title: Elevated GH/IGF-I, due to somatotrope-specific loss of both IGF-I and insulin receptors, alters glucose homeostasis and insulin sensitivity in a diet-dependent manner.
abstract: A unique mouse model was developed with elevated endogenous GH (2- to 3-fold) and IGF-I (1.2- to 1.4-fold), due to somatotrope-specific Cre-mediated inactivation of IGF-I receptor (IgfIr) and insulin receptor (Insr) genes (IgfIr,Insr(rGHpCre), referred to as HiGH mice). We demonstrate that the metabolic phenotype of HiGH mice is diet dependent and differs from that observed in other mouse models of GH excess due to ectopic heterologous transgene expression or pituitary tumor formation. Elevated endogenous GH promotes lean mass and whole-body lipid oxidation but has minimal effects on adiposity, even in response to diet-induced obesity. When caloric intake is moderated, elevated GH improves glucose clearance, despite low/normal insulin sensitivity, which may be explained in part by enhanced IGF-I and insulin output. However, when caloric intake is in excess, elevated GH promotes hepatic lipid accumulation, insulin resistance, hyperglycemia, and ketosis. The HiGH mouse model represents a useful tool to study the role endogenous circulating GH levels play in regulating health and disease.
authors: Jesse Brown Veterans Affairs Medical Center, Research and Development Division, 820 South Damen Avenue, Chicago, Illinois 60612, USA.
authors: Manuel D
authors: MD
authors: Gahete
authors: José
authors: J
authors: Córdoba-Chacón
authors: Chike V
authors: CV
authors: Anadumaka
authors: Qing
authors: Q
authors: Lin
authors: Jens C
authors: JC
authors: Brüning
authors: C Ronald
authors: CR
authors: Kahn
authors: Raúl M
authors: RM
authors: Luque
authors: Rhonda D
authors: RD
authors: Kineman
mesh_terms: D050154:Adiposity; D000818:Animals; D004032:Diet; D005947:Glucose / Q000378:metabolism*; D013006:Growth Hormone / Q000097:blood / Q000378:metabolism* / Q000502:physiology; D006706:Homeostasis; D007333:Insulin Resistance; D007334:Insulin-Like Growth Factor I / Q000378:metabolism* / Q000502:physiology; D050356:Lipid Metabolism; D051379:Mice; D009928:Organ Specificity; D017526:Receptor, IGF Type 1 / Q000172:deficiency / Q000378:metabolism*; D011972:Receptor, Insulin / Q000172:deficiency / Q000378:metabolism*
chemical_list: D007334:Insulin-Like Growth Factor I; D013006:Growth Hormone; D017526:Receptor, IGF Type 1; D011972:Receptor, Insulin; D005947:Glucose