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The Hypothalamus for whole-body physiology:from metabolism to aging

Protein & Cell 2022年第6期13卷 394-421页

作者： Tiemin Liu Yong Xu Chun-Xia Yi Qingchun Tong Dongsheng Cai State Key Laboratory of Genetic Engineering Department of Endocrinology and MetabolismInstitute of Metabolism and Integrative BiologyHuman Phenome Instituteand Collaborative Innovation Center for Genetics and DevelopmentZhongshan HospitalSchool of Life SciencesFudan UniversityShanghai 200438China Children’s Nutrition Research Center Department of PediatricsDepartment of Molecular and Cellular BiologyBaylor College of MedicineOne Baylor PlazaHoustonTX 77030USA Department of Endocrinology and Metabolism Amsterdam University Medical CentersAmsterdam Gastroenterology Endocrinology MetabolismUniversity of AmsterdamMeibergdreef 91105AZ AmsterdamNetherlands Brown Foundation Institute of Molecular Medicine Department of Neurobiology and AnatomyUniversity of Texas McGovern Medical SchoolGraduate Program in Neuroscience of MD Anderson UTHealth Graduate School of Biomedical SciencesHoustonTX 77030USA Department of Molecular Pharmacology Albert Einstein College of MedicineBronxNew YorkNY 10461USA

Obesity and aging are two important epidemic factors for metabolic syndrome and many other health issues,which contribute to devastating diseases such as cardiovascular diseases,stroke and cancers.The brain plays a central role in controlling metabolic physiology in that it integrates information from other metabolic organs,sends regulatory projections and orchestrates the whole-body function.Emerging studies suggest that brain dysfunction in sensing various internal cues or processing external cues may have profound effects on metabolic and other physiological functions.This review highlights brain dysfunction linked to genetic mutations,sex,brain inflammation,microbiota,stress as causes for whole-body pathophysiology,arguing brain dysfunction as a root cause for the epidemic of aging and obesity-related disorders.We also speculate key issues that need to be addressed on how to reveal relevant brain dysfunction that underlines the development of these disorders and diseases in order to develop new treatment strategies against these health problems.

关键词： neuron metabolism Hypothalamus obesity aging

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Chronic corticosterone disrupts the circadian rhythm of CRH expression and m^(6)A RNA methylation in the chicken Hypothalamus

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Journal of Animal Science and Biotechnology 2022年第4期13卷 1056-1068页

作者： Yang Yang Wanwan Han Aijia Zhang Mindie Zhao Wei Cong Yimin Jia Deyun Wang Ruqian Zhao MOE Joint International Research Laboratory of Animal Health&Food Safety Institute of ImmunologyNanjing Agricultural UniversityNanjing 210095People’s Republic of China Key Laboratory of Animal Physiology&Biochemistry College of Veterinary MedicineNanjing Agricultural UniversityNanjing 210095People’s Republic of China Institute of Traditional Chinese Veterinary Medicine College of Veterinary MedicineNanjing Agricultural UniversityNanjing 210095People’s Republic of China.

Background:Corticotropin-releasing hormone(CRH),the major secretagogue of the hypothalamic-pituitary-adrenal(HPA)axis,is intricately intertwined with the clock genes to regulate the circadian rhythm of various body functions.N6-methyladenosine(m^(6)A)RNA methylation is involved in the regulation of circadian rhythm,yet it remains unknown whether CRH expression and m^(6)A modification oscillate with the clock genes in chicken Hypothalamus and how the circadian rhythms change under chronic stress.Results:Chronic exposure to corticosterone(CORT)eliminated the diurnal patterns of plasma CORT and melatonin levels in the chicken.The circadian rhythms of clock genes in hippocampus,Hypothalamus and pituitary are all disturbed to different extent in CORT-treated chickens.The most striking changes occur in Hypothalamus in which the diurnal fluctuation of CRH mRNA is flattened,together with mRNA of other feeding-related neuropeptides.Interestingly,hypothalamic m^(6)A level oscillates in an opposite pattern to CRH mRNA,with lowestm^(6)A level after midnight(ZT18)corresponding to the peak of CRH mRNA before dawn(ZT22).CORT diminished the circadian rhythm of m^(6)A methylation with significantly increased level at night.Further site-specific m^(6)A analysis on 3’UTR of CRH mRNA indicates that higher m^(6)A on 3’UTR of CRH mRNA coincides with lower CRH mRNA at night(ZT18 and ZT22).Conclusions:Our results indicate that chronic stress disrupts the circadian rhythms of CRH expression in Hypothalamus,leading to dysfunction of HPA axis in the chicken.RNA m^(6)A modification is involved in the regulation of circadian rhythms in chicken Hypothalamus under both basal and chronic stress conditions.

