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1.
Endocrinology ; 161(8)2020 08 01.
Article in English | MEDLINE | ID: mdl-32556100

ABSTRACT

A rare 20K isoform of GH-V (here abbreviated as GHv) was discovered in 1998. To date, only 1 research article has characterized this isoform in vivo, observing that GHv treatment in male high-fat fed rats had several GH-like activities, but unlike GH lacked diabetogenic and lactogenic activities and failed to increase IGF-1 or body length. Therefore, the current study was conducted to further characterize the in vivo activities of GHv in a separate species and in a GH-deficient model (GH-/- mice) and with both sexes represented. GHv-treated GH-/- mice had significant increases to serum IGF-1, femur length, body length, body weight, and lean body mass and reduced body fat mass similar to mice receiving GH treatment. GH treatment increased circulating insulin levels and impaired insulin sensitivity; in contrast, both measures were unchanged in GHv-treated mice. Since GHv lacks prolactin receptor (PRLR) binding activity, we tested the ability of GH and GHv to stimulate the proliferation of human cancer cell lines and found that GHv has a decreased proliferative response in cancers with high PRLR. Our findings demonstrate that GHv can stimulate insulin-like growth factor-1 and subsequent longitudinal body growth in GH-deficient mice similar to GH, but unlike GH, GHv promoted growth without inhibiting insulin action and without promoting the growth of PRLR-positive cancers in vitro. Thus, GHv may represent improvements to current GH therapies especially for individuals at risk for metabolic syndrome or PRLR-positive cancers.


Subject(s)
Growth Hormone/genetics , Human Growth Hormone/pharmacology , Placental Hormones/pharmacology , Animals , Body Composition/drug effects , Body Weight/drug effects , Female , Growth Hormone/deficiency , Hormone Replacement Therapy , Human Growth Hormone/isolation & purification , Human Growth Hormone/metabolism , Human Growth Hormone/therapeutic use , Humans , Mice , Mice, Inbred C57BL , Mice, Knockout , Placenta/chemistry , Placenta/metabolism , Placental Hormones/therapeutic use , Pregnancy , Protein Isoforms
2.
Endocrinology ; 160(7): 1743-1756, 2019 07 01.
Article in English | MEDLINE | ID: mdl-31099824

ABSTRACT

In 1997, our laboratory used targeted gene disruption of the GH receptor (GHR) to generate GHR knockout (GHR-/-) mice, which have been used in >127 published studies to help elucidate GH's numerous activities. However, because GH replacement studies cannot be performed using this line, a GH knockout mouse line via targeted disruption of the GH gene is needed. Therefore, we created and characterized GH gene-disrupted (GH-/-) mice. GH-/- mice have severely decreased IGF-1 levels, small body size, and altered body composition with increased adiposity. GH-/- mice are extremely insulin sensitive but glucose intolerant, with a dramatic reduction in pancreatic islet size. Importantly, disruption of the GH gene had profound and depot-specific effects on white adipose tissue (WAT). Subcutaneous WAT from male and female GH-/- mice have significantly larger adipocytes and reduced fibrosis, neither of which occurred in perigonadal WAT, suggesting that GH has a more pronounced effect on subcutaneous WAT. Comparisons of GH-/- mice to previously published data on GHR-/- mice show a remarkably similar phenotype. Finally, we demonstrate that GH-/- mice are responsive to GH treatment, as shown by changes to serum IGF-1 levels; body length, weight, and composition; and insulin sensitivity. This study not only provides characterization of the first mouse line with targeted mutation of the GH gene but also indicates that GH gene disruption dramatically influences fibrosis of subcutaneous WAT.


Subject(s)
Adipocytes/metabolism , Growth Hormone/genetics , Insulin Resistance/physiology , Subcutaneous Fat/metabolism , Adipose Tissue, White/metabolism , Animals , Body Composition/physiology , Female , Fibrosis/genetics , Fibrosis/metabolism , Growth Hormone/metabolism , Islets of Langerhans/metabolism , Male , Mice , Mice, Knockout
3.
Endocrinology ; 160(1): 68-80, 2019 01 01.
Article in English | MEDLINE | ID: mdl-30462209

ABSTRACT

Global GH receptor-null or knockout (GHRKO) mice have been extensively studied owing to their unique phenotype (dwarf and obese but remarkably insulin sensitive and long-lived). To better understand the influence of adipose tissue (AT) on the GHRKO phenotype, we previously generated fat-specific GHRKO (FaGHRKO) mice using the adipocyte protein-2 (aP2) promoter driving Cre expression. Unlike global GHRKO mice, FaGHRKO mice are larger than control mice and have an increase in white AT (WAT) mass and adipocyte size as well as an increase in brown AT mass. FaGHRKO mice also have an unexpected increase in IGF-1, decrease in adiponectin, no change in insulin sensitivity or liver triglyceride content, and a decreased lifespan. Extensive analysis of the aP2 promoter/enhancer by multiple laboratories has revealed expression in nonadipose tissues, confounding interpretation of results. In the current study, we used the adiponectin promoter/enhancer to drive Cre expression, which better targets mature adipocytes, and generated a new line of adipocyte-specific GHRKO (AdGHRKO) mice. AdGHRKO mice have an increase in adipocyte size and WAT depot mass in all depots except male perigonadal, a WAT accumulation pattern similar to FaGHRKO mice. Likewise, adiponectin levels and WAT fibrosis are decreased in both tissue-specific mouse lines. However, unlike FaGHRKO mice, AdGHRKO mice have no change in IGF-1 levels, improved glucose homeostasis, and reduced liver triglycerides. Thus, AdGHRKO mice should be valuable for future studies assessing the contribution of adipocyte GHR signaling in long-term health and lifespan.


Subject(s)
Adipocytes/metabolism , Carrier Proteins/genetics , Insulin Resistance , Liver/metabolism , Triglycerides/metabolism , Adiponectin , Adipose Tissue, Brown/metabolism , Adipose Tissue, White/metabolism , Animals , Carrier Proteins/metabolism , Female , Humans , Insulin/metabolism , Insulin-Like Growth Factor I/genetics , Insulin-Like Growth Factor I/metabolism , Male , Mice , Mice, Knockout , Species Specificity
4.
Nutr Healthy Aging ; 4(1): 95-99, 2016 Oct 27.
Article in English | MEDLINE | ID: mdl-28035346

ABSTRACT

Previously, our laboratory reported that weight-cycled mice outlive their obese counterparts. To gain a better mechanistic understanding of these results, we evaluated cellular senescence in white adipose tissue (WAT) of lean, obese, and weight cycled mice. Our results show that at the end of a 28 day weight loss cycle cellular senescence is significantly reduced in multiple WAT depots compared to obese mice, which also corresponds to a reduction in circulating activin A (a marker of senescence). These findings suggest that a previously undescribed benefit to weight loss may be a reduction of cellular senescence in WAT.

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