metabolism by nutrient-regulated nuclear receptors acting in the brain. J Steroid Biochem Mol Biol 2012; 130:126-37. [PMID: 22033286 DOI: 10.1016/j.jsbmb.2011.10.002] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/18/2011] [Revised: 10/04/2011] [Accepted: 10/08/2011] [Indexed: 12/22/2022]
Abstract
Today, we are witnessing a rising incidence of obesity worldwide. This increase is due to a sedentary life style, an increased caloric intake and a decrease in physical activity. Obesity contributes to the appearance of type 2 diabetes, dyslipidemia and cardiovascular complications due to atherosclerosis, and nephropathy. Therefore, the development of new therapeutic strategies may become a necessity. Given the metabolism controlling properties of nuclear receptors in peripheral organs (such as liver, adipose tissues, pancreas) and their implication in various processes underlying metabolic diseases, they constitute interesting therapeutic targets for obesity, dyslipidemia, cardiovascular disease and type 2 diabetes. The recent identification of the central nervous system as a player in the control of peripheral metabolism opens new avenues to our understanding of the pathophysiology of obesity and type 2 diabetes and potential novel ways to treat these diseases. While the metabolic functions of nuclear receptors in peripheral organs have been extensively investigated, little is known about their functions in the brain, in particular with respect to brain control of energy homeostasis. This review provides an overview of the relationships between nuclear receptors in the brain, mainly at the hypothalamic level, and the central regulation of energy homeostasis. In this context, we will particularly focus on the role of PPARα, PPARγ, LXR and Rev-erbα.
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Affiliation(s)
- Kadiombo Bantubungi
- Univ Lille Nord de France, INSERM UMR1011, UDSL, Institut Pasteur de Lille, Lille, France
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22
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Page AJ, Symonds E, Peiris M, Blackshaw LA, Young RL. Peripheral neural targets in obesity. Br J Pharmacol 2012; 166:1537-58. [PMID: 22432806 PMCID: PMC3419899 DOI: 10.1111/j.1476-5381.2012.01951.x] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2011] [Revised: 02/20/2012] [Accepted: 02/22/2012] [Indexed: 12/15/2022] Open
Abstract
Interest in pharmacological treatments for obesity that act in the brain to reduce appetite has increased exponentially over recent years, but failures of clinical trials and withdrawals due to adverse effects have so far precluded any success. Treatments that do not act within the brain are, in contrast, a neglected area of research and development. This is despite the fact that a vast wealth of molecular mechanisms exists within the gut epithelium and vagal afferent system that could be manipulated to increase satiety. Here we discuss mechano- and chemosensory pathways from the gut involved in appetite suppression, and distinguish between gastric and intestinal vagal afferent pathways in terms of their basic physiology and activation by enteroendocrine factors. Gastric bypass surgery makes use of this system by exposing areas of the intestine to greater nutrient loads resulting in greater satiety hormone release and reduced food intake. A non-surgical approach to this system is preferable for many reasons. This review details where the opportunities may lie for such approaches by describing nutrient-sensing mechanisms throughout the gastrointestinal tract.
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Affiliation(s)
- Amanda J Page
- Nerve-Gut Research Laboratory, Discipline of Medicine, South Australia, Australia
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23
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Bruijnzeel AW. Tobacco addiction and the dysregulation of brain stress systems. Neurosci Biobehav Rev 2012; 36:1418-41. [PMID: 22405889 PMCID: PMC3340450 DOI: 10.1016/j.neubiorev.2012.02.015] [Citation(s) in RCA: 122] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2011] [Revised: 02/01/2012] [Accepted: 02/23/2012] [Indexed: 11/15/2022]
Abstract
Tobacco is a highly addictive drug and is one of the most widely abused drugs in the world. The first part of this review explores the role of stressors and stress-associated psychiatric disorders in the initiation of smoking, the maintenance of smoking, and relapse after a period of abstinence. The reviewed studies indicate that stressors facilitate the initiation of smoking, decrease the motivation to quit, and increase the risk for relapse. Furthermore, people with depression or an anxiety disorder are more likely to smoke than people without these disorders. The second part of this review describes animal studies that investigated the role of brain stress systems in nicotine addiction. These studies indicate that corticotropin-releasing factor, Neuropeptide Y, the hypocretins, and norepinephrine play a pivotal role in nicotine addiction. In conclusion, the reviewed studies indicate that smoking briefly decreases subjective stress levels but also leads to a further dysregulation of brain stress systems. Drugs that decrease the activity of brain stress systems may diminish nicotine withdrawal and improve smoking cessation rates.
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Affiliation(s)
- Adrie W Bruijnzeel
- Department of Psychiatry, McKnight Brain Institute, University of Florida, 1149 S. Newell Dr., Gainesville, FL 32611, USA.
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24
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Weston-Green K, Huang XF, Deng C. Alterations to melanocortinergic, GABAergic and cannabinoid neurotransmission associated with olanzapine-induced weight gain. PLoS One 2012; 7:e33548. [PMID: 22438946 PMCID: PMC3306411 DOI: 10.1371/journal.pone.0033548] [Citation(s) in RCA: 77] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2011] [Accepted: 02/11/2012] [Indexed: 12/30/2022] Open
Abstract
Background/Aim Second generation antipsychotics (SGAs) are used to treat schizophrenia but can cause serious metabolic side-effects, such as obesity and diabetes. This study examined the effects of low to high doses of olanzapine on appetite/metabolic regulatory signals in the hypothalamus and brainstem to elucidate the mechanisms underlying olanzapine-induced obesity. Methodology/Results Levels of pro-opiomelanocortin (POMC), neuropeptide Y (NPY) and glutamic acid decarboxylase (GAD65, enzyme for GABA synthesis) mRNA expression, and cannabinoid CB1 receptor (CB1R) binding density (using [3H]SR-141716A) were examined in the arcuate nucleus (Arc) and dorsal vagal complex (DVC) of female Sprague Dawley rats following 0.25, 0.5, 1.0 or 2.0 mg/kg olanzapine or vehicle (3×/day, 14-days). Consistent with its weight gain liability, olanzapine significantly decreased anorexigenic POMC and increased orexigenic NPY mRNA expression in a dose-sensitive manner in the Arc. GAD65 mRNA expression increased and CB1R binding density decreased in the Arc and DVC. Alterations to neurotransmission signals in the brain significantly correlated with body weight and adiposity. The minimum dosage threshold required to induce weight gain in the rat was 0.5 mg/kg olanzapine. Conclusions Olanzapine-induced weight gain is associated with reduced appetite-inhibiting POMC and increased NPY. This study also supports a role for the CB1R and GABA in the mechanisms underlying weight gain side-effects, possibly by altering POMC transmission. Metabolic dysfunction can be modelled in the female rat using low, clinically-comparable olanzapine doses when administered in-line with the half-life of the drug.
