Neonatal GLP1R activation limits adult adiposity by durably altering hypothalamic architecture

Andrea V. Rozo, Daniella A. Babu, Po Man A. Suen, David N. Groff, Randy J. Seeley, Rebecca A. Simmons, Patrick Seale, Rexford S. Ahima, Doris A. Stoffers

Research output: Contribution to journalArticle

Abstract

Objective Adult obesity risk is influenced by alterations to fetal and neonatal environments. Modifying neonatal gut or neurohormone signaling pathways can have negative metabolic consequences in adulthood. Here we characterize the effect of neonatal activation of glucagon like peptide-1 (GLP-1) receptor (GLP1R) signaling on adult adiposity and metabolism. Methods Wild type C57BL/6 mice were injected with 1 nmol/kg Exendin-4 (Ex-4), a GLP1R agonist, for 6 consecutive days after birth. Growth, body composition, serum analysis, energy expenditure, food intake, and brain and fat pad histology and gene expression were assessed at multiple time points through 42 weeks. Similar analyses were conducted in a Glp1r conditional allele crossed with a Sim1Cre deleter strain to produce Sim1Cre;Glp1rloxP/loxP mice and control littermates. Results Neonatal administration of Ex-4 reduced adult body weight and fat mass, increased energy expenditure, and conferred protection from diet-induced obesity in female mice. This was associated with induction of brown adipose genes and increased noradrenergic fiber density in parametrial white adipose tissue (WAT). We further observed durable alterations in orexigenic and anorexigenic projections to the paraventricular hypothalamic nucleus (PVH). Genetic deletion of Glp1r in the PVH by Sim1-Cre abrogated the impact of neonatal Ex-4 on adult body weight, WAT browning, and hypothalamic architecture. Conclusion These observations suggest that the acute activation of GLP1R in neonates durably alters hypothalamic architecture to limit adult weight gain and adiposity, identifying GLP1R as a therapeutic target for obesity prevention.

LanguageEnglish (US)
Pages748-759
Number of pages12
JournalMolecular Metabolism
Volume6
Issue number7
DOIs
StatePublished - Jul 1 2017
Externally publishedYes

Fingerprint

Adiposity
White Adipose Tissue
Obesity
Paraventricular Hypothalamic Nucleus
Energy Metabolism
Adipose Tissue
Body Weight
Body Composition
Inbred C57BL Mouse
Weight Gain
Neurotransmitter Agents
Histology
Eating
Alleles
Parturition
Newborn Infant
Diet
Gene Expression
Glucagon-Like Peptide-1 Receptor
Brain

Keywords

  • Beige fat
  • Hypothalamic architecture
  • Incretin
  • Metabolism
  • Obesity

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

Rozo, A. V., Babu, D. A., Suen, P. M. A., Groff, D. N., Seeley, R. J., Simmons, R. A., ... Stoffers, D. A. (2017). Neonatal GLP1R activation limits adult adiposity by durably altering hypothalamic architecture. Molecular Metabolism, 6(7), 748-759. DOI: 10.1016/j.molmet.2017.05.006

Neonatal GLP1R activation limits adult adiposity by durably altering hypothalamic architecture. / Rozo, Andrea V.; Babu, Daniella A.; Suen, Po Man A.; Groff, David N.; Seeley, Randy J.; Simmons, Rebecca A.; Seale, Patrick; Ahima, Rexford S.; Stoffers, Doris A.

In: Molecular Metabolism, Vol. 6, No. 7, 01.07.2017, p. 748-759.

