Two-Year Body Composition Analyses of Long-Lived GHR Null Mice

Berryman, Darlene E.; List, Edward O.; Palmer, Amanda J.; Chung, Min‐Yu; Wright-Piekarski, Jacob; Lubbers, Ellen R.; O’Connor, Patrick J.; Okada, Shigeru; Kopchick, John J.

doi:10.1093/gerona/glp175

Cited by 120 publications

(125 citation statements)

References 49 publications

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“…Third, GH-induced WAT loss was specific to subcutaneous and mesenteric fat. This result agrees with previously published work in which subcutaneous WAT depots were found to be increased in mice that lacked GH action (10)(11)(12). Thus, these data further support the notion that 'not all WAT depots are treated equally' in terms of GH action and should be evaluated independently in studies with GH or other treatments.…”

Section: Animal Studies Of the Actions Of Gh Versus Igf1supporting

confidence: 92%

Hypothesis: Extra-hepatic acromegaly: a new paradigm?

Neggers

Kopchick

Jørgensen

et al. 2011

European Journal of Endocrinology

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Medical treatment of acromegaly with long-acting somatostatin analogs (LA-SMSA) and the GH receptor antagonist, pegvisomant (PEGV), has made it possible to achieve normal serum IGF1 concentrations in a majority of patients with acromegaly. These two compounds, however, impact the GH-IGF1 axis differently, which challenges the traditional biochemical assessment of the therapeutic response. We postulate that LA-SMSA in certain patients normalizes serum IGF1 levels in the presence of elevated GH actions in extra-hepatic tissues. This may result in persistent disease activity for which we propose the term extra-hepatic acromegaly. PEGV, on the other hand, blocks systemic GH actions, which are not necessarily reliably reflected by serum IGF1 levels, and this treatment causes a further elevation of serum GH levels. Medical treatment is therefore difficult to monitor with the traditional biomarkers. Moreover, the different modes of actions of LA-SMSA and PEGV make it attractive to use the two drugs in combination. We believe that it is time to challenge the existing concepts of treatment and monitoring of patients with acromegaly.

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Section: Animal Studies Of the Actions Of Gh Versus Igf1supporting

confidence: 92%

Hypothesis: Extra-hepatic acromegaly: a new paradigm?

Neggers

Kopchick

Jørgensen

et al. 2011

European Journal of Endocrinology

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“…megaly or in transgenic mice with overexpression of GH (33,50,57). Further, increased visceral adiposity was reported in mice with global disruption of STAT5, and a recent publication described increased body fat in mice with global disruption of GHR (44,58). We reasoned that the development of FL in the liver-specific deletion of STAT5, GHR, and JAK2 were all at least somewhat related to dysregulated GH secretion and concomitant effects of increased GH on lipolysis.…”

Section: Figurementioning

confidence: 94%

Abrogation of growth hormone secretion rescues fatty liver in mice with hepatocyte-specific deletion of JAK2

Sos¹,

Harris²,

Nordstrom³

et al. 2011

J. Clin. Invest.

119

115

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Non-alcoholic fatty liver disease is associated with multiple comorbid conditions, including diabetes, obesity, infection, and malnutrition. Mice with hepatocyte-specific disruption of growth hormone (GH) signaling develop fatty liver (FL), although the precise mechanism underlying this finding remains unknown. Because GH signals through JAK2, we developed mice bearing hepatocyte-specific deletion of JAK2 (referred to herein as JAK2L mice). These mice were lean, but displayed markedly elevated levels of GH, liver triglycerides (TGs), and plasma FFAs. Because GH is known to promote lipolysis, we crossed GH-deficient little mice to JAK2L mice, and this rescued the FL phenotype. Expression of the fatty acid transporter CD36 was dramatically increased in livers of JAK2L mice, as was expression of Pparg. Since GH signaling represses PPARγ expression and Cd36 is a known transcriptional target of PPARγ, we treated JAK2L mice with the PPARγ-specific antagonist GW9662. This resulted in reduced expression of liver Cd36 and decreased liver TG content. These results provide a mechanism for the FL observed in mice with liver-specific disruption in GH signaling and suggest that the development of FL depends on both GH-dependent increases in plasma FFA and increased hepatic uptake of FFA, likely mediated by increased expression of CD36.

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“…In this study, we found that liver GHR, Jak2, and Stat5 were phosphorylated to some degree at nadir GH concentrations. Together, this could partly compensate for the reduced GH levels and explain why the growth deficit in bIGF1RKO C/K mutants is relatively small compared to complete GHR knockout: adult body weight in mice with constitutive GHRKO is about 40% lower than in controls, whereas adult body weight in bIGF1RKO C/K mice is only 10% less than controls (Kappeler et al 2008, Berryman et al 2010. Thus, it seems that even low GH concentrations together with rare peaks can support significant somatic growth.…”

Section: Plasma Gh and Jak/stat Pathway Activationmentioning

confidence: 99%

Exploring endocrine GH pattern in mice using rank plot analysis and random blood samples

Xu¹,

Bekaert²,

Dupont³

et al. 2010

Journal of Endocrinology

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GH plays important pleiotropic roles in development, growth, metabolism, and aging of vertebrate species. Mouse mutants with altered GH signaling have been increasingly instrumental in studying somatotropic pathophysiology. However, the pulsatile characteristics of GH secretion are difficult to study in mice because catheterization is cumbersome and long-term serial sampling is limited by small body size and blood volume. We therefore developed an approach routinely applicable to mice, which detects endogenous, physiological GH pattern from randomly obtained spot samples. We determined individual hormone concentration in large groups of mice, ranked the data by magnitude, and statistically analyzed the resulting profiles. This revealed that the nadir-to-peak distribution of plasma GH concentration in mice was similar to other mammals, and that nycthemeral and sex differences existed as well. We found handling stress to be a potent immediate downregulator of circulating GH. We showed that samples need to be taken within seconds to reflect true endogenous levels, unaffected by stress. GH receptor/Janus kinase 2/signal transducer and activator of transcription 5 activation measured in the liver correlated strongly with plasma GH levels, but peak concentrations did not further increase the pathway activation. We applied this rank plot analysis to the GH-deficient and long-lived brain-specific IGF-1 receptor knockout (bIGF1RKO) mouse mutant and found a high proportion of low GH concentrations, indicative of extended trough periods and rare peaks. Taken together, we showed that rank plot analysis is a useful method that allows straightforward studies of circadian endogenous GH levels in mice.

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Two-Year Body Composition Analyses of Long-Lived GHR Null Mice

Cited by 120 publications

References 49 publications

Hypothesis: Extra-hepatic acromegaly: a new paradigm?

Hypothesis: Extra-hepatic acromegaly: a new paradigm?

Abrogation of growth hormone secretion rescues fatty liver in mice with hepatocyte-specific deletion of JAK2

Exploring endocrine GH pattern in mice using rank plot analysis and random blood samples

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