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Affiliation(s)
- Katrina Weston-Green
- Centre for Translational Neuroscience, School of Health Sciences, University of Wollongong, Wollongong, Australia
- Schizophrenia Research Institute, Darlinghurst, Australia
| | - Xu-Feng Huang
- Centre for Translational Neuroscience, School of Health Sciences, University of Wollongong, Wollongong, Australia
- Schizophrenia Research Institute, Darlinghurst, Australia
| | - Chao Deng
- Centre for Translational Neuroscience, School of Health Sciences, University of Wollongong, Wollongong, Australia
- Schizophrenia Research Institute, Darlinghurst, Australia
- * E-mail:
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25
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Wang C, Guo F. Effects of activating transcription factor 4 deficiency on carbohydrate and lipid metabolism in mammals. IUBMB Life 2012; 64:226-30. [PMID: 22223547 DOI: 10.1002/iub.605] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2011] [Accepted: 11/23/2011] [Indexed: 01/13/2023]
Abstract
It has been shown that the mammalian activating transcription factor 4 (ATF4) is involved in many different physiological events, such as eye development, stress response, learning, and memory. However, several recent studies have demonstrated that ATF4 also plays an important role in the regulation of lipid and glucose metabolism, energy homeostasis, insulin secretion, and sensitivity, suggesting that ATF4 is a master regulator of metabolism. This review summarizes the most recent progress in the understanding of the novel roles of ATF4 in the regulation of metabolism.
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Affiliation(s)
- Chunxia Wang
- Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, The Graduate School of the Chinese Academy of Sciences, Chinese Academy of Sciences, China
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Biebermann H, Kühnen P, Kleinau G, Krude H. The neuroendocrine circuitry controlled by POMC, MSH, and AGRP. Handb Exp Pharmacol 2012:47-75. [PMID: 22249810 DOI: 10.1007/978-3-642-24716-3_3] [Citation(s) in RCA: 47] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Obesity is one of the most challenging health problems worldwide. Over the past few decades, our knowledge concerning mechanisms of weight regulation has increased tremendously leading to the identification of the leptin-melanocortin pathway. The filling level of energy stores is signaled to the brain, and the information is integrated by hypothalamic nuclei, resulting in a well-orchestrated response to food intake and energy expenditure to ensure constant body weight. One of the key players in this system is proopiomelanocortin (POMC), a precursor of a variety of neuropeptides. POMC-derived alpha- and beta-MSH play an important role in energy homeostasis by activating melanocortin receptors expressed in the arcuate nucleus (MC3R) and in the nucleus paraventricularis (MC4R). Activation of these two G protein-coupled receptors is antagonized by agouti-related peptide (AgRP). Naturally occurring mutations in this system were identified in patients suffering from common obesity as well as in patients demonstrating a phenotype of severe early-onset obesity, adrenal insufficiency, red hair, and pale skin. Detailed understanding of the complex system of POMC-AgRP-MC3R-MC4R and their interaction with other hypothalamic as well as peripheral signals is a prerequisite to combat the obesity epidemic.
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Affiliation(s)
- Heike Biebermann
- Institut für Experimentelle Pädiatrische Endokrinologie, Charité Universitätsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany.
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Cansell C, Denis RGP, Joly-Amado A, Castel J, Luquet S. Arcuate AgRP neurons and the regulation of energy balance. Front Endocrinol (Lausanne) 2012; 3:169. [PMID: 23293630 PMCID: PMC3530831 DOI: 10.3389/fendo.2012.00169] [Citation(s) in RCA: 55] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/03/2012] [Accepted: 12/05/2012] [Indexed: 11/13/2022] Open
Abstract
The arcuate nucleus of the hypothalamus contains at least two populations of neurons that continuously monitor signals reflecting energy status and promote the appropriate behavioral and metabolic responses to changes in energy demand. Activation of neurons making pro-opiomelanocortin (POMC) decreases food intake and increases energy expenditure through activation of G protein-coupled melanocortin receptors via the release of α-melanocyte-stimulating hormone. Until recently, the prevailing idea was that the neighboring neurons [agouti-related protein (AgRP) neurons] co-expressing the orexigenic neuropeptides, AgRP, and neuropeptide Y increase feeding by opposing the anorexigenic actions of the POMC neurons. However, it has now been demonstrated that only AgRP neurons activation - not POMC neurons inhibition - is necessary and sufficient to promote feeding. Projections of AgRP-expressing axons innervate mesolimbic, midbrain, and pontine structures where they regulate feeding and feeding-independent functions such as reward or peripheral nutrient partitioning. AgRP neurons also make gamma aminobutyric acid , which is now thought to mediate many of critical functions of these neurons in a melanocortin-independent manner and on a timescale compatible with neuromodulation.
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Affiliation(s)
- Céline Cansell
- Unité de Biologie Fonctionnelle et Adaptative, CNRS-EAC 4413, Sorbonne Paris Cité, Université Paris Diderot-Paris 7Paris, France
| | - Raphaël G. P. Denis
- Unité de Biologie Fonctionnelle et Adaptative, CNRS-EAC 4413, Sorbonne Paris Cité, Université Paris Diderot-Paris 7Paris, France
| | - Aurélie Joly-Amado
- Unité de Biologie Fonctionnelle et Adaptative, CNRS-EAC 4413, Sorbonne Paris Cité, Université Paris Diderot-Paris 7Paris, France
| | - Julien Castel
- Unité de Biologie Fonctionnelle et Adaptative, CNRS-EAC 4413, Sorbonne Paris Cité, Université Paris Diderot-Paris 7Paris, France
- Centre National de la Recherche Scientifique EAC 4413Paris, France
| | - Serge Luquet
- Unité de Biologie Fonctionnelle et Adaptative, CNRS-EAC 4413, Sorbonne Paris Cité, Université Paris Diderot-Paris 7Paris, France
- Centre National de la Recherche Scientifique EAC 4413Paris, France
- *Correspondence: Serge Luquet, Unité de Biologie Fonctionnelle et Adaptative, CNRS-EAC 4413, Sorbonne Paris Cité, Université Paris Diderot-Paris 7, 4 rue Marie-Andrée Lagroua Weill-Hallé, Bâtiment Buffon, Case courrier 7126, 75205 Paris Cedex 13, France. e-mail:
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Jeong JY, Ku BM, Lee YK, Ryu J, Choi J, Kim JS, Cho YW, Roh GS, Kim HJ, Cho GJ, Choi WS, Kang SS. Expression of pro-opiomelanocortin and agouti-related protein in the hypothalamus of caffeine-administered rats. Anim Cells Syst (Seoul) 2011. [DOI: 10.1080/19768354.2011.604946] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/17/2022] Open
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Seretis C, Seretis F, Liakos N, Pappas A, Keramidaris D, Gourgiotis S, Salemis N, Lagoudianakis E. Constipation-predominant irritable bowel syndrome associated to hyperprolactinemia. Case Rep Gastroenterol 2011; 5:523-7. [PMID: 22087083 PMCID: PMC3214685 DOI: 10.1159/000331806] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Irritable bowel syndrome (IBS) is considered to be a physical disorder that mainly affects the bowel and is clinically characterized by lower abdominal pain or discomfort, diarrhea, constipation (or alternating diarrhea/constipation), gas, bloating, and nausea. According to recent studies, it appears that there is an association with increased prolactin levels in patients suffering from IBS. We report a rare case of regression of IBS symptoms (constipation type) in a 16-year-old female adolescent after receiving cabergoline for treating hyperprolactinemia due to pituitary macroadenoma. Our hypothesis is that increased prolactin levels, for instance due to a pituitary adenoma, may suppress prolactin-releasing peptide release and lead to a reverse feedback interaction, consequently resulting in oversecretion of cholecystokinin, inducing the development of IBS.
