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Brial F, Le Lay A, Rouch C, Henrion E, Bourgey M, Bourque G, Lathrop M, Magnan C, Gauguier D. Transcriptome atlases of rat brain regions and their adaptation to diabetes resolution following gastrectomy in the Goto-Kakizaki rat. Mol Brain 2025; 18:9. [PMID: 39920851 PMCID: PMC11806591 DOI: 10.1186/s13041-025-01176-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2024] [Accepted: 01/13/2025] [Indexed: 02/09/2025] Open
Abstract
Brain regions drive multiple physiological functions through specific gene expression patterns that adapt to environmental influences, drug treatments and disease conditions. To generate a detailed atlas of the brain transcriptome in the context of diabetes, we carried out RNA sequencing in hypothalamus, hippocampus, brainstem and striatum of the Goto-Kakizaki (GK) rat model of spontaneous type 2 diabetes, which was applied to identify gene transcription adaptation to improved glycemic control following vertical sleeve gastrectomy (VSG) in the GK. Over 19,000 distinct transcripts were detected in the rat brain, including 2794 which were consistently expressed in the four brain regions. Region-specific gene expression was identified in hypothalamus (n = 477), hippocampus (n = 468), brainstem (n = 1173) and striatum (n = 791), resulting in differential regulation of biological processes between regions. Differentially expressed genes between VSG and sham operated rats were only found in the hypothalamus and were predominantly involved in the regulation of endothelium and extracellular matrix. These results provide a detailed atlas of regional gene expression in the diabetic rat brain and suggest that the long term effects of gastrectomy-promoted diabetes remission involve functional changes in the hypothalamus endothelium.
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Affiliation(s)
- François Brial
- Université Paris Cité, INSERM U1132 Biologie de l'os et du Cartilage (BIOSCAR), 75010, Paris, France
| | - Aurélie Le Lay
- Université Paris Cité, Functional and Adaptive Biology, UMR 8251, CNRS, 4 Rue Marie Andrée Lagroua Weill-Halle, 75013, Paris, France
| | - Claude Rouch
- Université Paris Cité, Functional and Adaptive Biology, UMR 8251, CNRS, 4 Rue Marie Andrée Lagroua Weill-Halle, 75013, Paris, France
| | - Edouard Henrion
- Victor Phillip Dahdaleh Institute of Genomic Medicine at McGill University, 740 Doctor Penfield Avenue, Montreal, QC, H3A 0G1, Canada
| | - Mathieu Bourgey
- Victor Phillip Dahdaleh Institute of Genomic Medicine at McGill University, 740 Doctor Penfield Avenue, Montreal, QC, H3A 0G1, Canada
| | - Guillaume Bourque
- Victor Phillip Dahdaleh Institute of Genomic Medicine at McGill University, 740 Doctor Penfield Avenue, Montreal, QC, H3A 0G1, Canada
| | - Mark Lathrop
- Victor Phillip Dahdaleh Institute of Genomic Medicine at McGill University, 740 Doctor Penfield Avenue, Montreal, QC, H3A 0G1, Canada
| | - Christophe Magnan
- Université Paris Cité, Functional and Adaptive Biology, UMR 8251, CNRS, 4 Rue Marie Andrée Lagroua Weill-Halle, 75013, Paris, France
| | - Dominique Gauguier
- Université Paris Cité, Functional and Adaptive Biology, UMR 8251, CNRS, 4 Rue Marie Andrée Lagroua Weill-Halle, 75013, Paris, France.
- Victor Phillip Dahdaleh Institute of Genomic Medicine at McGill University, 740 Doctor Penfield Avenue, Montreal, QC, H3A 0G1, Canada.
- Center for Genomic Medicine, Kyoto University Graduate School of Medicine, Kyoto, 606-8501, Japan.