Research output: Contribution to journalArticle

Rozo, AV, Babu, DA, Suen, PMA, Groff, DN, Seeley, RJ, Simmons, RA, Seale, P, Ahima, RS & Stoffers, DA 2017, 'Neonatal GLP1R activation limits adult adiposity by durably altering hypothalamic architecture' Molecular Metabolism, vol 6, no. 7, pp. 748-759. DOI: 10.1016/j.molmet.2017.05.006
Rozo AV, Babu DA, Suen PMA, Groff DN, Seeley RJ, Simmons RA et al. Neonatal GLP1R activation limits adult adiposity by durably altering hypothalamic architecture. Molecular Metabolism. 2017 Jul 1;6(7):748-759. Available from, DOI: 10.1016/j.molmet.2017.05.006
Rozo, Andrea V. ; Babu, Daniella A. ; Suen, Po Man A. ; Groff, David N. ; Seeley, Randy J. ; Simmons, Rebecca A. ; Seale, Patrick ; Ahima, Rexford S. ; Stoffers, Doris A./ Neonatal GLP1R activation limits adult adiposity by durably altering hypothalamic architecture. In: Molecular Metabolism. 2017 ; Vol. 6, No. 7. pp. 748-759
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abstract = "Objective Adult obesity risk is influenced by alterations to fetal and neonatal environments. Modifying neonatal gut or neurohormone signaling pathways can have negative metabolic consequences in adulthood. Here we characterize the effect of neonatal activation of glucagon like peptide-1 (GLP-1) receptor (GLP1R) signaling on adult adiposity and metabolism. Methods Wild type C57BL/6 mice were injected with 1 nmol/kg Exendin-4 (Ex-4), a GLP1R agonist, for 6 consecutive days after birth. Growth, body composition, serum analysis, energy expenditure, food intake, and brain and fat pad histology and gene expression were assessed at multiple time points through 42 weeks. Similar analyses were conducted in a Glp1r conditional allele crossed with a Sim1Cre deleter strain to produce Sim1Cre;Glp1rloxP/loxP mice and control littermates. Results Neonatal administration of Ex-4 reduced adult body weight and fat mass, increased energy expenditure, and conferred protection from diet-induced obesity in female mice. This was associated with induction of brown adipose genes and increased noradrenergic fiber density in parametrial white adipose tissue (WAT). We further observed durable alterations in orexigenic and anorexigenic projections to the paraventricular hypothalamic nucleus (PVH). Genetic deletion of Glp1r in the PVH by Sim1-Cre abrogated the impact of neonatal Ex-4 on adult body weight, WAT browning, and hypothalamic architecture. Conclusion These observations suggest that the acute activation of GLP1R in neonates durably alters hypothalamic architecture to limit adult weight gain and adiposity, identifying GLP1R as a therapeutic target for obesity prevention.",
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N2 - Objective Adult obesity risk is influenced by alterations to fetal and neonatal environments. Modifying neonatal gut or neurohormone signaling pathways can have negative metabolic consequences in adulthood. Here we characterize the effect of neonatal activation of glucagon like peptide-1 (GLP-1) receptor (GLP1R) signaling on adult adiposity and metabolism. Methods Wild type C57BL/6 mice were injected with 1 nmol/kg Exendin-4 (Ex-4), a GLP1R agonist, for 6 consecutive days after birth. Growth, body composition, serum analysis, energy expenditure, food intake, and brain and fat pad histology and gene expression were assessed at multiple time points through 42 weeks. Similar analyses were conducted in a Glp1r conditional allele crossed with a Sim1Cre deleter strain to produce Sim1Cre;Glp1rloxP/loxP mice and control littermates. Results Neonatal administration of Ex-4 reduced adult body weight and fat mass, increased energy expenditure, and conferred protection from diet-induced obesity in female mice. This was associated with induction of brown adipose genes and increased noradrenergic fiber density in parametrial white adipose tissue (WAT). We further observed durable alterations in orexigenic and anorexigenic projections to the paraventricular hypothalamic nucleus (PVH). Genetic deletion of Glp1r in the PVH by Sim1-Cre abrogated the impact of neonatal Ex-4 on adult body weight, WAT browning, and hypothalamic architecture. Conclusion These observations suggest that the acute activation of GLP1R in neonates durably alters hypothalamic architecture to limit adult weight gain and adiposity, identifying GLP1R as a therapeutic target for obesity prevention.

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