New insights of growth hormone (GH) actions from tissue-specific GH receptor knockouts in mice

List, Edward O.; Berryman, Darlene E.; Jensen, Elizabeth; Kulkarni, Prateek; McKenna, Savannah; Kopchick, John J.

doi:10.20945/2359-3997000000185

Cited by 15 publications

(9 citation statements)

References 41 publications

(95 reference statements)

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“…In addition to global Ghr-KO mice, multiple lines of conditional mutants lacking GHR in specific tissues have been generated (reviewed in 42,43). Many of these lines show alterations in glucose homeostasis and insulin secretion/action.…”

Section: The Ghr-ko Mousementioning

confidence: 99%

MECHANISMS IN ENDOCRINOLOGY: Transient juvenile hypoglycemia in growth hormone receptor deficiency – mechanistic insights from Laron syndrome and tailored animal models

Hinrichs

Bidlingmaier

Kopchick

et al. 2021

European Journal of Endocrinology

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Aim of the study is to find possible explanations for vanishing juvenile hypoglycemia in growth hormone receptor deficiency (GHRD) in human patients and animal models. We reviewed parameters of glucose metabolism in distinct age groups in two human cohorts (Israeli and Ecuadorian) of Laron syndrome (LS) patients, a mouse model (Ghr-KO mouse) and provide additional data for a porcine model (GHR-KO pig). Juvenile hypoglycemia is a common symptom of GHRD and vanishes in adulthood. In the Israeli cohort, developing metabolic syndrome is associated with decreasing insulin sensitivity, insulinopenia and glucose intolerance, increasing glucose levels with age. In Ecuadorian patients and both animal models, insulin sensitivity is preserved or even enhanced. Alterations in food intake and energy consumption do not explain the differences in glucose levels, neither is the accumulation of body fat associated with negative effects in the Ecuadorian cohort or the animal models. A reduced beta cell mass and resulting insulin secretory capacity is common and leads to glucose intolerance in Ghr-KO mice, while glucose tolerance is preserved in Ecuadorian patients and the GHR-KO pig. In human patients and the GHR-KO pig, a simultaneous occurrence of normoglycemia with the onset of puberty is reported. Reduced gluconeogenesis in GHRD is discussed to cause the juvenile hypoglycemia and a counter regulatory stimulation of gluconeogenesis can be hypothesized. A coherent study assessing endogenous glucose production and beta-cell capacity in the hypoglycemic and normoglycemic age group is needed. This can be performed in GHR-KO pigs, including castrated animals.

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Section: The Ghr-ko Mousementioning

confidence: 99%

MECHANISMS IN ENDOCRINOLOGY: Transient juvenile hypoglycemia in growth hormone receptor deficiency – mechanistic insights from Laron syndrome and tailored animal models

Hinrichs

Bidlingmaier

Kopchick

et al. 2021

European Journal of Endocrinology

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“…The strong relationship between circulating levels of GH and IGF-1 confounds the determination of the specific effects induced by each hormone individually, especially when considering the widespread expression of their receptors. However, with the generation of tissue-specific GHR- or IGF-1 receptor (IGF-1R)-deficient mice, the precise physiological role of each of these receptors in different tissues has been described [ 14 , 15 , 16 ]. In this regard, numerous studies produced tissue-specific knockout mice by deleting either GHR or IGF-1R from the bone, liver, adipose tissue, muscle, pancreatic β-cell and other organs [ 14 , 15 , 16 ].…”

Section: Introductionmentioning

confidence: 99%

“…However, with the generation of tissue-specific GHR- or IGF-1 receptor (IGF-1R)-deficient mice, the precise physiological role of each of these receptors in different tissues has been described [ 14 , 15 , 16 ]. In this regard, numerous studies produced tissue-specific knockout mice by deleting either GHR or IGF-1R from the bone, liver, adipose tissue, muscle, pancreatic β-cell and other organs [ 14 , 15 , 16 ]. Nevertheless, the distinct role of GHR signaling in the nervous system through the generation of brain-specific knockout mice has not been studied until recently [ 17 ].…”

