The Intricate Role of Growth Hormone in Metabolism

Growth hormone (GH), a master regulator of somatic growth, also regulates carbohydrate and lipid metabolism via complex interactions with insulin and insulin-like growth factor-1 (IGF-1). Data from human and rodent studies reveal the importance of GH in insulin synthesis and secretion, lipid metabolism and body fat remodeling. In this review, we will summarize the tissue-specific metabolic effects of GH, with emphasis on recent targets identified to mediate these effects. Furthermore, we will discuss what role GH plays in obesity and present possible mechanisms by which this may occur

A systematic review and meta-analysis on the efficacy of stem cell therapy on bone brittleness in mouse models of osteogenesis imperfecta

There is no cure for osteogenesis imperfecta (OI), and current treatments can only partially correct the bone phenotype. Stem cell therapy holds potential to improve bone quality and quantity in OI. Here, we conduct a systematic review and meta-analysis of published studies to investigate the efficacy of stem cell therapy to rescue bone brittleness in mouse models of OI. Identified studies included bone marrow, mesenchymal stem cells, and human fetal stem cells. Effect size of fracture incidence, maximum load, stiffness, cortical thickness, bone volume fraction, and raw engraftment rates were pooled in a random-effects meta-analysis. Cell type, cell number, injection route, mouse age, irradiation, anatomical bone, and follow up time were considered as moderators. It was not possible to investigate further parameters due to the lack of standards of investigation between the studies. Despite the use of oim mice in the majority of the investigations considered and the lack of sham mice as control, this study demonstrates the promising potential of stem cell therapy to reduce fractures in OI. Although their low engraftment, cell therapy in mouse models of OI had a beneficial effect on maximum load, but not on stiffness, cortical thickness and bone volume. These parameters all depend on bone geometry and do not inform on its material properties. Being bone fractures the primary symptom of OI, there is a critical need to measure the fracture toughness of OI bone treated with stem cells to assess the actual efficacy of the treatment to rescue OI bone brittleness

High-Efficient FLPo Deleter Mice in C57BL/6J Background

Conditional gene manipulation in mice becomes a routine for genetic studies of mammalian gene functions. Additional site-specific recombinases such as FLP or φ31 provide one more level of gene manipulation flexibility. The recombination activity of the currently available FLP deleter mice remains low. We generated a new FLP deleter mouse line with the mouse codon-optimized FLPo gene in C57BJ/6 background, which showed superior recombination efficacy in comparison to FLPe deleter mice. 100% complete removal of FRT-flanked Neo cassette was observed in all F1 progeny mice carrying both FLPo and Neo cassette, which can be transmitted to F2 generation independent of FLPo activity. Our new FLPo transgenic mice (on pure C57BJ/6 background) will largely facilitate the gene targeting process and is valuable for conditional gene manipulation

Elevated serum IGF-1 levels synergize PTH action on the skeleton only when the tissue IGF-1 axis is intact

Abstract There is growing evidence that IGF-1 and PTH have synergistic actions on bone and that part of the anabolic effects of PTH are mediated by local production of IGF-1. In this study we analyzed the skeletal response to PTH in mouse models with manipulated endocrine or autocrine/paracrine IGF-1. We utilized mice carrying a hepatic IGF-1 transgene (HIT), which results in a 3-fold increase in serum IGF-1 levels and normal tissue IGF-1 expression, and IGF-1 null mice with blunted IGF-1 expression in tissues but 3-fold increases in serum IGF-1 levels (KO-HIT). Evaluation of skeletal growth showed that elevations in serum IGF-1 in mice with igf-1 gene ablation in all tissues except the liver (KO-HIT) resulted in a restoration of skeletal morphology and mechanical properties by adulthood. Intermittent PTH treatment of adult HIT mice resulted in increases in serum osteocalcin levels, femoral total cross-sectional area, cortical bone area and cortical bone thickness, as well as bone mechanical properties. We found that the skeletal response of HIT mice to PTH was significantly higher than that of control mice, suggesting synergy between IGF-1 and PTH on bone. In sharp contrast, although PTH-treated KO-HIT mice demonstrated an anabolic response in cortical and trabecular bone compartments compared to vehicle treated KO-HITs, their response was identical to that of PTH-treated control mice. We conclude that 1) in the presence of elevated serum IGF-1 levels, PTH can exert an anabolic response in bone even in the total absence of tissue IGF-1 and, 2) elevations in serum IGF-1 levels synergize PTH action on bone only if the tissue IGF-1 axis is intact, thus enhancement of PTH anabolic actions is tissue IGF-1-dependent