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2
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Rapps K, Weller A, Meiri N. Epigenetic regulation is involved in reversal of obesity. Neurosci Biobehav Rev 2024; 167:105906. [PMID: 39343077 DOI: 10.1016/j.neubiorev.2024.105906] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2024] [Revised: 09/10/2024] [Accepted: 09/23/2024] [Indexed: 10/01/2024]
Abstract
Epigenetic processes play a crucial role in mediating the impact of environmental energetic challenges, from overconsumption to starvation. Over-nutrition of energy-dense foods and sedentary lifestyles contribute to the development of obesity, characterized by excessive fat storage and impaired metabolic signaling, stemming from disrupted brain signaling. Conversely, dieting and physical activity facilitate body weight rebalancing and trigger adaptive neural responses. These adaptations involve the upregulation of neurogenesis, synaptic plasticity and optimized brain function and energy homeostasis, balanced hormone signaling, normal metabolism, and reduced inflammation. The transition of the brain from a maladaptive to an adaptive state is partially guided by epigenetic mechanisms. While epigenetic mechanisms underlying obesity-related brain changes have been described, their role in mediating the reversal of maladaptation/obesity through lifestyle interventions remains less explored. This review focuses on elucidating epigenetic mechanisms involved in hypothalamic adaptations induced by lifestyle interventions. Given that lifestyle interventions are widely prescribed and accessible approaches for weight loss and maintenance, it is our challenge to uncover epigenetic mechanisms moderating these hypothalamic-functional beneficial changes.
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Affiliation(s)
- Kayla Rapps
- Faculty of Life Sciences, Bar Ilan University, Ramat-Gan, Israel; Institute of Animal Science, Agricultural Research Organization, The Volcani Center, Bet Dagan, Israel; Gonda Multidisciplinary Brain Research Center, Bar Ilan University, Ramat-Gan, Israel
| | - Aron Weller
- Gonda Multidisciplinary Brain Research Center, Bar Ilan University, Ramat-Gan, Israel; Department of Psychology, Bar Ilan University, Ramat-Gan, Israel
| | - Noam Meiri
- Institute of Animal Science, Agricultural Research Organization, The Volcani Center, Bet Dagan, Israel.
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Jovanovic VM, Narisu N, Bonnycastle LL, Tharakan R, Mesch KT, Glover HJ, Yan T, Sinha N, Sen C, Castellano D, Yang S, Blivis D, Ryu S, Bennett DF, Rosales-Soto G, Inman J, Ormanoglu P, LeClair CA, Xia M, Schneider M, Hernandez-Ochoa EO, Erdos MR, Simeonov A, Chen S, Collins FS, Doege CA, Tristan CA. Scalable Hypothalamic Arcuate Neuron Differentiation from Human Pluripotent Stem Cells Suitable for Modeling Metabolic and Reproductive Disorders. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.06.27.601062. [PMID: 39005353 PMCID: PMC11244856 DOI: 10.1101/2024.06.27.601062] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/16/2024]
Abstract
The hypothalamus, composed of several nuclei, is essential for maintaining our body's homeostasis. The arcuate nucleus (ARC), located in the mediobasal hypothalamus, contains neuronal populations with eminent roles in energy and glucose homeostasis as well as reproduction. These neuronal populations are of great interest for translational research. To fulfill this promise, we used a robotic cell culture platform to provide a scalable and chemically defined approach for differentiating human pluripotent stem cells (hPSCs) into pro-opiomelanocortin (POMC), somatostatin (SST), tyrosine hydroxylase (TH) and gonadotropin-releasing hormone (GnRH) neuronal subpopulations with an ARC-like signature. This robust approach is reproducible across several distinct hPSC lines and exhibits a stepwise induction of key ventral diencephalon and ARC markers in transcriptomic profiling experiments. This is further corroborated by direct comparison to human fetal hypothalamus, and the enriched expression of genes implicated in obesity and type 2 diabetes (T2D). Genome-wide chromatin accessibility profiling by ATAC-seq identified accessible regulatory regions that can be utilized to predict candidate enhancers related to metabolic disorders and hypothalamic development. In depth molecular, cellular, and functional experiments unveiled the responsiveness of the hPSC-derived hypothalamic neurons to hormonal stimuli, such as insulin, neuropeptides including kisspeptin, and incretin mimetic drugs such as Exendin-4, highlighting their potential utility as physiologically relevant cellular models for disease studies. In addition, differential glucose and insulin treatments uncovered adaptability within the generated ARC neurons in the dynamic regulation of POMC and insulin receptors. In summary, the establishment of this model represents a novel, chemically defined, and scalable platform for manufacturing large numbers of hypothalamic arcuate neurons and serves as a valuable resource for modeling metabolic and reproductive disorders.
