Leptin system loss of function in the absence of obesity in zebrafish

in Journal of Endocrinology
Authors:
Amrutha Bagivalu Lakshminarasimha Institute of Zoology, University of Cologne, Cologne, Germany

Search for other papers by Amrutha Bagivalu Lakshminarasimha in
Current site
Google Scholar
PubMed
Close
,
Patrick Page-McCaw Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, Tennessee, USA

Search for other papers by Patrick Page-McCaw in
Current site
Google Scholar
PubMed
Close
,
Diana Möckel Department of Nanomedicine and Theranostics, Institute for Experimental Molecular Imaging, Faculty of Medicine, RWTH Aachen University, Aachen, Germany

Search for other papers by Diana Möckel in
Current site
Google Scholar
PubMed
Close
,
Felix Gremse Department of Nanomedicine and Theranostics, Institute for Experimental Molecular Imaging, Faculty of Medicine, RWTH Aachen University, Aachen, Germany
Gremse-IT GmbH, Aachen, Germany

Search for other papers by Felix Gremse in
Current site
Google Scholar
PubMed
Close
, and
Maximilian Michel Institute of Zoology, University of Cologne, Cologne, Germany

Search for other papers by Maximilian Michel in
Current site
Google Scholar
PubMed
Close
https://orcid.org/0000-0002-5910-5363

Correspondence should be addressed to M Michel: maximichel@gmail.com
Restricted access
Rent on DeepDyve

Sign up for journal news

The leptin system plays a crucial role in the regulation of appetite and energy homeostasis in vertebrates. While the phenotype of morbid obesity due to leptin (Lep) or leptin receptor (LEPR) loss of function is well established in mammals, evidence in fish is controversial, questioning the role of leptin as the vertebrate adipostat. Here we report on three (Lepr) loss of function (LOF) and one leptin loss of function alleles in zebrafish. In order to demonstrate that the Lepr LOF alleles cannot transduce a leptin signal, we measured socs3a transcription after i.p. leptin which is abolished by Lepr LOF. None of the Lepr/Lepa LOF alleles leads to obesity/a body growth phenotype. We explore possible reasons leading to the difference in published results and find that even slight changes in background genetics such as inbreeding siblings and cousins can lead to significant variance in growth.

 

  • Collapse
  • Expand
  • Ahi EP, Brunel M, Tsakoumis E & Schmitz M 2019 Transcriptional study of appetite regulating genes in the brain of zebrafish (Danio rerio) with impaired leptin signalling. Scientific Reports 9 20166. (https://doi.org/10.1038/s41598-019-56779-z)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Audira G, Sarasamma S, Chen JR, Juniardi S, Sampurna BP, Liang ST, Lai YH, Lin GM, Hsieh MC & Hsiag CD 2018 Zebrafish mutants carrying leptin a (lepa) gene deficiency display obesity, anxiety, less aggression and fear, and circadian rhythm and color preference dysregulation. International Journal of Molecular Sciences 19 4038. (https://doi.org/10.3390/ijms19124038)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Baltzegar DA, Reading BJ, Douros JD & Borski RJ 2014 Role for leptin in promoting glucose mobilization during acute hyperosmotic stress in teleost fishes. Journal of Endocrinology 220 6172. (https://doi.org/10.1530/JOE-13-0292)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Barsh GS & Schwartz MW 2002 Genetic approaches to studying energy balance: Perception and integration. Nature Reviews: Genetics 3 589600. (https://doi.org/10.1038/nrg862)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Brand M, Granto M & Nusslein-Volhard C 2002 Keeping and raising zebrafish. In Zebrafish-A Practical Approach. Eds Dahm RN-V Oxford, UK: Oxford University Press.

  • Chisada S, Kurokawa T, Murashita K, Ronnestad I, Taniguchi Y, Toyoda A, Sakaki Y, Takeda S & Yoshiura Y 2014 Leptin receptor-deficient (knockout) medaka, Oryzias latipes, show chronical up-regulated levels of orexigenic neuropeptides, elevated food intake and stage specific effects on growth and fat allocation. General and Comparative Endocrinology 195 920. (https://doi.org/10.1016/j.ygcen.2013.10.008)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Coleman DL 1978 Obese and diabetes: two mutant genes causing diabetes-obesity syndromes in mice. Diabetologia 14 141148. (https://doi.org/10.1007/BF00429772)

