Hypothalamic-pituitary-adrenal axis activation precedes metabolic dysfunction in obesity in a porcine model

Miranda Dosi; Nicola Gould; Aileen Boyle; Yuki Otani; Carola Daniel; Calum Gray; Scott Denham; Joanna Simpson; Natalie Homer; Stephen Greenhalgh; Ruth Morgan

doi:10.1530/endoabs.109.OC5.2

OC5.2

Prev Next

Section Contents Cite

Endocrine Abstracts (2025) 109 OC5.2 | DOI: 10.1530/endoabs.109.OC5.2

SFEBES2025 Oral Communications Adrenal and Cardiovascular (6 abstracts)

Hypothalamic-pituitary-adrenal axis activation precedes metabolic dysfunction in obesity in a porcine model

Miranda Dosi ¹ , Nicola Gould ¹ , Aileen Boyle ¹ , Yuki Otani ^1,2 , Carola Daniel ² , Calum Gray ² , Scott Denham ² , Joanna Simpson ² , Natalie Homer ² , Stephen Greenhalgh ² & Ruth Morgan ^1,2

Author affiliations

¹SRUC, Edinburgh, United Kingdom; ²University of Edinburgh, Edinburgh, United Kingdom

The temporal relationship between obesity, hypothalamic-pituitary-adrenal (HPA) activation and metabolic disease is complex and poorly understood. It is difficult to model the HPA response to calorie overconsumption in humans/rodents. In this study, we hypothesise that HPA activation precedes metabolic dysfunction in a porcine model of obesity. Adult female pigs (LandraceXHampshire, n=7) underwent phenotyping before and during 12 weeks of high calorie feeding (HCF) (9,000 kcal/day vs 3500 kcal/day/100 kg pig). Unstressed blood sampling was achieved by use of vascular access ports. Average weight gain was 5±0.5 kg/week. Subcutaneous adipose (MRI/ultrasound) increased by 34+/-9.2% with minimal increase in visceral adipose. Pigs developed relatively “metabolically-healthy” obesity with no change in fasted insulin/glucose or response to oral glucose tests. There was, however, a reduction in glucose infusion rate during an euglycaemic-hyperinsulinaemic clamp at 12 weeks compared to baseline (9.5±2.38 vs 5.1±0.91 mg/kg/min, n=4, P=0.03). Plasma/salivary cortisol and cortisone were quantified by LC-MS/MS weekly; plasma concentrations were unaltered with HCF. Salivary cortisone, however, increased by 12 weeks (0.95±0.38 vs 1.52±0.32nM, P=0.04). Diurnal rhythm was assessed by 8-hourly sampling (0800hrs, 1400hrs, 2200hrs). All measured plasma/salivary glucocorticoids were increased at 1400hrs at 6 and 12 weeks, concentrations at 2200hrs were not different. The response of cortisol to ACTH (Synacthen) stimulation was increased at 6 and 12 weeks (AUC 207±23 vs 318±39, P=0.03). There was a small but non-significant reduction in suppression response to oral dexamethasone (1 mg) at 12 weeks. Liver biopsies showed hepatic expression of corticosteroid binding globulin (CBG) was significantly reduced by HCF. Hyperinsulinaemia has been posited as the driving force for HPA activation in obesity. Our data suggest the opposite - that high-calorie feeding alone is sufficient to activate the HPA axis and reduce CBG expression, and this precedes changes in insulin sensitivity/hyperinsulinemia.