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Affiliation(s)
- Vukasin M. Jovanovic
- National Center for Advancing Translational Sciences (NCATS), Division of Preclinical Innovation Rockville, MD 20850, USA
- Hypothalamus Consortium
| | - Narisu Narisu
- Center for Precision Health Research, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA
- Hypothalamus Consortium
| | - Lori L. Bonnycastle
- Center for Precision Health Research, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA
- Hypothalamus Consortium
| | - Ravi Tharakan
- National Center for Advancing Translational Sciences (NCATS), Division of Preclinical Innovation Rockville, MD 20850, USA
| | - Kendall T. Mesch
- National Center for Advancing Translational Sciences (NCATS), Division of Preclinical Innovation Rockville, MD 20850, USA
- Hypothalamus Consortium
| | - Hannah J. Glover
- Naomi Berrie Diabetes Center, Columbia Stem Cell Initiative, Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, NY, USA
- Hypothalamus Consortium
| | - Tingfen Yan
- Center for Precision Health Research, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA
- Hypothalamus Consortium
| | - Neelam Sinha
- Center for Precision Health Research, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA
- Hypothalamus Consortium
| | - Chaitali Sen
- National Center for Advancing Translational Sciences (NCATS), Division of Preclinical Innovation Rockville, MD 20850, USA
- Hypothalamus Consortium
| | - David Castellano
- National Center for Advancing Translational Sciences (NCATS), Division of Preclinical Innovation Rockville, MD 20850, USA
| | - Shu Yang
- National Center for Advancing Translational Sciences (NCATS), Division of Preclinical Innovation Rockville, MD 20850, USA
| | - Dvir Blivis
- National Center for Advancing Translational Sciences (NCATS), Division of Preclinical Innovation Rockville, MD 20850, USA
| | - Seungmi Ryu
- National Center for Advancing Translational Sciences (NCATS), Division of Preclinical Innovation Rockville, MD 20850, USA
| | - Daniel F. Bennett
- Department of Biochemistry and Molecular Biology, School of Medicine, University of Maryland, Baltimore, MD, USA
| | - Giovanni Rosales-Soto
- Department of Biochemistry and Molecular Biology, School of Medicine, University of Maryland, Baltimore, MD, USA
| | - Jason Inman
- National Center for Advancing Translational Sciences (NCATS), Division of Preclinical Innovation Rockville, MD 20850, USA
| | - Pinar Ormanoglu
- National Center for Advancing Translational Sciences (NCATS), Division of Preclinical Innovation Rockville, MD 20850, USA
| | - Christopher A. LeClair
- National Center for Advancing Translational Sciences (NCATS), Division of Preclinical Innovation Rockville, MD 20850, USA
| | - Menghang Xia
- National Center for Advancing Translational Sciences (NCATS), Division of Preclinical Innovation Rockville, MD 20850, USA
| | - Martin Schneider
- Department of Biochemistry and Molecular Biology, School of Medicine, University of Maryland, Baltimore, MD, USA
| | - Erick O. Hernandez-Ochoa
- Department of Biochemistry and Molecular Biology, School of Medicine, University of Maryland, Baltimore, MD, USA
| | - Michael R. Erdos
- Center for Precision Health Research, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA
- Hypothalamus Consortium
| | - Anton Simeonov
- National Center for Advancing Translational Sciences (NCATS), Division of Preclinical Innovation Rockville, MD 20850, USA
| | - Shuibing Chen
- Department of Surgery, Center for Genomic Health, Weill Cornell Medicine, New York, NY 10065, USA
- Hypothalamus Consortium
| | - Francis S. Collins
- Center for Precision Health Research, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA
- Hypothalamus Consortium
| | - Claudia A. Doege