Section: Introductionmentioning

confidence: 99%

“…Thus, GH stimulates lipolysis in white adipose tissue and antagonizes insulin effects on glycemic control [ 18 , 19 , 20 , 21 ]. Accordingly, GHR-deficient mice exhibit higher insulin sensitivity despite presenting increased percentages of body fat [ 13 , 15 , 16 , 21 ]. Since the classical target tissues of GH, including the liver, adipose tissue and muscle ( Figure 1 ), are directly involved in the regulation of lipid and glucose metabolism, it is commonly assumed that the metabolic effects of GH are mediated by these organs.…”

Section: Introductionmentioning

confidence: 99%

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Central Regulation of Metabolism by Growth Hormone

Donato

Wasinski

Furigo

et al. 2021

Cells

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Growth hormone (GH) is secreted by the pituitary gland, and in addition to its classical functions of regulating height, protein synthesis, tissue growth, and cell proliferation, GH exerts profound effects on metabolism. In this regard, GH stimulates lipolysis in white adipose tissue and antagonizes insulin’s effects on glycemic control. During the last decade, a wide distribution of GH-responsive neurons were identified in numerous brain areas, especially in hypothalamic nuclei, that control metabolism. The specific role of GH action in different neuronal populations is now starting to be uncovered, and so far, it indicates that the brain is an important target of GH for the regulation of food intake, energy expenditure, and glycemia and neuroendocrine changes, particularly in response to different forms of metabolic stress such as glucoprivation, food restriction, and physical exercise. The objective of the present review is to summarize the current knowledge about the potential role of GH action in the brain for the regulation of different metabolic aspects. The findings gathered here allow us to suggest that GH represents a hormonal factor that conveys homeostatic information to the brain to produce metabolic adjustments in order to promote energy homeostasis.

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“…To date, at least 21 distinct tissue-specific GHR gene disrupted mouse lines have been generated: liver, muscle, fat, brain, bone, heart, intestine, macrophage, pancreatic β cells, hematopoietic stem cells, and multi-tissue "global" [103,104].…”

Section: Membrane-bound Receptorsmentioning

confidence: 99%

Applying Bioinformatic Platforms, In Vitro, and In Vivo Functional Assays in the Characterization of Genetic Variants in the GH/IGF Pathway Affecting Growth and Development

Domené

Scaglia

Gutiérrez

et al. 2021

Cells

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Heritability accounts for over 80% of adult human height, indicating that genetic variability is the main determinant of stature. The rapid technological development of Next-Generation Sequencing (NGS), particularly Whole Exome Sequencing (WES), has resulted in the characterization of several genetic conditions affecting growth and development. The greatest challenge of NGS remains the high number of candidate variants identified. In silico bioinformatic tools represent the first approach for classifying these variants. However, solving the complicated problem of variant interpretation requires the use of experimental approaches such as in vitro and, when needed, in vivo functional assays. In this review, we will discuss a rational approach to apply to the gene variants identified in children with growth and developmental defects including: (i) bioinformatic tools; (ii) in silico modeling tools; (iii) in vitro functional assays; and (iv) the development of in vivo models. While bioinformatic tools are useful for a preliminary selection of potentially pathogenic variants, in vitro—and sometimes also in vivo—functional assays are further required to unequivocally determine the pathogenicity of a novel genetic variant. This long, time-consuming, and expensive process is the only scientifically proven method to determine causality between a genetic variant and a human genetic disease.

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New insights of growth hormone (GH) actions from tissue-specific GH receptor knockouts in mice

Cited by 15 publications

References 41 publications

MECHANISMS IN ENDOCRINOLOGY: Transient juvenile hypoglycemia in growth hormone receptor deficiency – mechanistic insights from Laron syndrome and tailored animal models

MECHANISMS IN ENDOCRINOLOGY: Transient juvenile hypoglycemia in growth hormone receptor deficiency – mechanistic insights from Laron syndrome and tailored animal models

Central Regulation of Metabolism by Growth Hormone

Applying Bioinformatic Platforms, In Vitro, and In Vivo Functional Assays in the Characterization of Genetic Variants in the GH/IGF Pathway Affecting Growth and Development

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