title: Insulin resistance secondary to a high-fat diet stimulates longitudinal bone growth and growth plate chondrogenesis in mice.
abstract: It is known that overweight children are often more insulin resistant and taller than normal-weight peers. Because it has been hypothesized that insulin is implicated in the obesity-associated growth acceleration, we aimed to determine whether insulin resistance and secondary hyperinsulinemia are the causative mechanisms of such growth acceleration. Three-week-old mice were fed with standard chow or with a high-fat diet without or with daily administration of pioglitazone. After 6 wk, high-fat mice' body and tibial growth, tibial growth plate height, and serum insulin were all greater than those of standard chow-fed mice. High-fat + pioglitazone mice were shorter, their tibial growth and the growth plate height reduced, and their insulin lower than those of high-fat mice. The addition of insulin to the culture medium of mouse metatarsal bones induced the metatarsal linear growth and increased the metatarsal growth plate height. In addition, insulin stimulated cultured chondrocyte proliferation and differentiation, with both effects being prevented by transfection with a small interfering RNA targeted to the insulin receptor. In conclusion, in high fat-fed mice, insulin resistance is causally related to accelerated skeletal growth. Our in vitro findings suggest that insulin may directly modulate skeletal growth by activating the insulin receptor directly at the growth plate.
authors.affiliation: Section of Endocrinology and Diabetes, St Christopher’s Hospital for Children, Department of Pediatrics, Drexel University College of Medicine, Philadelphia, Pennsylvania 19134, USA.
authors.forename: Shufang
authors.initials: S
authors.lastname: Wu
authors.forename: Alexandra L
authors.initials: AL
authors.lastname: Aguilar
authors.forename: Vlady
authors.initials: V
authors.lastname: Ostrow
authors.forename: Francesco
authors.initials: F
authors.lastname: De Luca
mesh_terms: D000818:Animals; D015153:Blotting, Western; D001846:Bone Development / Q000187:drug effects* / Q000235:genetics; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D019902:Chondrocytes / Q000166:cytology*; D020219:Chondrogenesis / Q000187:drug effects*; D004041:Dietary Fats / Q000494:pharmacology*; D006132:Growth Plate / Q000187:drug effects / Q000254:growth & development*; D007150:Immunohistochemistry; D007328:Insulin / Q000097:blood / Q000494:pharmacology; D007333:Insulin Resistance / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D000077205:Pioglitazone; D016133:Polymerase Chain Reaction; D034741:RNA, Small Interfering / Q000235:genetics; D017526:Receptor, IGF Type 1 / Q000235:genetics / Q000378:metabolism; D011972:Receptor, Insulin / Q000235:genetics / Q000378:metabolism; D045162:Thiazolidinediones / Q000494:pharmacology
chemical_list: D004041:Dietary Fats; D007328:Insulin; D034741:RNA, Small Interfering; D045162:Thiazolidinediones; D017526:Receptor, IGF Type 1; D011972:Receptor, Insulin; D000077205:Pioglitazone