- Naomi Berrie Diabetes Center, Columbia Stem Cell Initiative, Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, NY, USA
- Hypothalamus Consortium
| | - Carlos A. Tristan
- National Center for Advancing Translational Sciences (NCATS), Division of Preclinical Innovation Rockville, MD 20850, USA
- Hypothalamus Consortium
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Herb BR, Glover HJ, Bhaduri A, Colantuoni C, Bale TL, Siletti K, Hodge R, Lein E, Kriegstein AR, Doege CA, Ament SA. Single-cell genomics reveals region-specific developmental trajectories underlying neuronal diversity in the human hypothalamus. SCIENCE ADVANCES 2023; 9:eadf6251. [PMID: 37939194 PMCID: PMC10631741 DOI: 10.1126/sciadv.adf6251] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/02/2022] [Accepted: 10/24/2023] [Indexed: 11/10/2023]
Abstract
The development and diversity of neuronal subtypes in the human hypothalamus has been insufficiently characterized. To address this, we integrated transcriptomic data from 241,096 cells (126,840 newly generated) in the prenatal and adult human hypothalamus to reveal a temporal trajectory from proliferative stem cell populations to mature hypothalamic cell types. Iterative clustering of the adult neurons identified 108 robust transcriptionally distinct neuronal subtypes representing 10 hypothalamic nuclei. Pseudotime trajectories provided insights into the genes driving formation of these nuclei. Comparisons to single-cell transcriptomic data from the mouse hypothalamus suggested extensive conservation of neuronal subtypes despite certain differences in species-enriched gene expression. The uniqueness of hypothalamic neuronal lineages was examined developmentally by comparing excitatory lineages present in cortex and inhibitory lineages in ganglionic eminence, revealing both distinct and shared drivers of neuronal maturation across the human forebrain. These results provide a comprehensive transcriptomic view of human hypothalamus development through gestation and adulthood at cellular resolution.
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Affiliation(s)
- Brian R. Herb
- Institute for Genome Sciences, University of Maryland School of Medicine, Baltimore, MD, USA
- Department of Pharmacology, University of Maryland School of Medicine, Baltimore, MD, USA
- UM-MIND, University of Maryland School of Medicine, Baltimore, MD, USA
- Kahlert Institute for Addiction Medicine, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Hannah J. Glover
- Naomi Berrie Diabetes Center, Columbia Stem Cell Initiative, Department of Pediatrics, Columbia University Irving Medical Center, New York, NY, USA
| | - Aparna Bhaduri
- Department of Biological Chemistry, University of California, Los Angeles, Los Angeles, CA, USA
| | - Carlo Colantuoni
- Institute for Genome Sciences, University of Maryland School of Medicine, Baltimore, MD, USA
- Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Tracy L. Bale
- Department of Psychiatry, University of Colorado School of Medicine, Aurora, CO, USA
| | - Kimberly Siletti
- Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden
| | - Rebecca Hodge
- Allen Institute for Brain Science, Seattle, WA 98109
| | - Ed Lein
- Allen Institute for Brain Science, Seattle, WA 98109
| | - Arnold R. Kriegstein
- Department of Neurology, University of California, San Francisco, San Francisco, CA, USA
- The Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, CA, USA
| | - Claudia A. Doege
- Naomi Berrie Diabetes Center, Columbia Stem Cell Initiative, Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, NY, USA
| | - Seth A. Ament
- Institute for Genome Sciences, University of Maryland School of Medicine, Baltimore, MD, USA
- UM-MIND, University of Maryland School of Medicine, Baltimore, MD, USA