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Affiliation(s)
- C Seretis
- Gastrointestinal Endoscopy Department, Argos Hospital, Argos, Greece
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Ashley Blackshaw L, Young RL. Detection and signaling of glucose in the intestinal mucosa--vagal pathway. Neurogastroenterol Motil 2011; 23:591-4. [PMID: 21679344 DOI: 10.1111/j.1365-2982.2011.01719.x] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Intestinal luminal exposure to glucose initiates changes in food intake and gastrointestinal (GI) motor and secretory function. It does this by stimulating the release of GI hormones and 5-hydroxytryptamine (5-HT) from enteroendocrine and enterochromaffin cells (EC), respectively, which in turn activate intrinsic and extrinsic neuronal pathways. An article in this issue of the journal provides new insight into the mechanisms involved in luminal glucose sensing. Vincent et al. have used a novel in vivo technique to determine activation of gut epithelial cells and vagal afferent pathways in rats by staining for activated calcium-calmodulin kinase II (pCaMKII) along the pathway. In the mucosa, they found that intraluminal glucose activated EC cells and brush cells. At the next stage, pCaMKII was seen in neurons of the myenteric plexus and vagal afferent neurons in the nodose ganglia. In the central nervous system (CNS), activation was seen in second- and higher-order neurons in the dorsal vagal complex and hypothalamus. They found that 5-HT(3) receptors were involved in initiating neural signaling as activation of neurons, but not EC cells, was reduced by 5-HT(3) receptor antagonism. Selectively stimulating the sodium-glucose cotransporter (SGLT-3) had similar effects to glucose. This suggests that SGLT-3 behaves as a glucose sensor, mainly on EC cells, inducing the release of 5-HT, which activates 5-HT(3) receptors on vagal afferent endings nearby and in turn, their connections in the CNS. There is evidence elsewhere that other sensors and transmitter mechanisms are involved in this pathway, so the possibility exists of multiple redundant systems.
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Affiliation(s)
- L Ashley Blackshaw
- Nerve-Gut Research Laboratory, Discipline of Medicine, University of Adelaide, Adelaide, SA, Australia.
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31
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Wu Q, Palmiter RD. GABAergic signaling by AgRP neurons prevents anorexia via a melanocortin-independent mechanism. Eur J Pharmacol 2011; 660:21-7. [PMID: 21211531 PMCID: PMC3108334 DOI: 10.1016/j.ejphar.2010.10.110] [Citation(s) in RCA: 99] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2010] [Revised: 09/30/2010] [Accepted: 10/12/2010] [Indexed: 11/25/2022]
Abstract
The hypothalamic arcuate nucleus contains two anatomically and functionally distinct populations of neurons-the agouti-related peptide (AgRP)- and pro-opiomelanocortin (POMC)-expressing neurons that integrate various nutritional, hormonal, and neuronal signals to regulate food intake and energy expenditure, and thereby help achieve energy homeostasis. AgRP neurons, also co-release neuropeptide Y (NPY) and γ-aminobutyric acid (GABA) to promote feeding and inhibit metabolism through at least three possible mechanisms: (1) suppression of the melanocortin signaling system through competitive binding of AgRP with the melanocortin 4 receptors; (2) NPY-mediated inhibition of post-synaptic neurons that reside in hypothalamic nuclei; (3) GABAergic inhibition of POMC neurons in their post-synaptic targets including the parabrachial nucleus (PBN), a brainstem structure that relays gustatory and visceral sensory information. Acute ablation of AgRP neurons in adult mice by the action of diphtheria toxin (DT) results in precipitous reduction of food intake, and eventually leads to starvation within 6days of DT treatment. Chronic delivery of bretazenil, a GABA(A) receptor partial agonist, into the PBN is sufficient to restore feeding and body weight when AgRP neurons are ablated, whereas chronic blockade of melanocortin 4 receptor signaling is inadequate. This review summarizes the physiological roles of a neural circuitry regulated by AgRP neurons in control of feeding behavior with particular emphasis of the GABA output to the parabrachial nucleus. We also describe a compensatory mechanism that is gradually engaged after ablation of AgRP neurons that allows mice to continue eating without them.
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Affiliation(s)
- Qi Wu
- Howard Hughes Medical Institute and Departments of Biochemistry, University of Washington, Seattle, WA 98195, USA.
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Corander MP, Coll AP. Melanocortins and body weight regulation: glucocorticoids, Agouti-related protein and beyond. Eur J Pharmacol 2011; 660:111-8. [PMID: 21199644 DOI: 10.1016/j.ejphar.2010.10.103] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2010] [Revised: 09/29/2010] [Accepted: 10/12/2010] [Indexed: 11/20/2022]
Abstract
In the intervening three decades since Panksepp observed for the first time that centrally administered α-melanocyte stimulating hormone decreased food intake (Panksepp and Meeker, 1976), a wealth of data have accrued to firmly establish melanocortin signaling as a central regulator of food intake and fat mass. Advances in molecular biology have not only allowed detailed studies of spontaneously occurring obese mice with altered melanocortin signaling to be undertaken but also permitted the generation of a plethora of mouse models with precise perturbations at critical steps in the melanocortin system to finesse further the cellular and molecular architecture of relevant pathways. In this article we focus in upon a number of these mouse models which continue to help us tease apart the complexities of this critical system. Further, we review data on the important interaction between pro-opiomelanocortin derived peptides and the adrenal system and the relationship between agonist and antagonist peptides acting at central melanocortin receptors.
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Affiliation(s)
- Marcus P Corander
- University of Cambridge Metabolic Research Laboratories, Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK
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Kim KW, Sohn JW, Kohno D, Xu Y, Williams K, Elmquist JK. SF-1 in the ventral medial hypothalamic nucleus: a key regulator of homeostasis. Mol Cell Endocrinol 2011; 336:219-23. [PMID: 21111025 PMCID: PMC3057357 DOI: 10.1016/j.mce.2010.11.019] [Citation(s) in RCA: 46] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/06/2010] [Revised: 11/14/2010] [Accepted: 11/14/2010] [Indexed: 11/15/2022]
Abstract
The ventral medial hypothalamic nucleus (VMH) regulates food intake and body weight homeostasis. The nuclear receptor NR5A1 (steroidogenic factor 1; SF-1) is a transcription factor whose expression is highly restricted in the VMH and is required for the development of the nucleus. Neurons expressing SF-1 in the VMH have emerged as playing important roles in the regulation of body weight and energy homeostasis. Many of these studies have used site-specific gene KO approaches, providing insights into the molecular mechanisms underlying the regulation of energy homeostasis by the SF-1 neurons of the VMH. In this brief review, we will focus on recent studies defining the molecular mechanisms regulating energy homeostasis and body weight in the VMH, particularly stressing the SF-1 expressing neurons.
