Elsevier

Molecular Metabolism

Volume 6, Issue 7, July 2017, Pages 748-759
Molecular Metabolism

Original Article
Neonatal GLP1R activation limits adult adiposity by durably altering hypothalamic architecture

https://doi.org/10.1016/j.molmet.2017.05.006Get rights and content
Under a Creative Commons license
open access

Highlights

  • Neonatal Ex-4 attenuates diet-induced obesity in adult female mice.

  • Neonatal Ex-4 enhances adult energy expenditure and beiging of parametrial WAT.

  • Neonatal Ex-4 durably alters hypothalamic architecture.

  • The impact of neonatal Ex-4 was abrogated in Sim1Cre;Glp1rloxP/loxP mice.

  • GLP1R may be a therapeutic target for obesity prevention.

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

Obesity
Metabolism
Incretin
Beige fat
Hypothalamic architecture

Cited by (0)

5

Co-first authors.