IGF‐1 receptor deficiency in thyrocytes impairs thyroid hormone secretion and completely inhibits TSH‐stimulated goiter

Ock, Sangmi; Ahn, Jeongmin; Lee, Seok Hong; Kang, Hyun; Offermanns, Stefan; Ahn, Hwa Young; Jo, Young Suk; Shong, Minho; Cho, Bo Youn; Jo, Daewoong; Abel, E. Dale; Lee, Tae Jin; Park, Woo Jin; Lee, In Kyu; Kim, Jaetaek

doi:10.1096/fj.13-231381

Cited by 40 publications

(48 citation statements)

References 44 publications

(55 reference statements)

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“…Thus, although GH supplementation cannot restore normal TV in the absence of TSH, it can induce proliferation of thyrocytes and the appearance of thyroid nodules, due to its well-known proliferative and mitogenic effects, regardless of TSH levels. This novel finding fits with recent in vitro studies that proved that goiter development under experimental conditions was completely abrogated in IGF1 receptor knock-out mice, revealing an essential, autonomous role for IGF1 receptor signaling in the regulation of goitrogenesis (31).…”

Section: Discussionsupporting

confidence: 89%

Effects of GH replacement therapy on thyroid volume and nodule development in GH deficient adults: a retrospective cohort study

Curtò

Giovinazzo

Alibrandi

et al. 2015

European Journal of Endocrinology

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Objective: Despite the well-known effects of GH/IGF1 signaling on the thyroid, few data are available on the risk of developing nodular goiter in hypopituitary subjects during GH replacement therapy (GHRT). We aimed to define the effects of GH therapy on thyroid volume (TV) and nodular growth. Design: The records of 96 subjects (47 males and 49 females, median age 48 years) with GH deficit (GHD) were investigated. Seventy also had central hypothyroidism (CH). At the time of our retrospective evaluation, median treatment duration was 5 years. Results: Pre-treatment TV was smaller in GHD patients than in healthy subjects (PZ0.030). During GH treatment, TV significantly increased (PZ0.016 for the entire group and PZ0.014 in euthyroid GHD patients). Before starting GH therapy, 17 patients harbored thyroid nodules. During GH therapy, nodule size increased slightly in seven patients, and new thyroid nodules occurred in nine patients. Among the 79 patients without pre-existing thyroid nodules, 17 developed one or more nodules. There was no difference in the prevalence of CH in GHD patients with or without thyroid nodules (PZ0.915; PZ0.841, when patients with pre-therapy nodular goiter were excluded), the main predictor for nodule development being serum IGF1 (PZ0.038). Conclusions: GHRT is associated with TV's increase in GHD patients. Thyroid nodules developed in 27% of patients, mainly in relation to pre-therapy IGF1 levels, independently of normal or impaired TSH stimulation.

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Section: Discussionsupporting

confidence: 89%

Effects of GH replacement therapy on thyroid volume and nodule development in GH deficient adults: a retrospective cohort study

Curtò

Giovinazzo

Alibrandi

et al. 2015

European Journal of Endocrinology

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“…The authors also observed that short-term treatment using IGF1 induces AKT activation, which may induce the TSHstimulated IGF1R/mTOR/S6 signaling pathways in cultured thyrocytes (Ock et al 2013).…”

Section: Endocrine-related Cancermentioning

confidence: 88%

Obesity and thyroid cancer

Marcello,

Cunha,

Batista

et al. 2014

Endocrine Related Cancer

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Many studies have provided observational data on the association of obesity and thyroid cancers, but only few of them propose mechanisms that would permit a better understanding of the causal molecular mechanisms of this association. Considering that there is an increasing incidence of both obesity and thyroid cancers, we need to summarize and link recent studies in order to characterize and understand the contribution of obesity-related factors that might affect thyroid cancer development and progression. Adipose tissue is involved in many vital processes, including insulin sensitivity, angiogenesis, regulation of energy balance, activation of the complement system, and responses such as inflammation. Although these processes have their own molecular pathways, they involve the same molecules through which obesity and adipose tissue might exert their roles in carcinogenesis, not only affecting MAPK and PI3K or even insulin pathways, but also recruiting local inflammatory responses that could result in disease formation and progression. This review describes five important issues that might explain the link between excessive weight and thyroid cancer: thyroid hormones, insulin resistance, adipokines, inflammation, and sexual hormones.