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Affiliation(s)
- Ki Woo Kim
- Division of Hypothalamic Research, Department of Internal Medicine, UT Southwestern Medical Center, Dallas, TX 75390-9077, United States
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34
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Young RL. Sensing via intestinal sweet taste pathways. Front Neurosci 2011; 5:23. [PMID: 21519398 PMCID: PMC3080736 DOI: 10.3389/fnins.2011.00023] [Citation(s) in RCA: 51] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2010] [Accepted: 02/10/2011] [Indexed: 12/15/2022] Open
Abstract
The detection of nutrients in the gastrointestinal (GI) tract is of fundamental significance to the control of motility, glycemia and energy intake, and yet we barely know the most fundamental aspects of this process. This is in stark contrast to the mechanisms underlying the detection of lingual taste, which have been increasingly well characterized in recent years, and which provide an excellent starting point for characterizing nutrient detection in the intestine. This review focuses on the form and function of sweet taste transduction mechanisms identified in the intestinal tract; it does not focus on sensors for fatty acids or proteins. It examines the intestinal cell types equipped with sweet taste transduction molecules in animals and humans, their location, and potential signals that transduce the presence of nutrients to neural pathways involved in reflex control of GI motility.
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Affiliation(s)
- Richard L Young
- Discipline of Medicine, School of Medicine, University of Adelaide Adelaide, SA, Australia
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The role of hypothalamic AMP-activated protein kinase in ovariectomy-induced obesity in rats. Menopause 2011; 17:1194-200. [PMID: 20613671 DOI: 10.1097/gme.0b013e3181dfca27] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
OBJECTIVE Adenosine monophosphate-activated protein kinase (AMPK) acts as a cellular energy sensor, being activated during states of low energy charge. Hypothalamic AMPK is altered by hormonal and metabolic signals and mediates the feeding response. The aims of this study were to examine whether the phosphorylation of AMPKα in the hypothalamus is affected by ovariectomy (Ovx) and thus would be involved in the development of obesity in rats. METHODS Body weight, food intake, hypothalamic phosphorylated AMPKα (pAMPKα) protein expression, and plasma leptin and adiponectin levels were measured in female rats after either Ovx or sham operations. These patterns were also observed after treatment with 17β-estradiol, compound C, and leptin in Ovx rats. RESULTS Compared with control rats, Ovx led to increased body weight and food intake at 2 to 8 weeks after operation. Meanwhile, plasma leptin and adiponectin levels and hypothalamic pAMPKα expression were significantly increased after Ovx. Replacement of estradiol significantly reversed these effects. Treatment with compound C, an AMPKα inhibitor, for 1 week produced a reduction in food intake, body weight, and plasma leptin and adiponectin levels. Meanwhile, these effects were reversed upon withdrawal of compound C. In addition, central injection of leptin also significantly reduced body weight, food intake, plasma leptin and adiponectin levels, and hypothalamic pAMPKα expression relative to those of the Ovx group. CONCLUSIONS Increased hypothalamic pAMPKα expression may contribute to hyperphagia during the development of Ovx-induced obesity in rats.
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The fat-induced satiety factor oleoylethanolamide suppresses feeding through central release of oxytocin. J Neurosci 2010. [PMID: 20554860 DOI: 10.1523/jneur osci.0036-10.2010] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023] Open
Abstract
Oleoylethanolamide (OEA) is a biologically active lipid amide that is released by small-intestinal enterocytes during the absorption of dietary fat and inhibits feeding by engaging the nuclear receptor, peroxisome proliferator-activated receptor-alpha (PPAR-alpha). Previous studies have shown that the anorexic effects of systemically administered OEA require the activation of sensory afferents of the vagus nerve. The central circuits involved in mediating OEA-induced hypophagia remain unknown. In the present study, we report the results of in situ hybridization and immunohistochemistry experiments in rats and mice, which show that systemic injections of OEA (5-10 mg kg(-1), intraperitoneal) enhance expression of the neuropeptide oxytocin in magnocellular neurons of the paraventricular nucleus (PVN) and supraoptic nucleus (SON) of the hypothalamus. No such effect is observed with other hypothalamic neuropeptides, including vasopressin, thyrotropin-releasing hormone and pro-opiomelanocortin. The increase in oxytocin expression elicited by OEA was absent in mutant PPAR-alpha-null mice. Pharmacological blockade of oxytocin receptors in the brain by intracerebroventricular infusion of the selective oxytocin antagonist, L-368,899, prevented the anorexic effects of OEA. The results suggest that OEA suppresses feeding by activating central oxytocin transmission.
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Gaetani S, Fu J, Cassano T, Dipasquale P, Romano A, Righetti L, Cianci S, Laconca L, Giannini E, Scaccianoce S, Mairesse J, Cuomo V, Piomelli D. The fat-induced satiety factor oleoylethanolamide suppresses feeding through central release of oxytocin. J Neurosci 2010; 30:8096-101. [PMID: 20554860 PMCID: PMC2900249 DOI: 10.1523/jneurosci.0036-10.2010] [Citation(s) in RCA: 95] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2010] [Revised: 04/15/2010] [Accepted: 04/20/2010] [Indexed: 11/21/2022] Open
Abstract
Oleoylethanolamide (OEA) is a biologically active lipid amide that is released by small-intestinal enterocytes during the absorption of dietary fat and inhibits feeding by engaging the nuclear receptor, peroxisome proliferator-activated receptor-alpha (PPAR-alpha). Previous studies have shown that the anorexic effects of systemically administered OEA require the activation of sensory afferents of the vagus nerve. The central circuits involved in mediating OEA-induced hypophagia remain unknown. In the present study, we report the results of in situ hybridization and immunohistochemistry experiments in rats and mice, which show that systemic injections of OEA (5-10 mg kg(-1), intraperitoneal) enhance expression of the neuropeptide oxytocin in magnocellular neurons of the paraventricular nucleus (PVN) and supraoptic nucleus (SON) of the hypothalamus. No such effect is observed with other hypothalamic neuropeptides, including vasopressin, thyrotropin-releasing hormone and pro-opiomelanocortin. The increase in oxytocin expression elicited by OEA was absent in mutant PPAR-alpha-null mice. Pharmacological blockade of oxytocin receptors in the brain by intracerebroventricular infusion of the selective oxytocin antagonist, L-368,899, prevented the anorexic effects of OEA. The results suggest that OEA suppresses feeding by activating central oxytocin transmission.