- Kahlert Institute for Addiction Medicine, University of Maryland School of Medicine, Baltimore, MD, USA
- Maryland Psychiatric Research Center, Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD, USA
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5
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Zhu N, LeDuc CA, Fennoy I, Laferrère B, Doege CA, Shen Y, Chung WK, Leibel RL. Rare predicted loss of function alleles in Bassoon (BSN) are associated with obesity. NPJ Genom Med 2023; 8:33. [PMID: 37865656 PMCID: PMC10590409 DOI: 10.1038/s41525-023-00376-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2023] [Accepted: 10/02/2023] [Indexed: 10/23/2023] Open
Abstract
Bassoon (BSN) is a component of a hetero-dimeric presynaptic cytomatrix protein that orchestrates neurotransmitter release with Piccolo (PCLO) from glutamatergic neurons throughout the brain. Heterozygous missense variants in BSN have previously been associated with neurodegenerative disorders in humans. We performed an exome-wide association analysis of ultra-rare variants in about 140,000 unrelated individuals from the UK Biobank to search for new genes associated with obesity. We found that rare heterozygous predicted loss of function (pLoF) variants in BSN are associated with higher BMI with p-value of 3.6e-12 in the UK biobank cohort. Additionally, we identified two individuals (one of whom has a de novo variant) with a heterozygous pLoF variant in a cohort of early onset or extreme obesity and report the clinical histories of these individuals with non-syndromic obesity with no history of neurobehavioral or cognitive disability. The BMI association was replicated in the All of Us whole genome sequencing data. Heterozygous pLoF BSN variants constitute a new etiology for obesity.
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Affiliation(s)
- Na Zhu
- Department of Pediatrics, Columbia University Irving Medical Center, New York, NY, USA
- Department of Systems Biology, Columbia University Irving Medical Center, New York, NY, USA
| | - Charles A LeDuc
- Department of Pediatrics, Columbia University Irving Medical Center, New York, NY, USA
- NY Obesity Research Center, Columbia University Irving Medical Center, New York, NY, USA
- Naomi Berrie Diabetes Center, Columbia University Irving Medical Center, New York, NY, USA
| | - Ilene Fennoy
- Department of Pediatrics, Columbia University Irving Medical Center, New York, NY, USA
- Naomi Berrie Diabetes Center, Columbia University Irving Medical Center, New York, NY, USA
| | - Blandine Laferrère
- NY Obesity Research Center, Columbia University Irving Medical Center, New York, NY, USA
- Naomi Berrie Diabetes Center, Columbia University Irving Medical Center, New York, NY, USA
- Department of Medicine, Columbia University Irving Medical Center, New York, NY, USA
| | - Claudia A Doege
- NY Obesity Research Center, Columbia University Irving Medical Center, New York, NY, USA
- Department of Pathology, Columbia University Irving Medical Center, New York, NY, 10032, USA
| | - Yufeng Shen
- Department of Systems Biology, Columbia University Irving Medical Center, New York, NY, USA
- Department of Biomedical Informatics, Columbia University Irving Medical Center, New York, NY, USA
- JP Sulzberger Columbia Genome Center, Columbia University Irving Medical Center, New York, NY, USA
| | - Wendy K Chung
- Department of Pediatrics, Columbia University Irving Medical Center, New York, NY, USA.
- NY Obesity Research Center, Columbia University Irving Medical Center, New York, NY, USA.
- Naomi Berrie Diabetes Center, Columbia University Irving Medical Center, New York, NY, USA.
- Department of Medicine, Columbia University Irving Medical Center, New York, NY, USA.
- Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, NY, USA.
| | - Rudolph L Leibel
- Department of Pediatrics, Columbia University Irving Medical Center, New York, NY, USA.
- NY Obesity Research Center, Columbia University Irving Medical Center, New York, NY, USA.
- Naomi Berrie Diabetes Center, Columbia University Irving Medical Center, New York, NY, USA.
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6
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Zhu N, LeDuc CA, Fennoy I, Laferr Re B, Doege CA, Shen Y, Chung WK, Leibel RL. Predicted loss of function alleles in Bassoon (BSN) are associated with obesity. MEDRXIV : THE PREPRINT SERVER FOR HEALTH SCIENCES 2023:2023.02.19.23285978. [PMID: 36865254 PMCID: PMC9980265 DOI: 10.1101/2023.02.19.23285978] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/05/2023]
Abstract
Bassoon ( BSN ) is a component of a hetero-dimeric presynaptic cytomatrix protein that orchestrates neurotransmitter release with Piccolo ( PCLO ) from glutamatergic neurons throughout the brain. Heterozygous missense variants in BSN have previously been associated with neurodegenerative disorders in humans. We performed an exome-wide association analysis of ultra-rare variants in about 140,000 unrelated individuals from the UK Biobank to search for new genes associated with obesity. We found that rare heterozygous predicted loss of function (pLoF) variants in BSN are associated with higher BMI with log10-p value of 11.78 in the UK biobank cohort. The association was replicated in the All of Us whole genome sequencing data. Additionally, we have identified two individuals (one of whom has a de novo variant) with a heterozygous pLoF variant in a cohort of early onset or extreme obesity at Columbia University. Like the individuals identified in the UKBB and All of us Cohorts, these individuals have no history of neurobehavioral or cognitive disability. Heterozygosity for pLoF BSN variants constitutes a new etiology for obesity.
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Sena C, Iannello G, Skowronski AA, Dannheim K, Cheung L, Agrawal PB, Hirschhorn JN, Zeitler P, LeDuc CA, Stratigopoulos G, Thaker VV. Endocrine and behavioural features of Lowe syndrome and their potential molecular mechanisms. J Med Genet 2022; 59:1171-1178. [PMID: 35803701 PMCID: PMC10186212 DOI: 10.1136/jmedgenet-2022-108490] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2022] [Accepted: 06/11/2022] [Indexed: 01/12/2023]
Abstract
BACKGROUND Lowe syndrome (LS) is an X linked disease caused by pathogenic variants in the OCRL gene that impacts approximately 1 in 500 000 children. Classic features include congenital cataract, cognitive/behavioural impairment and renal tubulopathy. METHODS This study is a retrospective review of clinical features reported by family based survey conducted by Lowe Syndrome Association. Frequency of non-ocular clinical feature(s) of LS and their age of onset was summarised. An LS-specific therapy effectiveness scale was used to assess the response to the administered treatment. Expression of OCRL and relevant neuropeptides was measured in postmortem human brain by qPCR. Gene expression in the mouse brain was determined by reanalysis of publicly available bulk and single cell RNA sequencing. RESULTS A total of 137 individuals (1 female, 89.1% white, median age 14 years (range 0.8-56)) were included in the study. Short stature (height <3rd percentile) was noted in 81% (n=111) individuals, and 15% (n=20) received growth hormone therapy. Undescended testis was reported in 47% (n=64), and median age of onset of puberty was 15 years. Additional features were dental problems (n=77, 56%), bone fractures (n=63, 46%), hypophosphataemia (n=60, 44%), developmental delay and behavioural issues. OCRL is expressed in human and mouse hypothalami, and in hypothalamic cell clusters expressing Ghrh, Sst, Oxt, Pomc and pituitary cells expressing Gh and Prl. CONCLUSIONS There is a wide spectrum of the clinical phenotype of LS. Some of the features may be partly driven by the loss of function of OCRL in the hypothalamus and the pituitary.