Serum IGF-1 Affects Skeletal Acquisition in a Temporal and Compartment-Specific Manner

Insulin-like growth factor-1 (IGF-1) plays a critical role in the development of the growing skeleton by establishing both longitudinal and transverse bone accrual. IGF-1 has also been implicated in the maintenance of bone mass during late adulthood and aging, as decreases in serum IGF-1 levels appear to correlate with decreases in bone mineral density (BMD). Although informative, mouse models to date have been unable to separate the temporal effects of IGF-1 depletion on skeletal development. To address this problem, we performed a skeletal characterization of the inducible LID mouse (iLID), in which serum IGF-1 levels are depleted at selected ages. We found that depletion of serum IGF-1 in male iLID mice prior to adulthood (4 weeks) decreased trabecular bone architecture and significantly reduced transverse cortical bone properties (Ct.Ar, Ct.Th) by 16 weeks (adulthood). Likewise, depletion of serum IGF-1 in iLID males at 8 weeks of age, resulted in significantly reduced transverse cortical bone properties (Ct.Ar, Ct.Th) by 32 weeks (late adulthood), but had no effect on trabecular bone architecture. In contrast, depletion of serum IGF-1 after peak bone acquisition (at 16 weeks) resulted in enhancement of trabecular bone architecture, but no significant changes in cortical bone properties by 32 weeks as compared to controls. These results indicate that while serum IGF-1 is essential for bone accrual during the postnatal growth phase, depletion of IGF-1 after peak bone acquisition (16 weeks) is compartment-specific and does not have a detrimental effect on cortical bone mass in the older adult mouse

Growth Hormone Regulates the Balance Between Bone Formation and Bone Marrow Adiposity

Cancellous bone decreases and bone marrow fat content increases with age. Osteoblasts and adipocytes are derived from a common precursor, and growth hormone (GH), a key hormone in integration of energy metabolism, regulates the differentiation and function of both cell lineages. Since an age-related decline in GH is associated with bone loss, we investigated the relationship between GH and bone marrow adiposity in hypophysectomized (HYPOX) rats and in mice with defects in GH signaling. HYPOX dramatically reduced body weight gain, bone growth and mineralizing perimeter, serum insulin-like growth factor 1 (IGF-1) levels, and mRNA levels for IGF-1 in liver and bone. Despite reduced body mass and adipocyte precursor pool size, HYPOX resulted in a dramatic increase in bone lipid levels, as reflected by increased bone marrow adiposity and bone triglyceride and cholesterol content. GH replacement normalized bone marrow adiposity and precursor pool size, as well as mineralizing perimeter in HYPOX rats. In contrast, 17β -estradiol, IGF-1, thyroxine, and cortisone were ineffective. Parathyroid hormone (PTH) reversed the inhibitory effects of HYPOX on mineralizing perimeter but had no effect on adiposity. Finally, bone marrow adiposity was increased in mice deficient in GH and IGF-1 but not in mice deficient in serum IGF-1. Taken together, our findings indicate that the reciprocal changes in bone and fat mass in GH signaling-deficient rodents are not directly coupled with one another. Rather, GH enhances adipocyte as well as osteoblast precursor pool size. However, GH increases osteoblast differentiation while suppressing bone marrow lipid accumulation. © 2010 American Society for Bone and Mineral Researc

Serum IGF-1 is insufficient to restore skeletal size in the total absence of the growth hormone receptor