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Affiliation(s)
- Silvana Gaetani
- Department of Physiology and Pharmacology “V. Erspamer,” Sapienza University of Rome, 00185 Rome, Italy
| | - Jin Fu
- Department of Pharmacology, University of California, Irvine, Irvine, California 92697-4625
- Unit of Drug Discovery and Development, Italian Institute of Technology, 16163 Genoa, Italy, and
| | - Tommaso Cassano
- Department of Biomedical Sciences, University of Foggia, 71100 Foggia, Italy
| | - Pasqua Dipasquale
- Department of Physiology and Pharmacology “V. Erspamer,” Sapienza University of Rome, 00185 Rome, Italy
| | - Adele Romano
- Department of Physiology and Pharmacology “V. Erspamer,” Sapienza University of Rome, 00185 Rome, Italy
| | - Laura Righetti
- Department of Physiology and Pharmacology “V. Erspamer,” Sapienza University of Rome, 00185 Rome, Italy
| | - Silvia Cianci
- Department of Physiology and Pharmacology “V. Erspamer,” Sapienza University of Rome, 00185 Rome, Italy
| | - Leonardo Laconca
- Department of Physiology and Pharmacology “V. Erspamer,” Sapienza University of Rome, 00185 Rome, Italy
- Department of Biomedical Sciences, University of Foggia, 71100 Foggia, Italy
| | - Elisa Giannini
- Department of Physiology and Pharmacology “V. Erspamer,” Sapienza University of Rome, 00185 Rome, Italy
| | - Sergio Scaccianoce
- Department of Physiology and Pharmacology “V. Erspamer,” Sapienza University of Rome, 00185 Rome, Italy
| | - Jérôme Mairesse
- Department of Physiology and Pharmacology “V. Erspamer,” Sapienza University of Rome, 00185 Rome, Italy
| | - Vincenzo Cuomo
- Department of Physiology and Pharmacology “V. Erspamer,” Sapienza University of Rome, 00185 Rome, Italy
| | - Daniele Piomelli
- Department of Pharmacology, University of California, Irvine, Irvine, California 92697-4625
- Unit of Drug Discovery and Development, Italian Institute of Technology, 16163 Genoa, Italy, and
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Kim SK, Kim J, Woo HS, Jeong H, Lee H, Min BI, Nam S, Bae H. Electroacupuncture induces Fos expression in the nucleus tractus solitarius via cholecystokinin A receptor signaling in rats. Neurol Res 2010; 32 Suppl 1:116-9. [PMID: 20034459 DOI: 10.1179/016164109x12537002794525] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/31/2022]
Abstract
OBJECTIVES Cholecystokinin, a satiety hormone, acts on cholecystokinin A receptor on vagal afferent neurons that project to the nucleus tractus solitarius, resulting in inhibition of feeding. Cholecystokinin is known to be released by electroacupuncture stimulation at certain body sites which elicits profound psychophysiological responses. Our previous study has revealed the involvement of cholecystokinin and cholecystokinin A receptor in the electroacupuncture stimulation-induced modulation of feeding. The aim of the present study was to examine whether electroacupuncture stimulation at the acupuncture point ST36 (Joksamni) activates the nucleus tractus solitarius neurons and whether such effect is mediated by cholecystokinin A receptor. METHODS Using an immunofluorescent analysis of Fos, a neuronal activation marker, we compared the Fos immunoreactivity of the nucleus tractus solitarius among three groups of Sprague-Dawley rats: (1) control (48 hour fasting + saline pre-treatment + no electroacupuncture stimulation); (2) SalEA (48 hour fasting + saline pre-treatment + ST36 electroacupuncture stimulation); (3) LorEA (48 hour fasting + pre-treatment of cholecystokinin A receptor antagonist, lorglumide + ST36 electroacupuncture stimulation). RESULTS ST36 electroacupuncture stimulation significantly reduced 30 minute food intake (p<0.05, SalEA versus control) and increased Fos expression in the nucleus tractus solitarius (p<0.01, SalEA versus control). The effects of electroacupuncture on food intake and Fos were blocked by a lorglumide pre-treatment (p>0.05, LorEA versus control). DISCUSSION Our finding suggests that ST36 electroacupuncture stimulation activates the nucleus tractus solitarius neurons via cholecystokinin A receptor signaling pathway, which may be the underlying central mechanism of electroacupuncture-induced satiety effect.
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Affiliation(s)
- Sun Kwang Kim
- Department of Physiology, College of Korean Medicine, Kyung Hee University, Seoul 130-701, Korea; Acupuncture and Meridian Science Research Center, Kyung Hee University, Seoul 130-701, Korea
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Sabatier N, Leng G. Responses to cholecystokinin in the ventromedial nucleus of the rat hypothalamus in vivo. Eur J Neurosci 2010; 31:1127-35. [PMID: 20377625 DOI: 10.1111/j.1460-9568.2010.07144.x] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
The peptide cholecystokinin (CCK) is a short-term satiety signal released from the gastrointestinal tract during food intake. From the periphery, CCK signalling travels via the vagus nerve to reach the brainstem from which it is relayed higher into the brain. The hypothalamus is a key integrator of appetite-related stimuli and the ventromedial nucleus of the hypothalamus (VMN) is thought to have an important role in the regulation of satiety. We investigated the effect of intravenous injections of CCK on the spontaneous firing activity of single VMN neurons in urethane-anaesthetised rats in vivo. We found that the predominant effect of CCK on the electrical activity in the VMN is inhibitory. We analysed the responses to CCK according to electrophysiologically distinct subpopulations of VMN neurons and found that four of these VMN subpopulations were inhibited by CCK, while five were not significantly affected. Finally, CCK-induced inhibitory response in VMN neurons was not altered by pre-administration of intravenous leptin.
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Affiliation(s)
- Nancy Sabatier
- Centre for Integrative Physiology, The University of Edinburgh, Hugh Robson Building, George Square, Edinburgh EH8 9XD, UK
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40
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Griffond B, Risold PY. MCH and feeding behavior-interaction with peptidic network. Peptides 2009; 30:2045-51. [PMID: 19619600 DOI: 10.1016/j.peptides.2009.07.008] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/26/2009] [Revised: 04/17/2009] [Accepted: 07/09/2009] [Indexed: 12/20/2022]
Abstract
Numerous works associate the MCH peptide, and the hypothalamic neurons that produce it, to the feeding behavior and energy homeostasis. It is commonly admitted that MCH is an orexigenic peptide, and MCH neurons could be under the control of arcuate NPY and POMC neurons. However, the literature data is not always concordant. In particular questions about the intrahypothalamic circuit involving other neuropeptides and about the mechanisms through which MCH could act are not yet clearly answered. For example, which receptors mediate a MCH response to NPY or alpha-MSH, does MCH act alone, is there any local anatomical organization within the tuberal LHA? A review of the current literature is then needed to help focus attention on these unresolved and often neglected issues.
