Specific Subpopulations of Hypothalamic Leptin Receptor-Expressing Neurons Mediate the Effects of Early Developmental Leptin Receptor Deletion on Energy Balance

Alan C. Rupp, Margaret B. Allison, Justin C. Jones, Christa M. Patterson, Chelsea L. Faber, Nadeja Bozadjieva, Lora K. Heisler, Randy J. Seeley, David P. Olson, Martin G. Myers Jr.

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Abstract

Objective: To date, early developmental ablation of leptin receptor (LepRb) expression from circumscribed populations of hypothalamic neurons(e.g., arcuate nucleus (ARC) Pomc-orAgrp-expressing cells) has only minimally affected energy balance. In contrast, removal of LepRb from at least two large populations (expressing vGat or Nos1) spanning multiple hypothalamic regions produced profound obesity and metabolicdys function. Thus, we tested the notion that the total number of leptin-responsive hypothalamic neurons (rather than specific subsets of cells with a particular molecular or anatomical signature) subjected to early LepRb deletion might determine energy balance.
Methods: We generated new mouse lines deleted for LepRb in ARC Ghrh Cre neurons or in Htr2c Cre neurons (representing roughly half of all hypothalamic LepRb neurons, distributed across many nuclei). We compared the phenotypes of these mice to previously-reported models lacking LepRb in Pomc, Agrp, vGat or Nos1 cells.
Results: The early developmental deletion of LepRb from vGat or Nos1 neurons produced dramatic obesity, but deletion of LepRb from Pomc,Agrp, Ghrh,or Htr2c neurons minimally altered energy balance.
Conclusions: Although early developmental deletion of LepRb from known populations of ARC neurons fails to substantially alter body weight, the minimal phenotype of mice lacking LepRb in Htr2c cells suggests that the phenotype that results from early developmental LepRb deficiency depends not simply upon the total number of leptin-responsive hypothalamic LepRb cells. Rather, specific populations of LepRb neurons must play particularly important roles in body energy homeostasis; these as yet unidentified LepRb cells likely reside in the DMH
Original languageEnglish
Pages (from-to)130-138
Number of pages9
JournalMolecular Metabolism
Volume14
Early online date6 Jun 2018
DOIs
Publication statusPublished - Aug 2018

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Leptin Receptors
Neurons
Arcuate Nucleus of Hypothalamus
Leptin
Phenotype
Population
Obesity
Dimenhydrinate
Homeostasis
Body Weight

Keywords

  • leptin receptor
  • arcuate nucleus
  • DMH
  • obesity
  • cre recombinase
  • ghrh
  • htr2c

Cite this

Specific Subpopulations of Hypothalamic Leptin Receptor-Expressing Neurons Mediate the Effects of Early Developmental Leptin Receptor Deletion on Energy Balance. / Rupp, Alan C.; Allison, Margaret B.; Jones, Justin C.; Patterson, Christa M.; Faber, Chelsea L.; Bozadjieva, Nadeja; Heisler, Lora K.; Seeley, Randy J.; Olson, David P.; Myers Jr., Martin G.

In: Molecular Metabolism, Vol. 14, 08.2018, p. 130-138.

