Abstract
In addition to its essential role in the physiological control of longitudinal growth, growth-hormone (GH) is endowed with relevant metabolic functions, including anabolic actions in muscle, lipolysis in adipose-tissue and glycemic modulation. Adult obesity is known to negatively impact GH-axis, thereby promoting a vicious circle that may contribute to the exacerbation of the metabolic complications of overweight. Yet, to what extent early-overnutrition sensitizes the somatotropic-axis to the deleterious effects of obesity remains largely unexplored. Using a rat-model of sequential exposure to obesogenic insults, namely postnatal-overfeeding during lactation and high-fat diet (HFD) after weaning, we evaluated in both sexes the individual and combined impact of these nutritional challenges upon key elements of the somatotropic-axis. While feeding HFD per se had a modest impact on the adult GH-axis, early overnutrition had durable effects on key elements of the somatotropic-system, which were sexually different, with a significant inhibition of pituitary gene expression of GH-releasing hormone-receptor (GHRH-R) and somatostatin receptor-5 (SST5) in males, but an increase in pituitary GHRH-R, SST2, SST5, GH secretagogue-receptor (GHS-R) and ghrelin expression in females. Notably, early-overnutrition sensitized the GH-axis to the deleterious impact of HFD, with a significant suppression of pituitary GH expression in both sexes and lowering of circulating GH levels in females. Yet, despite their similar metabolic perturbations, males and females displayed rather distinct alterations of key somatotropic-regulators/ mediators. Our data document a synergistic effect of postnatal-overnutrition on the detrimental impact of HFD-induced obesity on key elements of the adult GH-axis, which is conducted via mechanisms that are sexually-divergent.
Highlights
In addition to its essential role in the physiological control of longitudinal growth, growth-hormone (GH) is endowed with relevant metabolic functions, including anabolic actions in muscle, lipolysis in adipose-tissue and glycemic modulation
Analyses of the elements of the somatotropic axis, including circulating levels of GH and insulin-like growth factor-1 (IGF-1), as well as the gene expression levels of key factors at the hypothalamus [GH-releasing hormone (GHRH), somatostatin (SRIF), Neuropeptide-Y (NPY) and ghrelin], pituitary [GH, somatostatin receptors (SSTs), Leptin-receptor (Lep-R), Insulin-receptor (Ins-R), ghrelin, ghrelin-receptor (GHS-R), and Ghrelin-O-Acyl Transferase (GOAT)] and liver [GH-receptor (GH-R) and IGF-1], were implemented in serum and tissue samples from cohorts of male and female rats, generated in the context of large longitudinal studies addressing the impact of sequential obesogenic insults, namely postnatal overfeeding (SL) and exposure to high-fat diet (HFD) after weaning, on various reproductive and metabolic parameters
Representation of delta body weight curves during this period revealed that males were more sensitive to the body weight gain effect of small litters (SL) than females, with an increase being detectable in SL/CD males versus normal litters (NL)/CD from postnatal day (PND) 50 onwards (Fig. 1)
Summary
In addition to its essential role in the physiological control of longitudinal growth, growth-hormone (GH) is endowed with relevant metabolic functions, including anabolic actions in muscle, lipolysis in adipose-tissue and glycemic modulation. It has been suggested that early overfeeding may sensitize for the deleterious effects of a high-fat diet (HFD) in adulthood In line with this hypothesis, our group and others have recently reported that early postnatal overnutrition exacerbates HFD-induced metabolic disturbances in adult life[27,28,29,30,31]. Recent studies have documented that early overnutrition may compromise the correct functioning of various neurohormonal axes in adulthood[27,32,33], including the GH axis[34] In this regard, it has been shown that early overnutrition increases somatic growth during development by altering hypothalamic GH-releasing hormone (GHRH) and pituitary GH expression in mice, changes that persisted in adult life[34]. Such possibility is of considerable translational interest, given the escalating trends of child o besity[35]
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