Lack of Dietary Carbohydrates Induces Hepatic Growth Hormone (GH) Resistance in Rats

• Published in: Endocrinology (Philadelphia) 2011-05, Vol.152 (5), p.1948-1960
• Main Authors: Bielohuby, Maximilian, Sawitzky, Mandy, Stoehr, Barbara J. M, Stock, Peggy, Menhofer, Dominik, Ebensing, Sabine, Bjerre, Mette, Frystyk, Jan, Binder, Gerhard, Strasburger, Christian, Wu, Zida, Christ, Bruno, Hoeflich, Andreas, Bidlingmaier, Martin
• Format: Article
• Language: English
• Subjects: Animal models; Animals; Biological and medical sciences; Blotting, Western; Body Composition - drug effects; Body mass; Body Weight - drug effects; Carbohydrates; Diet; Diet, Carbohydrate-Restricted; Dietary Carbohydrates - administration & dosage; Dietary Carbohydrates - pharmacology; Dietary Fats - administration & dosage; Dietary Fats - pharmacology; Dietary Proteins - administration & dosage; Dietary Proteins - pharmacology; Fundamental and applied biological sciences. Psychology; Gene expression; Gene Expression - drug effects; Glucose metabolism; Glycogen Synthase Kinase 3 - metabolism; Glycogen Synthase Kinase 3 beta; Growth Hormone - blood; Growth Hormone - genetics; Growth Hormone - metabolism; Growth hormones; High carbohydrate diet; High fat diet; Hypothalamus; Insulin-Like Growth Factor Binding Proteins - blood; Insulin-Like Growth Factor Binding Proteins - genetics; Insulin-Like Growth Factor Binding Proteins - metabolism; Insulin-like growth factor I; Insulin-Like Growth Factor I - genetics; Insulin-Like Growth Factor I - metabolism; Janus kinase; Kinases; Lean body mass; Lipid metabolism; Lipids; Liver; Liver - drug effects; Liver - metabolism; Low carbohydrate diet; Male; Muscles; Nutrient deficiency; Pituitary; Proteins; Proto-Oncogene Proteins c-akt - metabolism; Rats; Rats, Wistar; Receptors, Somatotropin - genetics; Receptors, Somatotropin - metabolism; Reverse Transcriptase Polymerase Chain Reaction; Secretion; Skeletal muscle; Somatostatin; STAT3 Transcription Factor - metabolism; STAT5 Transcription Factor - metabolism; Tibia; Transcription factors; Transducers; Vertebrates: endocrinology
• ISSN: 0013-7227; 1945-7170
• DOI: 10.1210/en.2010-1423

Low-carbohydrate/high fat diets leads to hepatic growth hormone resistance and impaired GH-receptor signaling in rats. GH is a well established regulator of growth, lipid, and glucose metabolism and therefore important for fuel utilization. However, little is known about the effects of macronutrients on the GH/IGF system. We used low-carbohydrate/high-fat diets (LC-HFD) as a model to study the impact of fat, protein, and carbohydrates on the GH/IGF-axis; 12-wk-old Wistar rats were fed either regular chow, a moderate, protein-matched LC-HFD, or a ketogenic LC-HFD (percentage of fat/protein/carbohydrates: chow, 16.7/19/64.3; LC-HF-1, 78.7/19.1/2.2; LC-HF-2, 92.8/5.5/1.7). After 4 wk, body and tibia length, lean body mass, and fat pad weights were measured. Furthermore, we investigated the effects of LC-HFD on 1) secretion of GH and GH-dependent factors, 2) expression and signaling of components of the GH/IGF system in liver and muscle, and 3) hypothalamic and pituitary regulation of GH release. Serum concentrations of IGF-I, IGF binding protein-1, and IGF binding protein-3 were lower with LC-HF-1 and LC-HF-2 (P < 0.01). Both LC-HFD-reduced hepatic GH receptor mRNA and protein expression, decreased basal levels of total and phosphorylated Janus kinase/signal transducers and activators of transcription signaling proteins and reduced hepatic IGF-I gene expression. Hypothalamic somatostatin expression was reduced only with LC-HF-1, leading to increased pituitary GH secretion, higher IGF-I gene expression, and activation of IGF-dependent signaling pathways in skeletal muscle. In contrast, despite severely reduced IGF-I concentrations, GH secretion did not increase with LC-HF-2 diet. In conclusion, lack of carbohydrates in LC-HFD induces hepatic GH resistance. Furthermore, central feedback mechanisms of the GH/IGF system are impaired with extreme, ketogenic LC-HFD.