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Affiliation(s)
- B Griffond
- Université de Franche-Comté, Besançon, France
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Wu Q, Boyle MP, Palmiter RD. Loss of GABAergic signaling by AgRP neurons to the parabrachial nucleus leads to starvation. Cell 2009; 137:1225-34. [PMID: 19563755 PMCID: PMC2729323 DOI: 10.1016/j.cell.2009.04.022] [Citation(s) in RCA: 355] [Impact Index Per Article: 22.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2008] [Revised: 02/09/2009] [Accepted: 04/07/2009] [Indexed: 10/20/2022]
Abstract
Neurons in the arcuate nucleus that produce AgRP, NPY, and GABA (AgRP neurons) promote feeding. Ablation of AgRP neurons in adult mice results in Fos activation in postsynaptic neurons and starvation. Loss of GABA is implicated in starvation because chronic subcutaneous delivery of bretazenil (a GABA(A) receptor partial agonist) suppresses Fos activation and maintains feeding during ablation of AgRP neurons. Moreover, under these conditions, direct delivery of bretazenil into the parabrachial nucleus (PBN), a direct target of AgRP neurons that also relays gustatory and visceral sensory information, is sufficient to maintain feeding. Conversely, inactivation of GABA biosynthesis in the ARC or blockade of GABA(A) receptors in the PBN of mice promote anorexia. We suggest that activation of the PBN by AgRP neuron ablation or gastrointestinal malaise inhibits feeding. Chronic delivery of bretazenil during loss of AgRP neurons provides time to establish compensatory mechanisms that eventually allow mice to eat.
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Affiliation(s)
- Qi Wu
- Howard Hughes Medical Institute and Department of Biochemistry, University of Washington, Seattle, WA 98195, USA
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43
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Dockray GJ. The versatility of the vagus. Physiol Behav 2009; 97:531-6. [PMID: 19419683 DOI: 10.1016/j.physbeh.2009.01.009] [Citation(s) in RCA: 54] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2008] [Revised: 01/13/2009] [Accepted: 01/14/2009] [Indexed: 12/24/2022]
Abstract
The gut is one of several organs contributing to the peripheral signalling network that controls food intake. Afferent neurons of the vagus nerve provide an important pathway for gut signals that act by triggering ascending pathways from the brain stem to hypothalamus. Recent work indicates the existence of mechanisms operating at the level of vagal afferent neurons to modulate the effect of gastrointestinal satiety signals. Thus, the well known satiety hormone cholecystokinin (CCK) not only stimulates the discharge of these neurons but also controls their expression of both G-protein coupled receptors and peptide neurotransmitters known to influence food intake. When plasma CCK concentrations are low e.g. in fasting, the expression by vagal afferent neurons of cannabinoid (CB)-1 and melanin concentrating hormone (MCH)-1 receptors is increased. Release of CCK by feeding leads to a rapid down-regulation of expression of both receptors and to increased expression of Y2 receptors. In fasting, there is also increased expression in these neurons of the appetite-stimulating neuropeptide transmitter MCH, and depressed expression of the satiety-peptide cocaine and amphetamine regulated transcript (CARTp); endogenous CCK decreases MCH expression and stimulates CART expression. The gastric orexigenic hormone ghrelin blocks these actions of CCK at least in part by excluding phosphoCREB from the nucleus. The data suggest that CCK acts as a gatekeeper to determine the capacity of other neuroendocrine signals to act via vagal afferent neurons to influence food intake.
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Affiliation(s)
- Graham J Dockray
- Physiological Laboratory, School of Biomedical Sciences, University of Liverpool, Liverpool, UK.
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44
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LEE CH, CHOI JH, HWANG IK, YOO KY, LI H, PARK OK, YAN B, SHIN HC, WON MH. Immunohistochemical Changes in Orexigenic and Anorexigenic Neuropeptides in the Rat Hypothalamus after Capsaicin Administration. J Vet Med Sci 2009; 71:1337-42. [DOI: 10.1292/jvms.001337] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Affiliation(s)
- Choong Hyun LEE
- Department of Anatomy and Neurobiology, and Institute of Neurodegeneration and Neuroregeneration, College of Medicine, Hallym University
| | - Jung Hoon CHOI
- Department of Anatomy and Neurobiology, and Institute of Neurodegeneration and Neuroregeneration, College of Medicine, Hallym University
- Institute of Natural Medicine, Hallym University
| | - In Koo HWANG
- Department of Anatomy and Cell Biology, College of Veterinary Medicine and BK21 Program for Veterinary Science, Seoul National University
| | - Ki-Yeon YOO
- Department of Anatomy and Neurobiology, and Institute of Neurodegeneration and Neuroregeneration, College of Medicine, Hallym University
- Institute of Natural Medicine, Hallym University
| | - Hua LI
- Department of Anatomy and Neurobiology, and Institute of Neurodegeneration and Neuroregeneration, College of Medicine, Hallym University
| | - Ok Kyu PARK
- Department of Anatomy and Neurobiology, and Institute of Neurodegeneration and Neuroregeneration, College of Medicine, Hallym University
| | - Bingchun YAN
- Department of Anatomy and Neurobiology, and Institute of Neurodegeneration and Neuroregeneration, College of Medicine, Hallym University
| | - Hyung-Cheul SHIN
- Department of Physiology, College of Medicine, Hallym University
- Institute of Natural Medicine, Hallym University
| | - Moo-Ho WON
- Department of Anatomy and Neurobiology, and Institute of Neurodegeneration and Neuroregeneration, College of Medicine, Hallym University
- Institute of Natural Medicine, Hallym University
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Takayanagi Y, Matsumoto H, Nakata M, Mera T, Fukusumi S, Hinuma S, Ueta Y, Yada T, Leng G, Onaka T. Endogenous prolactin-releasing peptide regulates food intake in rodents. J Clin Invest 2008; 118:4014-24. [PMID: 19033670 PMCID: PMC2575834 DOI: 10.1172/jci34682] [Citation(s) in RCA: 72] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2007] [Accepted: 09/17/2008] [Indexed: 02/03/2023] Open
Abstract
Food intake is regulated by a network of signals that emanate from the gut and the brainstem. The peripheral satiety signal cholecystokinin is released from the gut following food intake and acts on fibers of the vagus nerve, which project to the brainstem and activate neurons that modulate both gastrointestinal function and appetite. In this study, we found that neurons in the nucleus tractus solitarii of the brainstem that express prolactin-releasing peptide (PrRP) are activated rapidly by food ingestion. To further examine the role of this peptide in the control of food intake and energy metabolism, we generated PrRP-deficient mice and found that they displayed late-onset obesity and adiposity, phenotypes that reflected an increase in meal size, hyperphagia, and attenuated responses to the anorexigenic signals cholecystokinin and leptin. Hypothalamic expression of 6 other appetite-regulating peptides remained unchanged in the PrRP-deficient mice. Blockade of endogenous PrRP signaling in WT rats by central injection of PrRP-specific mAb resulted in an increase in food intake, as reflected by an increase in meal size. These data suggest that PrRP relays satiety signals within the brain and that selective disturbance of this system can result in obesity and associated metabolic disorders.
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Affiliation(s)
- Yuki Takayanagi
- Division of Brain and Neurophysiology, Department of Physiology, Jichi Medical University, Shimotsuke, Tochigi, Japan.
Frontier Research Laboratories I, Pharmaceutical Research Division, Takeda Chemical Industries Ltd., Tsukuba, Ibaraki, Japan.
Division of Integrative Physiology, Department of Physiology, Jichi Medical University, Shimotsuke, Tochigi, Japan.