States of growth hormone (GH) resistance, such those observed in Laron dwarf patients, are characterized by mutations in the GH receptor (GHR), decreased serum and tissue IGF-1 levels, impaired glucose tolerance, and impaired skeletal acquisition. IGF-1 replacement therapy in such patients increases growth velocity but does not normalize growth. Herein we combined the GH-resistant (GHR knockout [GHRKO]) mouse model with mice expressing the hepatic Igf-1 transgene (HIT) to generate the GHRKO-HIT mouse model. In GHRKO-HIT mice, serum IGF-1 levels were restored via transgenic expression of Igf-1, allowing us to study how endocrine IGF-1 affects growth, metabolic homeostasis, and skeletal integrity. We show that in a GH-resistant state, normalization of serum IGF-1 improved body adiposity and restored glucose tolerance but was insufficient to support normal skeletal growth, resulting in an osteopenic skeletal phenotype. The inability of serum IGF-1 to restore skeletal integrity in the total absence of GHR likely resulted from reduced skeletal Igf-1 gene expression, blunted GH-mediated effects on the skeleton that are independent of serum or tissue IGF-1, and poor delivery of IGF-1 to the tissues. These findings are consistent with clinical data showing that IGF-I replacement therapy in patients with Laron syndrome does not achieve full skeletal growth.Fil: Wu, Yingjie. University Of New York; Estados UnidosFil: Sun, Hui. University Of New York; Estados UnidosFil: Basta Pljakic, Jelena. City College of New York; Estados UnidosFil: Cardoso, Luis. City College of New York; Estados UnidosFil: Kennedy, Oran D.. City College of New York; Estados UnidosFil: Jasper, Hector Guillermo. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Centro de Investigaciones Endocrinológicas; ArgentinaFil: Domene, Horacio Mario. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Centro de Investigaciones Endocrinológicas; ArgentinaFil: Karabatas, Liliana Margarita. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Centro de Investigaciones Endocrinológicas; ArgentinaFil: Guida, María Clara. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Centro de Investigaciones Endocrinológicas; ArgentinaFil: Schaffler, Mitchell B.. City College of New York; Estados UnidosFil: Rosen, Clifford J.. Maine Medical Center Research Institute; Estados UnidosFil: Yakar, Shoshana. University Of New York; Estados Unido

Growth Hormone Protects Against Ovariectomy-Induced Bone Loss in States of Low Circulating Insulin-like Growth Factor (IGF-1)*

Early after estrogen loss in postmenopausal women and ovariectomy (OVX) of animals, accelerated endosteal bone resorption leads to marrow expansion of long bone shafts that reduce mechanical integrity. Both growth hormone (GH) and insulin-like growth factor (IGF-1) are potent regulators of bone remodeling processes. To investigate the role of the GH/IGF-1 axis with estrogen deficiency, we used the liver IGF-1-deficient (LID) mouse. Contrary to deficits in controls, OVX of LID mice resulted in maintenance of cortical bone mechanical integrity primarily owing to an enhanced periosteal expansion affect on cross-sectional structure (total area and cortical width). The serum balance in LID that favors GH over IGF-1 diminished the effects of ablated ovarian function on numbers of osteoclast precursors in the marrow and viability of osteocytes within the cortical matrix and led to less endosteal resorption in addition to greater periosteal bone formation. Interactions between estrogen and the GH/IGF-1 system as related to bone remodeling provide a pathway to minimize degeneration of bone tissue structure and osteoporotic fracture. © 2010 American Society for Bone and Mineral Researc

Reductions in serum IGF-1 during aging impair health span

In lower or simple species, such as worms and flies, disruption of the insulin-like growth factor (IGF)-1 and the insulin signaling pathways has been shown to increase lifespan. In rodents, however, growth hormone (GH) regulates IGF-1 levels in serum and tissues and can modulate lifespan via/or independent of IGF- 1. Rodent models, where the GH/IGF-1 axis was ablated congenitally, show increased lifespan. However, in contrast to rodents where serum IGF-1 levels are high throughout life, in humans, serum IGF-1 peaks during puberty and declines thereafter during aging. Thus, animal models with congenital disruption of the GH/ IGF-1 axis are unable to clearly distinguish between developmental and age-related effects of GH/IGF-1 on health. To overcome this caveat, we developed an inducible liver IGF-1- deficient (iLID) mouse that allows temporal control of serum IGF- 1. Deletion of liver Igf -1 gene at one year of age reduced serum IGF-1 by 70% and dramatically impaired health span of the iLID mice. Reductions in serum IGF-1 were coupled with increased GH levels and increased basal STAT5B phosphorylation in livers of iLID mice. These changes were associated with increased liver weight, increased liver inflammation, increased oxidative stress in liver and muscle, and increased incidence of hepatic tumors. Lastly, despite elevations in serum GH, low levels of serum IGF-1 from 1 year of age compromised skeletal integrity and accelerated bone loss. We conclude that an intact GH/IGF-1 axis is essential to maintain health span and that elevated GH, even late in life, associates with increased pathology