Research output: Contribution to journalArticle

Rupp, Alan C. ; Allison, Margaret B. ; Jones, Justin C. ; Patterson, Christa M. ; Faber, Chelsea L. ; Bozadjieva, Nadeja ; Heisler, Lora K. ; Seeley, Randy J. ; Olson, David P. ; Myers Jr., Martin G. / Specific Subpopulations of Hypothalamic Leptin Receptor-Expressing Neurons Mediate the Effects of Early Developmental Leptin Receptor Deletion on Energy Balance. In: Molecular Metabolism. 2018 ; Vol. 14. pp. 130-138.
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title = "Specific Subpopulations of Hypothalamic Leptin Receptor-Expressing Neurons Mediate the Effects of Early Developmental Leptin Receptor Deletion on Energy Balance",
abstract = "Objective: To date, early developmental ablation of leptin receptor (LepRb) expression from circumscribed populations of hypothalamic neurons(e.g., arcuate nucleus (ARC) Pomc-orAgrp-expressing cells) has only minimally affected energy balance. In contrast, removal of LepRb from at least two large populations (expressing vGat or Nos1) spanning multiple hypothalamic regions produced profound obesity and metabolicdys function. Thus, we tested the notion that the total number of leptin-responsive hypothalamic neurons (rather than specific subsets of cells with a particular molecular or anatomical signature) subjected to early LepRb deletion might determine energy balance.Methods: We generated new mouse lines deleted for LepRb in ARC Ghrh Cre neurons or in Htr2c Cre neurons (representing roughly half of all hypothalamic LepRb neurons, distributed across many nuclei). We compared the phenotypes of these mice to previously-reported models lacking LepRb in Pomc, Agrp, vGat or Nos1 cells.Results: The early developmental deletion of LepRb from vGat or Nos1 neurons produced dramatic obesity, but deletion of LepRb from Pomc,Agrp, Ghrh,or Htr2c neurons minimally altered energy balance.Conclusions: Although early developmental deletion of LepRb from known populations of ARC neurons fails to substantially alter body weight, the minimal phenotype of mice lacking LepRb in Htr2c cells suggests that the phenotype that results from early developmental LepRb deficiency depends not simply upon the total number of leptin-responsive hypothalamic LepRb cells. Rather, specific populations of LepRb neurons must play particularly important roles in body energy homeostasis; these as yet unidentified LepRb cells likely reside in the DMH",
keywords = "leptin receptor, arcuate nucleus, DMH, obesity, cre recombinase, ghrh, htr2c",
author = "Rupp, {Alan C.} and Allison, {Margaret B.} and Jones, {Justin C.} and Patterson, {Christa M.} and Faber, {Chelsea L.} and Nadeja Bozadjieva and Heisler, {Lora K.} and Seeley, {Randy J.} and Olson, {David P.} and {Myers Jr.}, {Martin G.}",
note = "ACKNOWLEDGEMENTS We thank MedImmune, Inc. and James Trevaskis, PhD and Christopher Rhodes, PhD for the gift of leptin. We thank members of the Myers and Olson labs for helpful discussions. Research support was provided by the Michigan Diabetes Research Center (NIH P3 0 DK020572, including the Molecular Genetics, Animal Phenotyping, and Clinical Cores), the American Diabetes Association (MGM), the Marilyn H. Vincent Foundation (MGM), the NIH (MGM: D K05673 1; ACR:DK071212; MBA: DK097861), the BBSRC (LKH: BB/NO17838/1) and WellcomeTrust (LKH: 098012).",
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language = "English",
volume = "14",
pages = "130--138",
journal = "Molecular Metabolism",
issn = "2212-8778",
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TY - JOUR

T1 - Specific Subpopulations of Hypothalamic Leptin Receptor-Expressing Neurons Mediate the Effects of Early Developmental Leptin Receptor Deletion on Energy Balance

AU - Rupp, Alan C.

AU - Allison, Margaret B.

AU - Jones, Justin C.

AU - Patterson, Christa M.

AU - Faber, Chelsea L.

AU - Bozadjieva, Nadeja

AU - Heisler, Lora K.

AU - Seeley, Randy J.

AU - Olson, David P.

AU - Myers Jr., Martin G.

N1 - ACKNOWLEDGEMENTS We thank MedImmune, Inc. and James Trevaskis, PhD and Christopher Rhodes, PhD for the gift of leptin. We thank members of the Myers and Olson labs for helpful discussions. Research support was provided by the Michigan Diabetes Research Center (NIH P3 0 DK020572, including the Molecular Genetics, Animal Phenotyping, and Clinical Cores), the American Diabetes Association (MGM), the Marilyn H. Vincent Foundation (MGM), the NIH (MGM: D K05673 1; ACR:DK071212; MBA: DK097861), the BBSRC (LKH: BB/NO17838/1) and WellcomeTrust (LKH: 098012).

