Early overnutrition sensitizes the growth hormone axis to the impact of diet-induced obesity via sex-divergent mechanisms

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 somatotropicaxis 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. Growth hormone (GH) plays a pivotal role in longitudinal growth during development 1. In addition, GH also exerts important actions on metabolic processes by promoting anabolic effects in the muscle and catabolic actions in the adipose tissue 2,3. It is well established that adult GH deficiency causes alterations in body composition and lipid metabolism 4-7. Adult GH deficiency is usually accompanied by increased abdominal fat accumulation, which is attenuated after GH replacement 8-11. It is also known that abdominal obesity negatively affects GH secretion. This effect has been documented in obese humans and rodents, where spontaneous, as well as stimulated, GH secretion is markedly reduced 12-17. Due to the lipolytic effect of GH on the adipose tissue, it has been suggested that such obesity-related disruption of GH secretion may promote a vicious cycle that might enhance adiposity and exacerbate the metabolic comorbidities linked to obesity 18. Interestingly, weight loss

Overnutrition during Pregnancy and Lactation Induces Gender-Dependent Dysmetabolism in the Offspring Accompanied by Heightened Stress and Anxiety

“…Conversely, in females, who commence hormone production at day 28 [ 29 ], the impact of diet on weight variation gradually diminishes. The estrogen hormone plays a pivotal role in regulating food intake and body weight, extending its influence to the modulation of insulin receptor abundance and ultimately being responsible for these differences between genders in overnutrition-dependent body weight gain [ 30 ].…”

Multi-Organ Increase in Norepinephrine Levels after Central Leptin Administration and Diet-Induced Obesity

“…We used a previously validated model of overnutrition in which litters are reduced to 4 pups (small litters, SL) and then, from weaning onwards, they are fed with a high-fat (HF) diet (45% fat, Research Diets, New Brunswick, NJ, USA) [46][47][48][49]. Control animals were maintained as normal litters (NL, 12 pups per dam), and after weaning they were fed with a chow standard diet (SD).…”

Understanding the role of growth hormone in situations of metabolic stress

“…Although obesity is not an acute situation of metabolic stress, the chronic energy imbalance and the consequent accumulation of body fat induce important metabolic and endocrine alterations in the organism. Notably, obese humans and animals frequently present reduced GH levels, compared to lean individuals (Rasmussen et al 1995, Cordido et al 1996, Luque & Kineman 2006, Luque et al 2011, Steyn et al 2013, Roelfsema & Veldhuis 2016, Sanchez-Garrido et al 2020. BMI (Roelfsema & Veldhuis 2016) and intra-abdominal fat (Vahl et al 1997) are inversely correlated with GH secretion in healthy adults.…”