关键词： Chronic corticosterone exposure Circadian rhythms CRH Hypothalamus m^(6)A

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Ginsenoside Rg1 and astaxanthin act on the Hypothalamus to protect female mice against reproductive aging

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Chinese Medical Journal 2022年第1期135卷 107-109页

作者： Xiaoman Dai Guirong Zeng Luyan Hong Qinyong Ye Xiaochun Chen Jing Zhang Department of Neurology and Geriatrics Fujian Institute of GeriatricsFujian Medical University Union HospitalFuzhouFujian 350001China Fujian Key Laboratory of Molecular Neurology Institute of NeuroscienceFujian Medical UniversityFuzhouFujian 350005China

To the Editor:Female infertility due to reproductive aging has become a prominent concern in the population.Evidence indicates that oxidative stress is one of the dominant mechanisms underlying reproductive aging.[1,2]Although female reproductive aging involves gradual changes to the hypothalamic-pituitary-ovarian(HPO)axis,previous studies support a key involvement of the Hypothalamus.[3,4]In our recent dataset,it was shown that estrogen-induced oxidative stress led to the senescence of hypothalamic astrocytes that predated reproductive dysfunction.[3]Growing evidence has demonstrated that antioxidants might delay reproductive aging by reducing oxidative damage to ovaries.[1,2]However,the effect of antioxidants on the Hypothalamus has not been reported.Astaxanthin(AST),3,3'-dihydroxy-β-carotene-4,4'-dione,is a xanthophyll carotenoid found predominantly in marine animals such as salmon,trout,lobster,and shrimp.Ginseng is a tonic drug in traditional Chinese medicine.Ginsenoside Rg1,a class of steroidal glycosides,is a prominent active anti-aging ingredient within ginseng responsible for these effects.Notably,the two antioxidants freely cross the blood-brain barrier.In this study,we evaluated the effects of these two natural compounds on the Hypothalamus and ovaries in protecting female mice from reproductive aging.

关键词： Hypothalamus female involvement

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Loss of the centrosomal protein Cenpj leads to dysfunction of the Hypothalamus and obesity in mice

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Science China(Life Sciences) 2021年第3期64卷 419-433页

作者： Wenyu Ding Changjiang Zhang Baisong Wang Xin Zhou Le Sun Suijuan Zhong Jing Liu Junjing Zhang Xiaoqun Wang Qian Wu State Key Laboratory of Cognitive Neuroscience and Learning Beijing Normal UniversityBeijing 100875China IDG/McGovern Institute for Brain Research Beijing Normal UniversityBeijing 100875China State Key Laboratory of Brain and Cognitive Science CAS Center for Excellence in Brain Science and Intelligence TechnologyInstitute of Brain-Intelligence Technology(Shanghai)Institute of BiophysicsChinese Academy of SciencesBeijing 100101China University of Chinese Academy of Sciences Beijing 100049China Institute for Stem Cell and Regeneration Chinese Academy of SciencesBeijing 100101China Advanced Innovation Center for Human Brain Protection Beijing Institute for Brain DisordersCapital Medical UniversityBeijing 100069China

Cenpj is a centrosomal protein located at the centrosomes and the base of cilia,it plays essential roles in regulating neurogenesis and cerebral cortex development.Although centrosomal and cilium dysfunction are one of the causes of obesity,insulin resistance,and type 2 diabetes,the role that Cenpj plays in the regulation of body weight remains unclear.Here,we deleted Cenpj by crossing Cenpjflox/flox mice with Nkx2.1-Cre mice.Loss of the centrosomal protein Cenpj in Nkx2.1-expressing cells causes morbid obesity in mice at approximately 4 months of age with expended brain ventricles but no change of brain size.We found that hypothalamic cells exhibited reduced proliferation and increased apoptosis upon Cenpj depletion at the embryonic stages,resulting in a dramatic decrease in the number of Proopiomelanocortin(POMC)neurons and electrophysiological dysfunction of NPY neurons in the arcuate nucleus(ARC)in adults.Furthermore,depletion of Cenpj also reduced the neuronal projection from the ARC to the paraventricular nucleus(PVN),with decreased melanocortin-4 receptors(MC4R)expression in PVN neurons.The study defines the roles that Cenpj plays in regulating Hypothalamus development and body weight,providing a foundation for further understanding of the pathological mechanisms of related diseases.