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“…Phenotypes of multiple Igf1r tissue-specific mutant lines were postnatally analyzed after mating them with diverse cell-type Cre-expressing transgenics. Conditional deletion of Igf1r in adult animals was described in many cells including pancreatic beta-cells, osteoblasts, endothelial cells, hepatocytes, prostate epithelium, thyrocytes, adipocytes, oligodendrocytes and neurons, resulting in different cell-or tissue-specific effects, which support IGF1R pleiotropic function (Abbas et al 2011;Boucher et al 2012;Cadoret et al 2005;DiGirolamo et al 2007;Kappeler et al 2008;Kloting et al 2008;Kondo et al 2003;Kulkarni et al 2002;Mason et al 2003;Muller et al 2011;Ock et al 2013;Sutherland et al 2008;Xuan et al 2010;Zeger et al 2007). Absence of IGF1R caused opposite results on different tissues depending on the cell-type specificity of Cre mouse lines.…”

Section: Introductionmentioning

confidence: 99%

Differential organ phenotypes after postnatal Igf1r gene conditional deletion induced by tamoxifen in UBC-CreERT2; Igf1r fl/fl double transgenic mice

et al. 2014

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Insulin-like growth factor type 1 receptor (IGF1R) is a ubiquitously expressed tyrosine kinase that regulates cell proliferation, differentiation and survival. It controls body growth and organ homeostasis, but with specific functions depending on developmental time and cell type. Human deficiency in IGF1R is involved in growth failure, microcephaly, mental retardation and deafness, and its overactivation is implicated in oncogenesis. Igf1r-deficient mice die at birth due to growth retardation and respiratory failure. Although multiple Igf1r tissue-specific mutant lines have been analyzed postnatally, using Igf1r-floxed (Igf1r (fl/fl) ) mice mated with diverse cell-type recombinase Cre-expressing transgenics, no mouse models for the study of generalized Igf1r deficiency in adults have been reported. To this end we generated UBC-CreERT2; Igf1r (fl/fl) transgenic mice with an inducible deletion of Igf1r activated by tamoxifen. Tamoxifen administration to 4 week-old prepuberal male mice delayed their growth, producing a distinct impact on organ size 4 weeks later. Whereas testes were smaller, spleen and heart showed an increased organ to body weight ratio. Mosaic Igf1r genomic deletions caused a significant reduction in Igf1r mRNA in all organs analyzed, resulting in diverse phenotypes. While kidneys, spleen and cochlea had unaltered gross morphology, testes revealed halted spermatogenesis, and liver and alveolar lung parenchyma showed increased cell proliferation rates without affecting apoptosis. We demonstrate that UBC-CreERT2 transgenic mice efficiently delete Igf1r upon postnatal tamoxifen treatment in multiple mouse organs, and corroborate that IGF1R function is highly dependent on cell, tissue and organ type.

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IGF‐1 receptor deficiency in thyrocytes impairs thyroid hormone secretion and completely inhibits TSH‐stimulated goiter

Cited by 40 publications

References 44 publications

Effects of GH replacement therapy on thyroid volume and nodule development in GH deficient adults: a retrospective cohort study

Effects of GH replacement therapy on thyroid volume and nodule development in GH deficient adults: a retrospective cohort study

Obesity and thyroid cancer

Differential organ phenotypes after postnatal Igf1r gene conditional deletion induced by tamoxifen in UBC-CreERT2; Igf1r fl/fl double transgenic mice

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