Postembryonic ablation of AgRP neurons in mice leads to a lean, hypophagic phenotype

GA Bewick; JV Gardiner; WS Dhillo; AS Kent; NE White; Z Webster; MA Ghatei; S. R. Bloom

doi:10.1096/fj.04-3434fje

Postembryonic ablation of AgRP neurons in mice leads to a lean, hypophagic phenotype

GA Bewick, JV Gardiner, WS Dhillo, AS Kent, NE White, Z Webster, MA Ghatei, S. R. Bloom

Diabetes

Research output: Contribution to journal › Article › peer-review

214 Citations (Scopus)

Abstract

Agouti-related protein ( AgRP) and neuropeptide Y ( NPY) are colocalized in arcuate nucleus ( arcuate) neurons implicated in the regulation of energy balance. Both AgRP and NPY stimulate food intake when administered into the third ventricle and are up- regulated in states of negative energy balance. However, mice with targeted deletion of either NPY or AgRP or both do not have major alterations in energy homeostasis. Using bacterial artificial chromosome ( BAC) transgenesis we have targeted expression of a neurotoxic CAG expanded form of ataxin- 3 to AgRP- expressing neurons in the arcuate. This resulted in a 47% loss of AgRP neurons by 16 weeks of age, a significantly reduced body weight, ( wild- type mice ( WT) 34.7 +/- 0.7 g vs. transgenic mice ( Tg) 28.6 +/- 0.6 g, P <0.001), and reduced food intake ( WT 5.0 +/- 0.2 vs. Tg 3.6 +/- 0.1 g per day, P <0.001). Transgenic mice had significantly reduced total body fat, plasma insulin, and increased brown adipose tissue UCP1 expression. Transgenic mice failed to respond to peripherally administered ghrelin but retained sensitivity to PYY 3- 36. These data suggest that postembryonic partial loss of AgRP/ NPY neurons leads to a lean, hypophagic phenotype.

Original language	English
Pages (from-to)	1680-+
Number of pages	21
Journal	Faseb Journal
Volume	19
Issue number	10
DOIs	https://doi.org/10.1096/fj.04-3434fje
Publication status	Published - Aug 2005

Keywords

neuropeptide Y
hypothalamic arcuate nucleus
food intake regulation
neuroendocrinology
gut hormone
AGOUTI-RELATED-PROTEIN
AMPHETAMINE-REGULATED TRANSCRIPT
DISEASE GENE-PRODUCT
INHIBITS FOOD-INTAKE
IN-VIVO
NEUROPEPTIDE-Y
HYPOTHALAMIC NEURONS
ENERGY HOMEOSTASIS
MESSENGER-RNA
MALE RATS

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1096/fj.04-3434fje

Novartis Young Endocrinologist prize
Bewick, G. (Recipient), 2005
Prize: Prize (including medals and awards)

Cite this

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title = "Postembryonic ablation of AgRP neurons in mice leads to a lean, hypophagic phenotype",

abstract = "Agouti-related protein ( AgRP) and neuropeptide Y ( NPY) are colocalized in arcuate nucleus ( arcuate) neurons implicated in the regulation of energy balance. Both AgRP and NPY stimulate food intake when administered into the third ventricle and are up- regulated in states of negative energy balance. However, mice with targeted deletion of either NPY or AgRP or both do not have major alterations in energy homeostasis. Using bacterial artificial chromosome ( BAC) transgenesis we have targeted expression of a neurotoxic CAG expanded form of ataxin- 3 to AgRP- expressing neurons in the arcuate. This resulted in a 47% loss of AgRP neurons by 16 weeks of age, a significantly reduced body weight, ( wild- type mice ( WT) 34.7 +/- 0.7 g vs. transgenic mice ( Tg) 28.6 +/- 0.6 g, P <0.001), and reduced food intake ( WT 5.0 +/- 0.2 vs. Tg 3.6 +/- 0.1 g per day, P <0.001). Transgenic mice had significantly reduced total body fat, plasma insulin, and increased brown adipose tissue UCP1 expression. Transgenic mice failed to respond to peripherally administered ghrelin but retained sensitivity to PYY 3- 36. These data suggest that postembryonic partial loss of AgRP/ NPY neurons leads to a lean, hypophagic phenotype.",

keywords = "neuropeptide Y, hypothalamic arcuate nucleus, food intake regulation, neuroendocrinology, gut hormone, AGOUTI-RELATED-PROTEIN, AMPHETAMINE-REGULATED TRANSCRIPT, DISEASE GENE-PRODUCT, INHIBITS FOOD-INTAKE, IN-VIVO, NEUROPEPTIDE-Y, HYPOTHALAMIC NEURONS, ENERGY HOMEOSTASIS, MESSENGER-RNA, MALE RATS",

author = "GA Bewick and JV Gardiner and WS Dhillo and AS Kent and NE White and Z Webster and MA Ghatei and Bloom, {S. R.}",

year = "2005",

month = aug,

doi = "10.1096/fj.04-3434fje",

language = "English",

volume = "19",

pages = "1680--+",

journal = "Faseb Journal",

issn = "0892-6638",

publisher = "Federation of American Societies for Experimental Biology",

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TY - JOUR

T1 - Postembryonic ablation of AgRP neurons in mice leads to a lean, hypophagic phenotype