关键词： arcuate nucleus centrosomal protein Cenpj Nkx2.1 Hypothalamus paraventricular nucleus

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Profiles of metabolic gene expression in the white adipose tissue, liver and Hypothalamus in leptin knockout(Lep^(△I14/△I14)) rats

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The Journal of Biomedical Research 2017年第6期31卷 528-540页

作者： Leijian Guan Kaixuan Xu Shuyang Xu Ningning Li Xinru Wang Yankai Xia Di Wu State Key Laboratory of Reproductive Medicine Institute of Toxicology School of Public Health Nanjing Medical University Xuzhou Central Hospital The Affiliated Xuzhou Hospital of Medical College of Southeast University School of Life Sciences and Technology Tongji University

Leptin deficiency is principally linked to metabolic disorders. Leptin knockout（Lep△I14/△I14 Sprague Dawley rats created by CRISPR/Cas9 is a new model to study metabolic disorders. We used a whole rat genome oligonucleotide microarray to obtain tissue-specific gene expression profiles of the white adipose tissue, liver and Hypothalamus in Lep△I14/△I14）and wild-type（WT） rats. We found 1,651 differentially expressed（enriched） genes in white adipose tissue,916 in the liver, and 306 in the Hypothalamus in the Lep△I14/△I14 rats compared to WT. Gene ontology category and KEGG pathway analysis of the relationships among differentially expressed genes showed that these genes were represented in a variety of functional categories, including fatty acid metabolism, molecular transducers and cellular processes. The reliability of the data obtained from microarray was verified by quantitative real-time PCR on 14 representative genes. These data will contribute to a greater understanding of different metabolic disorders, such as obesity and diabetes.

关键词： Lep△I14/△I14 microarray analysis white adipose liver Hypothalamus

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Hypothalamus

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China Medical Abstracts(Internal Medicine) 2008年第3期25卷 150-151页

2008403 Analysis of catch-up growth pattern to recombinant human growth hormone treatment in prepubertal children with short stature and various secretory forms of growth hormone. SU Zhe(苏吉吉), et al. Dept Pediat, 1... 详细信息

关键词： secretory children Metab catch Hypothalamus Guangzhou gonadotropin rhGH retardation endocrine

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Transcriptome responses to heat stress in Hypothalamus of a meat-type chicken

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Journal of Animal Science and Biotechnology 2015年第3期6卷 291-302页

作者： Hongyan Sun Runshen Jiang Shengyou Xu Zebin Zhang Guiyun Xu Jiangxia Zheng Lujiang Qu Department of Animal Genetics and Breeding National Engineering Laboratory for Animal BreedingCollege of Animal Science and TechnologyChina Agricultural University College of Animal Science and Technology Anhui Agricultural University

Background： Heat stress has resulted in great losses in poultry production. To address this issue, we systematically analyzed chicken Hypothalamus transcriptome responses to thermal stress using a 44 k chicken Agilent microarray, Methods： Hypothalamus samples were collected from a control group reared at 25℃, a heat-stress group treated at 34℃ for 24 h, and a temperature-recovery group reared at 25℃ for 24 h following a heat-stress treatment. We compared the expression profiles between each pair of the three groups using microarray data. Results： A total of 1,967 probe sets were found to be differentially expressed in the three comparisons with P 〈 0.05 and a fold change （FC） higher than 1.5, and the genes were mainly involved in self-regulation and compensation required to maintain homeostasis. Consistent expression results were found for 11 selected genes by quantitative real-time PCR. Thirty-eight interesting differential expression genes were found from GO term annotation and those genes were related to meat quality, growth, and crucial enzymes. Using these genes for genetic network analysis, we obtained three genetic networks. Moreover, the transcripts of heat-shock protein, including Hsp 40 and Hsp 90, were significantly altered in response to thermal stress. Conclusions： This study provides a broader understanding of molecular mechanisms underlying stress response in chickens and discovery of novel genes that are regulated in a specific thermal-stress manner.

