@article{006cefd9386a49aaaac9f68e5ad95a54,
title = "Neonatal GLP1R activation limits adult adiposity by durably altering hypothalamic architecture",
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.",
keywords = "Beige fat, Hypothalamic architecture, Incretin, Metabolism, Obesity",
author = "Rozo, {Andrea V.} and Babu, {Daniella A.} and Suen, {Po Man A.} and Groff, {David N.} and Seeley, {Randy J.} and Simmons, {Rebecca A.} and Patrick Seale and Ahima, {Rexford S.} and Stoffers, {Doris A.}",
note = "Funding Information: We thank M. Lazar, K. Bence, L. Zeltser, M. Meyers, S. Mullican, S. Soleimanpour, and J. Raum for technical support and for helpful discussions. This work was supported by the Raymond and Joanna Welsh gift, the Cox Medical Institute, pilot funding from the University of Pennsylvania Perelman School of Medicine Penn Medicine Translational Neuroscience Center, and the Institute for Diabetes, Obesity and Metabolism of the University of Pennsylvania, and by the National Institutes of Health R01 DK062965 (D.A.S), NIH T32 DK007314 (A.V.R), and NRSA F32 DK085939 (D.A.B). We thank B. Kublaoui for gifting us the Sim1Cre mouse line. We acknowledge the University of Pennsylvania Diabetes Research Center for the use of the Mouse Phenotyping, Physiology and Metabolism Core, the Islet Cell Biology Core, the Radioimmunoassay/Biomarkers Core (P30DK19525) and the Molecular Pathology and Imaging Core of the Digestive Disease Center (MPIC, P30DK050306). Funding Information: We thank M. Lazar, K. Bence, L. Zeltser, M. Meyers, S. Mullican, S. Soleimanpour, and J. Raum for technical support and for helpful discussions. This work was supported by the Raymond and Joanna Welsh gift, the Cox Medical Institute , pilot funding from the University of Pennsylvania Perelman School of Medicine Penn Medicine Translational Neuroscience Center , and the Institute for Diabetes, Obesity and Metabolism of the University of Pennsylvania , and by the National Institutes of Health R01 DK062965 (D.A.S), NIH T32 DK007314 (A.V.R), and NRSA F32 DK085939 (D.A.B). We thank B. Kublaoui for gifting us the Sim1Cre mouse line. We acknowledge the University of Pennsylvania Diabetes Research Center for the use of the Mouse Phenotyping, Physiology and Metabolism Core, the Islet Cell Biology Core, the Radioimmunoassay/Biomarkers Core ( P30DK19525 ) and the Molecular Pathology and Imaging Core of the Digestive Disease Center (MPIC, P30DK050306 ). Funding Information: This work was supported by the National Institutes of Health R01 DK062965 (D.A.S), a gift fund from the Welsh family. (D.A.S), NRSA F32 DK085939 (D.A.B), and NIH T32 DK007314 (A.V.R). Publisher Copyright: {\textcopyright} 2017",
year = "2017",
month = jul,
doi = "10.1016/j.molmet.2017.05.006",
language = "English (US)",
volume = "6",
pages = "748--759",
journal = "Molecular Metabolism",
issn = "2212-8778",
publisher = "Elsevier GmbH",
number = "7",
}