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Affiliation(s)
- Cecilia Sena
- Department of Pediatrics, College of Physicians and Surgeons, Columbia University, New York, New York, USA
- Naomi Berrie Diabetes Center, Columbia University Irving Medical Center, New York, New York, USA
| | - Grazia Iannello
- Columbia Stem Cell Initiative, Stem Cell Core, Columbia University Irving Medical Center, New York, New York, USA
| | - Alicja A Skowronski
- Department of Pediatrics, College of Physicians and Surgeons, Columbia University, New York, New York, USA
- Naomi Berrie Diabetes Center, Columbia University Irving Medical Center, New York, New York, USA
| | - Katelyn Dannheim
- Department of Pathology and Laboratory Medicine, Rhode Island and Hasbro Children's Hospitals and the Warren Alpert Medical School of Brown University, Providence, Rhode Island, USA
| | - Leonard Cheung
- Department of Human Genetics, University of Michigan Medical School, Ann Arbor, Michigan, USA
| | - Pankaj B Agrawal
- Division of Neonatology, Boston Children's Hospital, Boston, Massachusetts, USA
| | - Joel N Hirschhorn
- Division of Endocrinology, Boston Children's Hospital, Boston, Massachusetts, USA
| | - Phillip Zeitler
- Department of Endocrinology, Children's Hospital Colorado, Aurora, Colorado, USA
| | - Charles A LeDuc
- Department of Pediatrics, College of Physicians and Surgeons, Columbia University, New York, New York, USA
- Naomi Berrie Diabetes Center, Columbia University Irving Medical Center, New York, New York, USA
| | - George Stratigopoulos
- Department of Pediatrics, College of Physicians and Surgeons, Columbia University, New York, New York, USA
- Naomi Berrie Diabetes Center, Columbia University Irving Medical Center, New York, New York, USA
| | - Vidhu V Thaker
- Department of Pediatrics, College of Physicians and Surgeons, Columbia University, New York, New York, USA
- Naomi Berrie Diabetes Center, Columbia University Irving Medical Center, New York, New York, USA
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Gvazava IG, Karimova MV, Vasiliev AV, Vorotelyak EA. Type 2 Diabetes Mellitus: Pathogenic Features and Experimental Models in Rodents. Acta Naturae 2022; 14:57-68. [PMID: 36348712 PMCID: PMC9611859 DOI: 10.32607/actanaturae.11751] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2022] [Accepted: 07/19/2022] [Indexed: 11/20/2022] Open
Abstract
Type 2 diabetes mellitus (T2DM) is the most common endocrine disorder (90%) in the world; it has numerous clinical, immunological, and genetic differences from type 1 diabetes mellitus. The pathogenesis of T2DM is complex and not fully clear. To date, animal models remain the main tool by which to study the pathophysiology and therapy of T2DM. Rodents are considered the best choice among animal models, because they are characterized by a small size, short induction period, easy diabetes induction, and economic efficiency. This review summarizes data on experimental models of T2DM that are currently used, evaluates their advantages and disadvantages vis-a-vis research, and describes in detail the factors that should be taken into account when using these models. Selection of a suitable model for tackling a particular issue is not always trivial; it affects study results and their interpretation.
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Affiliation(s)
- I. G. Gvazava
- Institute of Developmental Biology, Russian Academy of Sciences, Moscow, 119334 Russia
| | - M. V. Karimova
- Institute of Developmental Biology, Russian Academy of Sciences, Moscow, 119334 Russia
| | - A. V. Vasiliev
- Institute of Developmental Biology, Russian Academy of Sciences, Moscow, 119334 Russia
- Lomonosov Moscow State University, Faculty of Biology, Moscow, 119234 Russia
| | - E. A. Vorotelyak
- Institute of Developmental Biology, Russian Academy of Sciences, Moscow, 119334 Russia
- Lomonosov Moscow State University, Faculty of Biology, Moscow, 119234 Russia
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