关键词： Chicken Heat shock protein Heat stress Hypothalamus Microarray Transcription

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Neuropeptide Y and leptin receptor expression in the Hypothalamus of rats with chronic immobilization stress

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Neural Regeneration Research 2013年第18期8卷 1721-1726页

作者： Shaoxian Wang Jiaxu Chen Guangxin Yue Minghua Bai Meijing Kou Zhongye Jin School of Pre-clinical Medicine Beijing University of Chinese Medicine Traditional Chinese Medicine College of Hebei Medical University Institute of Basic Theory in Chinese Medicine China Academy of Chinese Medical Sciences

In this study, Sprague-Dawley rats were immobilized to a frame for 3 hours a day for 21 days to establish a model of chronic immobilization stress. The body weight and food intake of rats subjected to chronic immobilization stress were significantly decreased compared with the control group. Dual-labeling immunofluorescence revealed that the expression of leptin receptor and the co-localization coeffient in these leptic receptor neurons in the arcuate nucleus of the Hypothalamus were both upregulated, while the number of neuropeptide Y neurons was decreased. Chronic immobilization stress induced high expression of leptin receptor in the arcuate nucleus and suppressed the synthesis and secretion of neuropeptide Y, thereby disrupting the pathways in the arcuate nucleus that regulate feeding behavior, resulting in diminished food intake and reduced body weight.

关键词： neural regeneration chronic immobilization stress Hypothalamus arcuate nucleus doubleimmunofluorescence neuropeptide Y leptin receptor feeding center body weight grants-supported paper neuroregeneration

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EphA3 deficiency in the Hypothalamus promotes high-fat diet-induced obesity in mice

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The Journal of Biomedical Research 2023年第3期37卷 179-193页

作者： Jubiao Zhang Yang Chen Lihong Yan Xin Zhang Xiaoyan Zheng Junxia Qi Fen Yang Juxue Li State Key Laboratory of Reproductive Medicine Nanjing Medical UniversityNanjingJiangsu 211166China Key Laboratory of Human Functional Genomics of Jiangsu Province Nanjing Medical UniversityNanjingJiangsu 211166China The Affiliated Eye Hospital of Nanjing Medical University NanjingJiangsu 210029China The Second Affiliated Hospital of Nanjing Medical University NanjingJiangsu 210011China.

Erythropoietin-producing hepatocellular carcinoma A3(EphA3)is a member of the largest subfamily of tyrosine kinase receptors-Eph receptors.Previous studies have shown that EphA3 is associated with tissue development.Recently,we have found that the expression of EphA3 is elevated in the Hypothalamus of mice with diet-induced obesity(DIO).However,the role of EphA3 in hypothalamic-controlled energy metabolism remains unclear.In the current study,we demonstrated that the deletion of EphA3 in the Hypothalamus by CRISPR/Cas9-mediated gene editing promotes obesity in male mice with high-fat diet feeding rather than those with normal chow diet feeding.Moreover,the deletion of hypothalamic EphA3 promotes high-fat DIO by increasing food intake and reducing energy expenditure.Knockdown of EphA3 leads to smaller intracellular vesicles in GT1-7 cells.The current study reveals that hypothalamic EphA3 plays important roles in promoting DIO.

关键词： EphA3 Hypothalamus metabolism CRISPR-Cas9 obesity

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Metformin inhibits food intake and neuropeptide Y gene expression in the Hypothalamus

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Neural Regeneration Research 2013年第25期8卷 2379-2388页

作者： Yale Duan Rui Zhang Min Zhang Lijuan Sun Suzhen Dong Gang Wang Jun Zhang Zheng Zhao Key Laboratory of Brain Functional Genomics Ministry of EducationShanghai Key Laboratory of Brain Functional GenomicsEast China Normal University Department of Clinical Laboratory Shanghai Public Health Clinical Center Affiliated to Fudan University

Metformin may reduce food intake and body weight, but the anorexigenic effects of metformin are still poorly understood. In this study, Sprague-Dawley rats were administered a single intracere- broventricular dose of metformin and compound C, in a broader attempt to investigate the regula- tory effects of metformin on food intake and to explore the possible mechanism. Results showed that central administration of metformin significantly reduced food intake and body weight gain, par- ticularly after 4 hours. A reduction of neuropeptide Y expression and induction of AMP-activated protein kinase phosphorylation in the Hypothalamus were also observed 4 hours after metformin administration, which could be reversed by compound C, a commonly-used antagonist of AMP-activated protein kinase. Furthermore, metformin also improved lipid metabolism by reducing plasma low-density lipoprotein. Our findings suggest that under normal physiological conditions, central regulation of appetite by metformin is related to a decrease in neuropeptide Y gene expres- sion, and that the activation of AMP-activated protein kinase may simply be a response to the anorexigenic effect of metformin.

关键词： neural regeneration metformin food intake body weight gain Hypothalamus AMP-activated pro-tein kinase neuropeptide Y grants-supported paper neuroregeneration

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