Department of Physiology, University of Occupational and Environmental Health, Kitakyushu, Japan.
Research Information & Alliances Strategic Research Planning Department, Pharmaceutical Research Division, Takeda Chemical Industries Ltd., Juso-honmachi, Yodogawaku, Osaka, Japan.
Centre for Integrative Physiology, School of Biomedical Sciences, University of Edinburgh, Edinburgh, United Kingdom
| | - Hirokazu Matsumoto
- Division of Brain and Neurophysiology, Department of Physiology, Jichi Medical University, Shimotsuke, Tochigi, Japan.
Frontier Research Laboratories I, Pharmaceutical Research Division, Takeda Chemical Industries Ltd., Tsukuba, Ibaraki, Japan.
Division of Integrative Physiology, Department of Physiology, Jichi Medical University, Shimotsuke, Tochigi, Japan.
Department of Physiology, University of Occupational and Environmental Health, Kitakyushu, Japan.
Research Information & Alliances Strategic Research Planning Department, Pharmaceutical Research Division, Takeda Chemical Industries Ltd., Juso-honmachi, Yodogawaku, Osaka, Japan.
Centre for Integrative Physiology, School of Biomedical Sciences, University of Edinburgh, Edinburgh, United Kingdom
| | - Masanori Nakata
- Division of Brain and Neurophysiology, Department of Physiology, Jichi Medical University, Shimotsuke, Tochigi, Japan.
Frontier Research Laboratories I, Pharmaceutical Research Division, Takeda Chemical Industries Ltd., Tsukuba, Ibaraki, Japan.
Division of Integrative Physiology, Department of Physiology, Jichi Medical University, Shimotsuke, Tochigi, Japan.
Department of Physiology, University of Occupational and Environmental Health, Kitakyushu, Japan.
Research Information & Alliances Strategic Research Planning Department, Pharmaceutical Research Division, Takeda Chemical Industries Ltd., Juso-honmachi, Yodogawaku, Osaka, Japan.
Centre for Integrative Physiology, School of Biomedical Sciences, University of Edinburgh, Edinburgh, United Kingdom
| | - Takashi Mera
- Division of Brain and Neurophysiology, Department of Physiology, Jichi Medical University, Shimotsuke, Tochigi, Japan.
Frontier Research Laboratories I, Pharmaceutical Research Division, Takeda Chemical Industries Ltd., Tsukuba, Ibaraki, Japan.
Division of Integrative Physiology, Department of Physiology, Jichi Medical University, Shimotsuke, Tochigi, Japan.
Department of Physiology, University of Occupational and Environmental Health, Kitakyushu, Japan.
Research Information & Alliances Strategic Research Planning Department, Pharmaceutical Research Division, Takeda Chemical Industries Ltd., Juso-honmachi, Yodogawaku, Osaka, Japan.
Centre for Integrative Physiology, School of Biomedical Sciences, University of Edinburgh, Edinburgh, United Kingdom
| | - Shoji Fukusumi
- Division of Brain and Neurophysiology, Department of Physiology, Jichi Medical University, Shimotsuke, Tochigi, Japan.
Frontier Research Laboratories I, Pharmaceutical Research Division, Takeda Chemical Industries Ltd., Tsukuba, Ibaraki, Japan.
Division of Integrative Physiology, Department of Physiology, Jichi Medical University, Shimotsuke, Tochigi, Japan.
Department of Physiology, University of Occupational and Environmental Health, Kitakyushu, Japan.
Research Information & Alliances Strategic Research Planning Department, Pharmaceutical Research Division, Takeda Chemical Industries Ltd., Juso-honmachi, Yodogawaku, Osaka, Japan.
Centre for Integrative Physiology, School of Biomedical Sciences, University of Edinburgh, Edinburgh, United Kingdom
| | - Shuji Hinuma
- Division of Brain and Neurophysiology, Department of Physiology, Jichi Medical University, Shimotsuke, Tochigi, Japan.
Frontier Research Laboratories I, Pharmaceutical Research Division, Takeda Chemical Industries Ltd., Tsukuba, Ibaraki, Japan.
Division of Integrative Physiology, Department of Physiology, Jichi Medical University, Shimotsuke, Tochigi, Japan.
Department of Physiology, University of Occupational and Environmental Health, Kitakyushu, Japan.
Research Information & Alliances Strategic Research Planning Department, Pharmaceutical Research Division, Takeda Chemical Industries Ltd., Juso-honmachi, Yodogawaku, Osaka, Japan.
Centre for Integrative Physiology, School of Biomedical Sciences, University of Edinburgh, Edinburgh, United Kingdom
| | - Yoichi Ueta
- Division of Brain and Neurophysiology, Department of Physiology, Jichi Medical University, Shimotsuke, Tochigi, Japan.
Frontier Research Laboratories I, Pharmaceutical Research Division, Takeda Chemical Industries Ltd., Tsukuba, Ibaraki, Japan.
Division of Integrative Physiology, Department of Physiology, Jichi Medical University, Shimotsuke, Tochigi, Japan.
Department of Physiology, University of Occupational and Environmental Health, Kitakyushu, Japan.
Research Information & Alliances Strategic Research Planning Department, Pharmaceutical Research Division, Takeda Chemical Industries Ltd., Juso-honmachi, Yodogawaku, Osaka, Japan.
Centre for Integrative Physiology, School of Biomedical Sciences, University of Edinburgh, Edinburgh, United Kingdom
| | - Toshihiko Yada
- Division of Brain and Neurophysiology, Department of Physiology, Jichi Medical University, Shimotsuke, Tochigi, Japan.
Frontier Research Laboratories I, Pharmaceutical Research Division, Takeda Chemical Industries Ltd., Tsukuba, Ibaraki, Japan.
Division of Integrative Physiology, Department of Physiology, Jichi Medical University, Shimotsuke, Tochigi, Japan.
Department of Physiology, University of Occupational and Environmental Health, Kitakyushu, Japan.
Research Information & Alliances Strategic Research Planning Department, Pharmaceutical Research Division, Takeda Chemical Industries Ltd., Juso-honmachi, Yodogawaku, Osaka, Japan.
Centre for Integrative Physiology, School of Biomedical Sciences, University of Edinburgh, Edinburgh, United Kingdom
| | - Gareth Leng
- Division of Brain and Neurophysiology, Department of Physiology, Jichi Medical University, Shimotsuke, Tochigi, Japan.
Frontier Research Laboratories I, Pharmaceutical Research Division, Takeda Chemical Industries Ltd., Tsukuba, Ibaraki, Japan.
Division of Integrative Physiology, Department of Physiology, Jichi Medical University, Shimotsuke, Tochigi, Japan.
Department of Physiology, University of Occupational and Environmental Health, Kitakyushu, Japan.
Research Information & Alliances Strategic Research Planning Department, Pharmaceutical Research Division, Takeda Chemical Industries Ltd., Juso-honmachi, Yodogawaku, Osaka, Japan.
