Ghrelin:RegulationofFoodIntakeandEnergyHomeostasis

The somatotropic axis. The synthesis and release of growth hormone (GH) from the pituitary are controlled by the hypothalamic hormones GH-releasing hormone (GHRH) and somatostatin (SRIF), which in turn are regulated by feedback (dashed lines) from blood GH and insulin-like growth factor-I (IGF-I) concentrations. The recently discovered endogenous GH-releasing peptide, called ghrelin, also stimulates GH release. Circulating GH acts directly on many organs to stimulate IGF-I production, with IGF-I production in the liver providing the main source of blood IGF-I. Most of the IGF-I in the circulation is bound to IGF-binding protein-3 (IGFBP-3) in a ternary complex with acid-labile subunit (ALS); a smaller fraction is bound to the five other IGFBP. A small fraction of the total IGF-I in blood is in a bioactive-free fraction. In the kidney, IGF-I increases renal plasma flow and GFR, whereas on bone it acts on the epiphysial plate, which leads to longitudinal bone growth. As illustrated, GH also has direct effects on many organs, including kidney and cartilage, which can be independent of IGF-I action.Deranged somatotropic axis in chronic renal failure. The GH/IGF-I axis in chronic renal failure (CRF) is changed markedly compared with the normal axis. In CRF, the total concentrations of the hormones in the GH/IGF-I axis are not reduced, but there is reduced effectiveness of endogenous GH and IGF-I, which probably plays a major role in reducing linear bone growth. The reduced effectiveness of endogenous IGF-I likely is due to decreased levels of free, bioactive IGF-I as levels of circulating inhibitory IGFBP are increased. In addition, less IGF-I is circulating in the complex with ALS and IGFBP-3 as a result of increased proteolysis of IGFBP-3. Together, these lead to decreased IGF-I receptor activation and a decreased feedback to the hypothalamus and pituitary. Low free IGF-I and high IGFBP-1 and -2 levels probably contribute to a reduced renal function and lead to a reduced stature. The direct effects of GH on bone, which are poorly understood, also are blunted.

Contributor: Kosi Gramatikoff, PhD

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