Maternal obesity programs reduced leptin signaling in the pituitary and altered GH/IGF1 axis function leading to increased adiposity in adult sheep offspring.

Nuermaimaiti Tuersunjiang,Stephen P Ford,Peter W Nathanielsz,Desiree R Shasa,Ashley M Smith,John F Odhiambo

doi:10.1371/journal.pone.0181795

Abstract

Studies in rodents highlight a role for leptin in stimulation of pituitary growth hormone (GH) secretion, with an impact on body composition regulation. We have reported that maternal obesity (MO) during ovine pregnancy results in hyperphagia, glucose-insulin dysregulation, increased adiposity, hypercortisolemia and hyperleptinemia in mature offspring subjected to a bout of ad libitum feeding. We hypothesized that MO reduces leptin signaling in the pituitary and down regulates the GH/IGF1 axis and increases circulating cortisol leading to increased adiposity in their adult offspring. Male lambs born to MO (n = 6) or control (CON, n = 6) ewes were fed only to requirements until placed on a 12 week ad libitum feeding trial at maturity. The pituitary, hypothalamic arcuate nucleus, and liver were collected at necropsy and mRNA and protein expression determined. Plasma cortisol concentrations were increased (P<0.05) in MO vs. CON offspring at the end of the feeding trial. Further, serum concentrations of IGF1 decreased (P<0.01) and GH tended to decrease (P<0.08) in MO vs. CON offspring. Pituitary mRNA and leptin receptor protein expression were decreased in MO vs. CON offspring in association with decreased GH mRNA expression, and decreased IGF1 mRNA and protein expression in liver. Liver 11β-hydroxysteroid dehydrogenase 1 (11βHSD1) expression was increased (P<0.01) and its cofactor hexose-6-phosphate dehydrogenase tended to increase (P<0.06) in MO vs. CON offspring. 11βHSD2 expression remained unchanged. These data indicate that MO induced an increase in liver conversion of cortisone to cortisol in adult offspring and support a role for leptin signaling in the pituitary in mediating offspring adiposity.

Highlights

Obesity is a major human health concern
We have reported that maternal obesity (MO) during ovine pregnancy results in hyperphagia, glucose-insulin dysregulation, increased adiposity, hypercortisolemia and hyperleptinemia in mature offspring subjected to a bout of ad libitum feeding
No significant differences (P>0.05) were found in liver insulin-like growth factor binding protein-3 (IGFBP3) mRNA or protein expression (Figs 4E & 5E). It is well-documented that maternal overnutrition/obesity during pregnancy can increase the risk of insulin resistance and obesity in offspring postnatally [33,34,35]

Summary

Introduction

Obesity is a major human health concern. The current global obesity epidemic, together with its associated chronic diseases, represents a significant economic cost [1,2]. There is strong evidence that maternal obesity and overnutrition during human pregnancy is associated with an increased incidence of insulin resistance and obesity later in life [2,4,5]. An in vivo study showed that exogenous leptin infusion in ob/ob mice restored GH secretion, but hypothalamic growth hormone releasing hormone (GHRH) mRNA expression was not altered [19]. These data highlight the importance of leptin in modulating somatotrope GH secretion and regulation of hepatic IGF1 secretion

Methods

Results

Conclusion