Centre for Integrative Physiology, School of Biomedical Sciences, University of Edinburgh, Edinburgh, United Kingdom
| | - Tatsushi Onaka
- Division of Brain and Neurophysiology, Department of Physiology, Jichi Medical University, Shimotsuke, Tochigi, Japan.
Frontier Research Laboratories I, Pharmaceutical Research Division, Takeda Chemical Industries Ltd., Tsukuba, Ibaraki, Japan.
Division of Integrative Physiology, Department of Physiology, Jichi Medical University, Shimotsuke, Tochigi, Japan.
Department of Physiology, University of Occupational and Environmental Health, Kitakyushu, Japan.
Research Information & Alliances Strategic Research Planning Department, Pharmaceutical Research Division, Takeda Chemical Industries Ltd., Juso-honmachi, Yodogawaku, Osaka, Japan.
Centre for Integrative Physiology, School of Biomedical Sciences, University of Edinburgh, Edinburgh, United Kingdom
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Hypothalamic CaMKK2 contributes to the regulation of energy balance. Cell Metab 2008; 7:377-88. [PMID: 18460329 DOI: 10.1016/j.cmet.2008.02.011] [Citation(s) in RCA: 295] [Impact Index Per Article: 17.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/16/2007] [Revised: 01/07/2008] [Accepted: 02/25/2008] [Indexed: 12/14/2022]
Abstract
Detailed knowledge of the pathways by which ghrelin and leptin signal to AMPK in hypothalamic neurons and lead to regulation of appetite and glucose homeostasis is central to the development of effective means to combat obesity. Here we identify CaMKK2 as a component of one of these pathways, show that it regulates hypothalamic production of the orexigenic hormone NPY, provide evidence that it functions as an AMPKalpha kinase in the hypothalamus, and demonstrate that it forms a unique signaling complex with AMPKalpha and beta. Acute pharmacologic inhibition of CaMKK2 in wild-type mice, but not CaMKK2 null mice, inhibits appetite and promotes weight loss consistent with decreased NPY and AgRP mRNAs. Moreover, the loss of CaMKK2 protects mice from high-fat diet-induced obesity, insulin resistance, and glucose intolerance. These data underscore the potential of targeting CaMKK2 as a therapeutic intervention.
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Nilsson I, Lindfors C, Fetissov SO, Hökfelt T, Johansen JE. Aberrant agouti-related protein system in the hypothalamus of the anx/anx mouse is associated with activation of microglia. J Comp Neurol 2008; 507:1128-40. [PMID: 18098136 DOI: 10.1002/cne.21599] [Citation(s) in RCA: 41] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
Abstract
Agouti-related protein (AgRP) is a key orexigenic neuropeptide expressed in the hypothalamic arcuate nucleus and a marker for neurons conveying hormonal signals of hunger to the brain. Mice homozygous for the anorexia (anx) mutation are characterized by decreased food intake, starvation, and death by 3-5 weeks of age. At this stage immunoreactivity for AgRP is increased in cell bodies but decreased in the nerve terminals. We studied when during early postnatal development the aberrant phenotype of the AgRP system becomes apparent in anx/anx mice and possible underlying mechanisms. AgRP and ionized calcium binding adapter molecule (Iba1), a marker for activated microglia, as well as Toll-like receptor 2 (TLR-2), were studied by immunohistochemistry at postnatal days P1, P5, P10, P12, P15 and P21 in anx/anx and wild-type mice. We found that the AgRP system in the anx/anx mouse develops similarly to the wild type until P12, when AgRP fibers in anx/anx mice cease to increase in density in the main projection areas. At P21, AgRP fiber density in anx/anx mice was significantly reduced vs. P15, in certain regions. At P21, many strongly AgRP-positive cell bodies were observed in the anx/anx arcuate nucleus vs. only few and weakly fluorescent ones in the wild type. The decrease in AgRP fiber density in anx/anx mice overlapped with an increase in Iba1 and TLR-2 immunoreactivities. Thus, the aberrant appearance of the AgRP system in the anx/anx mouse in the early postnatal development could involve a microglia-associated process and the innate immune system.
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Affiliation(s)
- Ida Nilsson
- Department of Molecular Medicine and Surgery, Karolinska Institutet, 171 76 Stockholm, Sweden.
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Yoo SB, Lee JH, Ryu V, Jahng JW. Ingestion of non-caloric liquid diet is sufficient to restore plasma corticosterone level, but not to induce the hypothalamic c-Fos expression in food-deprived rats. Nutr Neurosci 2008; 10:261-7. [PMID: 18284034 DOI: 10.1080/10284150701723859] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/22/2022]
Abstract
Male Sprague-Dawley rats were subjected to four different conditions; free fed control (FC), 48 h of food deprivation (FD), 1 h of refeeding with chow (RF/CW) or with a non-caloric liquid diet following FD (RF/NC) and then sacrificed for c-Fos immunohistochemistry in the hypothalamic paraventricular nucleus (PVN) and the nucleus tractus of solitarius (NTS). Plasma corticosterone level and the postmortem weight of gastric contents were measured. Plasma level of corticosterone significantly increased during FD, and then decreased within 1 h after ad libitum access to chow or non-caloric liquid diet. c-Fos-ir in the brain regions was not changed by FD; however, significantly increased by chow refeeding, but not by non-caloric diet. Chow, but not the non-caloric, refeeding significantly increased gastric contents. Results suggest that caloric load and/or gastric distension may require for the postprandial activation of neurons in the PVN and NTS, but ingestion of non-caloric palatable mixture may be sufficient to normalize the fasting-induced increase of plasma corticosterone. In conclusion, feeding-related changes in the HPA axis activity may not be related with meal-induced c-Fos expression in the PVN and NTS.
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Affiliation(s)
- Sang Bae Yoo
- Department of Oral and Maxillofacial Surgery, Dental Research Institute, Seoul National University School of Dentistry, Seoul 110-768, South Korea
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Starvation after AgRP neuron ablation is independent of melanocortin signaling. Proc Natl Acad Sci U S A 2008; 105:2687-92. [PMID: 18272480 DOI: 10.1073/pnas.0712062105] [Citation(s) in RCA: 91] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
Abstract
Ablation of inhibitory agouti-related protein (AgRP)-expressing neurons in the arcuate nucleus that also synthesize gamma-amino-butyric acid (GABA) and neuropeptide Y in adult mice leads to starvation within 1 week. The removal of inhibition from the AgRP neurons onto neighboring proopiomelanocortin neurons and their common postsynaptic neurons is predicted to stimulate melanocortin signaling, which is known to inhibit appetite. To examine the importance of uncontrolled melanocortin signaling in mediating starvation in this model, we ablated AgRP neurons in A(y)/a mice that have chronic blockade of the melanocortin signaling. The blockade of melanocortin signaling did not ameliorate the rate of starvation. On both WT and A(y)/a genetic backgrounds, there was a progressive decrease in meal frequency after AgRP neuron ablation. Surprisingly, intraoral feeding also was dramatically reduced after the ablation of AgRP neurons. These results indicate that both the appetitive and consummatory aspects of feeding become impaired in a melanocortin-independent manner after AgRP neuron ablation.
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