  • Coleman DL 2010 A historical perspective on leptin. Nature Medicine 16 10971099. (https://doi.org/10.1038/nm1010-1097)

  • Deck CA, Honeycutt JL, Cheung E, Reynolds HM & Borski RJ 2017 Assessing the functional role of leptin in energy homeostasis and the stress response in vertebrates. Frontiers in Endocrinology 8 63. (https://doi.org/10.3389/fendo.2017.00063)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Denver RJ, Bonett RM & Boorse GC 2011 Evolution of leptin structure and function. Neuroendocrinology 94 2138. (https://doi.org/10.1159/000328435)

  • Doran AG, Wong K, Flint J, Adams DJ, Hunter KW & Keane TM 2016 Deep genome sequencing and variation analysis of 13 inbred mouse strains defines candidate phenotypic alleles, private variation and homozygous truncating mutations. Genome Biology 17 167. (https://doi.org/10.1186/s13059-016-1024-y)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Farooqi IS & O’Rahilly S 2014 Twenty years of leptin: human disorders of leptin action. Journal of Endocrinology 223 T63T70. (https://doi.org/10.1530/JOE-14-0480)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Fei F, Sun SY, Yao YX & Wang X 2017 Generation and phenotype analysis of zebrafish mutations of obesity-related genes lepr and mc4r. Sheng Li Xue Bao: Acta Physiologica Sinica 69 6169.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Friedman J 2014 Twenty years of leptin: an overview. Journal of Endocrinology 223 T1T8. (https://doi.org/10.1530/JOE-14-0405)

  • Gong N & Bjornsson BT 2014 Leptin signaling in the rainbow trout central nervous system is modulated by a truncated leptin receptor isoform. Endocrinology 155 24452455. (https://doi.org/10.1210/en.2013-2131)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Gremse F, Stark M, Ehling J, Menzel JR, Lammers T & Kiessling F 2016 Imalytics preclinical: interactive analysis of biomedical volume data. Theranostics 6 328341. (https://doi.org/10.7150/thno.13624)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • He J, Ding Y, Nowik N, Jager C, Eeza MNH, Alia A, Baelde HJ & Spaink HP 2021 Leptin deficiency affects glucose homeostasis and results in adiposity in zebrafish. Journal of Endocrinology 249 125134. (https://doi.org/10.1530/JOE-20-0437)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Hodgens C, Nimchuk ZL & Kieber JJ 2017 Indcaps: a tool for designing screening primers for CRISPR/Cas9 mutagenesis events. PLoS ONE 12 e0188406. (https://doi.org/10.1371/journal.pone.0188406)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Hummel KP, Dickie MM & Coleman DL 1966 Diabetes, a new mutation in the mouse. Science 153 11271128. (https://doi.org/10.1126/science.153.3740.1127)

  • Ingalls AM, Dickie MM & Snell GD 1950 Obese, a new mutation in the house mouse. Journal of Heredity 41 317318. (https://doi.org/10.1093/oxfordjournals.jhered.a106073)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Jao LE, Wente SR & Chen W 2013 Efficient multiplex biallelic zebrafish genome editing using a CRISPR nuclease system. PNAS 110 1390413909. (https://doi.org/10.1073/pnas.1308335110)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Kinkel MD, Eames SC, Philipson LH & Prince VE 2010 Intraperitoneal injection into adult zebrafish. Journal of Visualized Experiments 42 2126. (https://doi.org/10.3791/2126)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Kwon O, Kim KW & Kim MS 2016 Leptin signalling pathways in hypothalamic neurons. Cellular and Molecular Life Sciences 73 14571477. (https://doi.org/10.1007/s00018-016-2133-1)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • LaFave MC, Varshney GK, Vemulapalli M, Mullikin JC & Burgess SM 2014 A defined zebrafish line for high-throughput genetics and genomics: NHGRI-1. Genetics 198 167170. (https://doi.org/10.1534/genetics.114.166769)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Leibold S & Hammerschmidt M 2015 Long-term hyperphagia and caloric restriction caused by low- or high-density husbandry have differential effects on zebrafish postembryonic development, somatic growth, fat accumulation and reproduction. PLoS ONE 10 e0120776. (https://doi.org/10.1371/journal.pone.0120776)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Liongue C, Sertori R & Ward AC 2016 Evolution of cytokine receptor signaling. Journal of Immunology 197 1118. (https://doi.org/10.4049/jimmunol.1600372)

