Neonatal GLP1R activation limits adult adiposity by durably altering hypothalamic architecture

Abstract

ObjectiveAdult 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.MethodsWild 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.ResultsNeonatal 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.ConclusionThese 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.

Neuroprotective exendin-4 enhances hypothermia therapy in a model of hypoxic-ischaemic encephalopathy

“…Neonatal exendin-4 protected against juvenile and adult rat myocardial ischaemic injury and preconditioned mitochondria ( Brown et al , 2010 ). Its administration in neonatal wild-type C57BL/6 mice prevented increased adult body weight and fat mass, and increased energy levels via GLP1R activation ( Rozo et al , 2017 ).…”

Oleoylethanolamide modulates glucagon-like peptide-1 receptor agonist signaling and enhances exendin-4-mediated weight loss in obese mice

“…The present findings provide evidence that chronic Ex4 treatment, in the presence or absence of OEA, incites an elevation in energy expenditure in the setting of obesity. Previous studies have suggested such an effect of chronic GLP-1R activation to elevate energy expenditure in rodents (32,48,62) and humans (3); however, in those studies, energy expenditure was only assessed toward the end of GLP-1RA treatment. To our knowledge, our studies are the first to measure these energy balance components continuously throughout the duration of treatment with OEA, Ex4, or the Ex4ϩOEA combination.…”

Developmental programming of hypothalamic melanocortin circuits

“…The incretin hormone glucagon-like peptide 1 (GLP1) is secreted postprandially by intestinal enteroendocrine cells to promote satiety and glucose-induced insulin release 46 . The administration of the GLP1-R agonist exendin-4 during the first week of postnatal life decreases the density of NPY fibers innervating the PVH and has a protective effect against both age-related and diet-induced obesity 47 . Moreover, genetic deletion of Glp1r in Sim1 neurons of the PVH reduces AgRP/NPY projections, while it increases POMC projections to the PVH 47 .…”