PY - 2018/8

Y1 - 2018/8

N2 - Objective: To date, early developmental ablation of leptin receptor (LepRb) expression from circumscribed populations of hypothalamic neurons(e.g., arcuate nucleus (ARC) Pomc-orAgrp-expressing cells) has only minimally affected energy balance. In contrast, removal of LepRb from at least two large populations (expressing vGat or Nos1) spanning multiple hypothalamic regions produced profound obesity and metabolicdys function. Thus, we tested the notion that the total number of leptin-responsive hypothalamic neurons (rather than specific subsets of cells with a particular molecular or anatomical signature) subjected to early LepRb deletion might determine energy balance.Methods: We generated new mouse lines deleted for LepRb in ARC Ghrh Cre neurons or in Htr2c Cre neurons (representing roughly half of all hypothalamic LepRb neurons, distributed across many nuclei). We compared the phenotypes of these mice to previously-reported models lacking LepRb in Pomc, Agrp, vGat or Nos1 cells.Results: The early developmental deletion of LepRb from vGat or Nos1 neurons produced dramatic obesity, but deletion of LepRb from Pomc,Agrp, Ghrh,or Htr2c neurons minimally altered energy balance.Conclusions: Although early developmental deletion of LepRb from known populations of ARC neurons fails to substantially alter body weight, the minimal phenotype of mice lacking LepRb in Htr2c cells suggests that the phenotype that results from early developmental LepRb deficiency depends not simply upon the total number of leptin-responsive hypothalamic LepRb cells. Rather, specific populations of LepRb neurons must play particularly important roles in body energy homeostasis; these as yet unidentified LepRb cells likely reside in the DMH

AB - Objective: To date, early developmental ablation of leptin receptor (LepRb) expression from circumscribed populations of hypothalamic neurons(e.g., arcuate nucleus (ARC) Pomc-orAgrp-expressing cells) has only minimally affected energy balance. In contrast, removal of LepRb from at least two large populations (expressing vGat or Nos1) spanning multiple hypothalamic regions produced profound obesity and metabolicdys function. Thus, we tested the notion that the total number of leptin-responsive hypothalamic neurons (rather than specific subsets of cells with a particular molecular or anatomical signature) subjected to early LepRb deletion might determine energy balance.Methods: We generated new mouse lines deleted for LepRb in ARC Ghrh Cre neurons or in Htr2c Cre neurons (representing roughly half of all hypothalamic LepRb neurons, distributed across many nuclei). We compared the phenotypes of these mice to previously-reported models lacking LepRb in Pomc, Agrp, vGat or Nos1 cells.Results: The early developmental deletion of LepRb from vGat or Nos1 neurons produced dramatic obesity, but deletion of LepRb from Pomc,Agrp, Ghrh,or Htr2c neurons minimally altered energy balance.Conclusions: Although early developmental deletion of LepRb from known populations of ARC neurons fails to substantially alter body weight, the minimal phenotype of mice lacking LepRb in Htr2c cells suggests that the phenotype that results from early developmental LepRb deficiency depends not simply upon the total number of leptin-responsive hypothalamic LepRb cells. Rather, specific populations of LepRb neurons must play particularly important roles in body energy homeostasis; these as yet unidentified LepRb cells likely reside in the DMH

KW - leptin receptor

KW - arcuate nucleus

KW - DMH

KW - obesity

KW - cre recombinase

KW - ghrh

KW - htr2c

U2 - 10.1016/j.molmet.2018.06.001

DO - 10.1016/j.molmet.2018.06.001

M3 - Article

VL - 14

SP - 130

EP - 138

JO - Molecular Metabolism

JF - Molecular Metabolism

SN - 2212-8778

ER -