  • Londraville RL, Macotela Y, Duff RJ, Easterling MR, Liu Q & Crespi EJ 2014 Comparative endocrinology of leptin: assessing function in a phylogenetic context. General and Comparative Endocrinology 203 146157. (https://doi.org/10.1016/j.ygcen.2014.02.002)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Mankiewicz JL, Deck CA, Taylor JD, Douros JD & Borski RJ 2021 Epinephrine and glucose regulation of leptin synthesis and secretion in a teleost fish, the tilapia (Oreochromis mossambicus). General and Comparative Endocrinology 302 113669. (https://doi.org/10.1016/j.ygcen.2020.113669)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • McCurley AT & Callard GV 2008 Characterization of housekeeping genes in zebrafish: male-female differences and effects of tissue type, developmental stage and chemical treatment. BMC Molecular Biology 9 102. (https://doi.org/10.1186/1471-2199-9-102)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Michel M, Page-Mccaw PS, Chen W & Cone RD 2016 Leptin signaling regulates glucose homeostasis, but not adipostasis, in the zebrafish. PNAS 113 30843089. (https://doi.org/10.1073/pnas.1513212113)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Montague CT, Farooqi IS, Whitehead JP, Soos MA, Rau H, Wareham NJ, Sewter CP, Digby JE, Mohammed SN & Hurst JA et al.1997 Congenital leptin deficiency is associated with severe early-onset obesity in humans. Nature 387 903908. (https://doi.org/10.1038/43185)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Ota S, Hisano Y, Muraki M, Hoshijima K, Dahlem TJ, Grunwald DJ, Okada Y & Kawahara A 2013 Efficient identification of TALEN-mediated genome modifications using heteroduplex mobility assays. Genes to Cells 18 450458. (https://doi.org/10.1111/gtc.12050)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Parichy DM, Elizondo MR, Mills MG, Gordon TN & Engeszer RE 2009 Normal table of postembryonic zebrafish development: staging by externally visible anatomy of the living fish. Developmental Dynamics 238 29753015. (https://doi.org/10.1002/dvdy.22113)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Peelman F, Zabeau L, Moharana K, Savvides SN & Tavernier J 2014 Twenty years of leptin: insights into signaling assemblies of the leptin receptor. Journal of Endocrinology 223 T9T23. (https://doi.org/10.1530/JOE-14-0264)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Pfaffl MW 2001 A new mathematical model for relative quantification in real-time RT-PCR. Nucleic Acids Research 29 e45. (https://doi.org/10.1093/nar/29.9.e45)

  • Prokop JW, Duff RJ, Ball HC, Copeland DL & Londraville RL 2012 Leptin and leptin receptor: analysis of a structure to function relationship in interaction and evolution from humans to fish. Peptides 38 326336. (https://doi.org/10.1016/j.peptides.2012.10.002)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Ronnestad I, Gomes AS, Murashita K, Angotzi R, Jonsson E & Volkoff H 2017 Appetite-controlling endocrine systems in teleosts. Frontiers in Endocrinology 8 73. (https://doi.org/10.3389/fendo.2017.00073)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Salmeron C, Johansson M, Asaad M, Angotzi AR, Ronnestad I, Stefansson SO, Jonsson E, Bjornsson BT, Gutierrez J & Navarro I et al.2015 Roles of leptin and ghrelin in adipogenesis and lipid metabolism of rainbow trout adipocytes in vitro. Comparative Biochemistry and Physiology: Part A, Molecular and Integrative Physiology 188 4048. (https://doi.org/10.1016/j.cbpa.2015.06.017)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Shpilman M, Hollander-Cohen L, Ventura T, Gertler A & Levavi-Sivan B 2014 Production, gene structure and characterization of two orthologs of leptin and a leptin receptor in tilapia. General and Comparative Endocrinology 207 7485. (https://doi.org/10.1016/j.ygcen.2014.05.006)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Stevenson RD & Woods Jr WA 2006 Condition indices for conservation: new uses for evolving tools. Integrative and Comparative Biology 46 11691190. (https://doi.org/10.1093/icb/icl052)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Volkoff H 2016 The neuroendocrine regulation of food intake in fish: a review of current knowledge. Frontiers in Neuroscience 10 540. (https://doi.org/10.3389/fnins.2016.00540)

    • PubMed
    • Search Google Scholar
    • Export Citation