Читать книгу Nutrition and Growth - Группа авторов - Страница 12

Wu S^1,2, Zhang Y², De Luca F¹

¹Section of Endocrinology and Diabetes, St. Christopher’s Hospital for Children, Drexel University College of Medicine, Philadelphia, PA, USA; ²Center for Translational Medicine, the First Affiliated Hospital of Xi’an Jiaotong University School of Medicine, Xi’an Shaanxi PR China Bone 2019;122:166–175

Background: Obese children grow faster than their normal-weight peers. Insulin resistance and hyperinsulinemia have been associated with obesity-related growth acceleration.

Methods: To determine whether obesity-associated hyperinsulinemia promotes bone growth by activating the insulin receptor (IR) in the growth plate, we generated ^TamCartIR^flox/flox mice. The injection of 4 doses of tamoxifen in these mice (beginning at postnatal day 5th with 2 days interval between injections) resulted in the IR gene excision exclusively in the cartilage. ^TamCartIR^flox/flox tamoxifen-treated mice (KO mice) and their IR^flox/flox control littermates (C mice) at 3 weeks of age were exposed to a standard or hypercaloric (high-fat) diet for 4 weeks.

Results: At the end of study, C and KO mice fed with a high-fat diet exhibited greater weight gain than the respective strains fed with a standard diet. Body and tibial growth and growth plate height of C mice fed with high-fat diet were greater than those of standard-diet-fed C mice; however, no difference was observed between KO mice fed with standard or high-fat diet with respect to body and tibial growth and growth plate height. Circulating levels of insulin, insulin-like growth factor (IGF)-1 and leptin were significantly higher in C and KO mice exposed to high-fat diet compared to those in the same strain exposed to standard diet. Increased phosphorylation of Akt (one of the intracellular mediators of insulin action in bone) in the growth plate of C mice on high-fat diet (compared to those on standard diet) suggests that high-fat-mediated increased circulating insulin levels may directly affect growth plate function and bone growth. High-fat diet was not associated with any change of Akt phosphorylation in KO mice. In addition, in vitro studies in cultured primary chondrocytes revealed that Akt mediates the stimulatory effects of insulin on chondrocyte proliferation and differentiation.

Conclusions: In conclusion, the activation of the IR in the growth plate of mice fed with a hypercaloric diet stimulates skeletal growth and growth plate chondrogenesis.

Reprinted with permission from Elsevier.

Comments

Insulin resistance and hyperinsulinemia are suggested to be important mechanisms involved in accelerated longitudinal growth in childhood obesity [1]. Role of insulin receptor (IR) at the growth plate, as an IGF-independent mechanism promoting growth, was studied in mice with isolated excision of the IR gene in cartilage. Both in vivo and in vitro data support this hypothesis. Namely, following a hypercaloric diet that results in insulin resistance and hyperinsulinism, growth at the level of growth plate was not increased in mice with a knockout of IR in comparison to controls. In addition, it was determined that in cultured primary chondrocytes, Akt mediates the stimulatory effects of insulin on chondrocyte proliferation and differentiation. Studies in humans are needed to further establish signaling through the IR as the mechanism involved in accelerated longitudinal growth in childhood obesity [2]. Unraveling IGF-independent mechanisms involved in bone growth is important for the development of novel therapeutic strategies in individuals with dysfunctional IGF signaling pathway and short stature.

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