Altered somatotroph feedback regulation improves metabolic efficiency and limits adipose deposition in male mice

Abstract

Several transgenic mouse models with disruption in the growth hormone (GH) axis support the role of GH in augmenting metabolic homeostasis. Specifically, interest has focused on GH's lipolytic properties and ability to affect adipose deposition. Furthermore, both GH and insulin growth factor 1 (IGF-1) may also play a direct or indirect role in adipose development. The somatotroph insulin-like growth factor-1 receptor knockout (SIGFRKO) mouse with only a modest increase in serum GH and IGF-1 demonstrates less adipose tissue than controls. In order to characterize the metabolic phenotype of SIGFRKO mice, histologic analysis of fat depots confirmed a smaller average diameter of adipocytes in the SIGFRKO mice compared to controls. These changes were accompanied by an increase in lipolytic gene expression in fat depots. Indirect calorimetry performed on 6-8 week old male mice and again at 25 weeks of age demonstrated that SIGFRKO mice, at both ages, had a higher VO 2 and increased energy expenditure when compared with controls. The calculated respiratory exchange ratio (RER) was lower in the younger SIGFRKO mice compared to controls. No differences in food consumption or in either ambulatory or total activity were seen between SIGFRKO and control mice in either age group. These studies highlight the role of GH in adipose deposition and its influence on the expression of lipolytic genes resulting in an altered metabolic state, thus providing a mechanism for the decrease in weight gain seen in the SIGFRKO mouse model.

The Role of the Growth Hormone/Insulin-Like Growth Factor System in Visceral Adiposity

“… 78 Mice with knockout of the somatotroph type 1 IGF receptor, and a modest increase in GH expression, have less visceral and SAT with adipocytes that are small in size and have increased expression of lipolytic genes and decreased lipid content. 79 A rat transgenic model with human GH expression targeted to the posterior pituitary leads to inhibited endogenous GH production and moderate GH deficiency. 80 The resulting phenotype is remarkable, and unexplained, with males developing a late-onset, selectively visceral, adiposity and preserved insulin sensitivity.…”

The Role of Insulin-like Growth Factor-1 (IGF-1) in the Control of Neuroendocrine Regulation of Growth

“…In addition, the calculated respiratory exchange ratio (RER) was significantly decreased in the SIGFRKO mice compared to the controls [51]. Histological examination of the fat depots confirmed a decreased size of the adipocytes in SIGFRKO mice [51]. This mouse model suggested an additional regulatory role of the IGF-1 in the hypothalamus, which required additional studies.…”

“…SIGFRKO mice had significantly higher energy expenditure, higher VO 2 , lower VCO 2 , and less fat mass and percentage body fat with no change in lean muscle mass. In addition, the calculated respiratory exchange ratio (RER) was significantly decreased in the SIGFRKO mice compared to the controls [51]. Histological examination of the fat depots confirmed a decreased size of the adipocytes in SIGFRKO mice [51].…”

Exploring the Therapeutic Potential of Targeting GH and IGF-1 in the Management of Obesity: Insights from the Interplay between These Hormones and Metabolism

“…The pituitary gland's anterior lobe produces several hormones that are involved in energy metabolism, including GH and TSH. GH is known to increase energy expenditure by promoting the breakdown of fat and by stimulating the production of IGF-1, which also promotes lipolysis under special circumstances [18,40,41]. TSH plays a crucial role in regulating the metabolic processes that are essential for normal growth and development, as well as metabolic homeostasis in adults.…”

“…Hepatocytes, which make up about 60-70% of the liver, are the primary functional cells of the liver and are responsible for most of the metabolic activity of the liver [47]. Sinusoidal endothelial cells line the blood sinusoids and regulate the flow of blood and nutrients through the liver [38][39][40].…”