AU - Bewick, GA

AU - Gardiner, JV

AU - Dhillo, WS

AU - Kent, AS

AU - White, NE

AU - Webster, Z

AU - Ghatei, MA

AU - Bloom, S. R.

PY - 2005/8

Y1 - 2005/8

N2 - Agouti-related protein ( AgRP) and neuropeptide Y ( NPY) are colocalized in arcuate nucleus ( arcuate) neurons implicated in the regulation of energy balance. Both AgRP and NPY stimulate food intake when administered into the third ventricle and are up- regulated in states of negative energy balance. However, mice with targeted deletion of either NPY or AgRP or both do not have major alterations in energy homeostasis. Using bacterial artificial chromosome ( BAC) transgenesis we have targeted expression of a neurotoxic CAG expanded form of ataxin- 3 to AgRP- expressing neurons in the arcuate. This resulted in a 47% loss of AgRP neurons by 16 weeks of age, a significantly reduced body weight, ( wild- type mice ( WT) 34.7 +/- 0.7 g vs. transgenic mice ( Tg) 28.6 +/- 0.6 g, P <0.001), and reduced food intake ( WT 5.0 +/- 0.2 vs. Tg 3.6 +/- 0.1 g per day, P <0.001). Transgenic mice had significantly reduced total body fat, plasma insulin, and increased brown adipose tissue UCP1 expression. Transgenic mice failed to respond to peripherally administered ghrelin but retained sensitivity to PYY 3- 36. These data suggest that postembryonic partial loss of AgRP/ NPY neurons leads to a lean, hypophagic phenotype.

AB - Agouti-related protein ( AgRP) and neuropeptide Y ( NPY) are colocalized in arcuate nucleus ( arcuate) neurons implicated in the regulation of energy balance. Both AgRP and NPY stimulate food intake when administered into the third ventricle and are up- regulated in states of negative energy balance. However, mice with targeted deletion of either NPY or AgRP or both do not have major alterations in energy homeostasis. Using bacterial artificial chromosome ( BAC) transgenesis we have targeted expression of a neurotoxic CAG expanded form of ataxin- 3 to AgRP- expressing neurons in the arcuate. This resulted in a 47% loss of AgRP neurons by 16 weeks of age, a significantly reduced body weight, ( wild- type mice ( WT) 34.7 +/- 0.7 g vs. transgenic mice ( Tg) 28.6 +/- 0.6 g, P <0.001), and reduced food intake ( WT 5.0 +/- 0.2 vs. Tg 3.6 +/- 0.1 g per day, P <0.001). Transgenic mice had significantly reduced total body fat, plasma insulin, and increased brown adipose tissue UCP1 expression. Transgenic mice failed to respond to peripherally administered ghrelin but retained sensitivity to PYY 3- 36. These data suggest that postembryonic partial loss of AgRP/ NPY neurons leads to a lean, hypophagic phenotype.

KW - neuropeptide Y

KW - hypothalamic arcuate nucleus

KW - food intake regulation

KW - neuroendocrinology

KW - gut hormone

KW - AGOUTI-RELATED-PROTEIN

KW - AMPHETAMINE-REGULATED TRANSCRIPT

KW - DISEASE GENE-PRODUCT

KW - INHIBITS FOOD-INTAKE

KW - IN-VIVO

KW - NEUROPEPTIDE-Y

KW - HYPOTHALAMIC NEURONS

KW - ENERGY HOMEOSTASIS

KW - MESSENGER-RNA

KW - MALE RATS

U2 - 10.1096/fj.04-3434fje

DO - 10.1096/fj.04-3434fje

M3 - Article

SN - 0892-6638

VL - 19

SP - 1680-+

JO - Faseb Journal

JF - Faseb Journal

IS - 10

ER -

Postembryonic ablation of AgRP neurons in mice leads to a lean, hypophagic phenotype

Abstract

Keywords

UN SDGs

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Prizes

Novartis Young Endocrinologist prize

Cite this