Tissue-specific response of IGF-I mRNA expression to obesity-associated GH decline in the male Zucker fatty rat

Melián, Elvira M.; Gonzalez, B.; Ajo, R; González, Nava; Franco, F. Sánchez

doi:10.1677/joe.0.1600049

Cited by 9 publications

(7 citation statements)

References 48 publications

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“…10–12 The diminished growth hormone secretion may be accompanied with overtly elevated levels of reactive oxygen species (ROS) and reduced lean body mass in obesity. 2, 9, 10, 13 Thus the present study was undertaken to examine the impact of overexpression of IGF-1, an essential cardiac survival factor, 14 on high fat diet-induced cardiac geometric, morphological and functional defects. In an effort to elucidate the cellular mechanisms underscoring IGF-1- and high fat diet-induced myocardial alterations, if any, special attention was paid to insulin signaling, apoptosis, mitochondrial integrity including ATP content, cytochrome C release, peroxisome proliferator-activated receptor γ (PPARγ) coactivator 1α (PGC1α) and uncoupling protein 2 (UCP-2).…”

Section: Introductionmentioning

confidence: 99%

Insulin-Like Growth Factor 1 Alleviates High-Fat Diet–Induced Myocardial Contractile Dysfunction

et al. 2012

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Obesity is often associated with reduced plasma IGF-1 levels, oxidative stress, mitochondrial damage and cardiac dysfunction. This study was designed to evaluate the impact of IGF-1 on high fat diet-induced oxidative, myocardial, geometric and mitochondrial responses. FVB and cardiomyocyte-specific IGF-1 overexpression transgenic mice were fed a low (10%) or high fat (45%) diet to induce obesity. High fat diet feeding led to glucose intolerance, elevated plasma levels of leptin, interleukin-6, insulin and triglyceride as well as reduced circulating IGF-1 levels. Echocardiography revealed reduced fractional shortening, increased end systolic and diastolic diameter, increased wall thickness, and cardiac hypertrophy in high fat-fed FVB mice. High fat diet promoted ROS generation, apoptosis, protein and mitochondrial damage, reduced ATP content, cardiomyocyte cross-sectional area, contractile and intracellular Ca2+ dysregulation, including depressed peak shortening and maximal velocity of shortening/relengthening, prolonged duration of relengthening, and dampened intracellular Ca2+ rise and clearance. Western blot analysis revealed disrupted phosphorylation of insulin receptor, post-receptor signaling molecules IRS-1 (tyrosine/serine phosphorylation), Akt, GSK3β, Foxo3a, mTOR, as well as downregulated expression of mitochondrial proteins PPARγ coactivator 1α (PGC1α) and UCP-2. Intriguingly, IGF-1 mitigated high fat diet feeding-induced alterations in ROS, protein and mitochondrial damage, ATP content, apoptosis, myocardial contraction, intracellular Ca2+ handling and insulin signaling, but not whole body glucose intolerance and cardiac hypertrophy. Exogenous IGF-1 treatment also alleviated high fat diet-induced cardiac dysfunction. Our data revealed that IGF-1 alleviates high fat diet-induced cardiac dysfunction despite persistent cardiac remodeling, possibly due to preserved cell survival, mitochondrial function and insulin signaling.

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Section: Introductionmentioning

confidence: 99%

Insulin-Like Growth Factor 1 Alleviates High-Fat Diet–Induced Myocardial Contractile Dysfunction

et al. 2012

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“…Our results obtained in PCH were, surprisingly, not consistent with those reported previously by Melián et al [23]who observed a decreased IGF-1 mRNA expression in liver and other tissues in the male Zucker fatty rat. We, therefore, decided to investigate freshly isolated hepatocytes and whole-liver tissue from obese and lean Zucker rats.…”

Section: Resultscontrasting

confidence: 99%

“…Our results using hepatocytes in culture contrast with those of Melián et al [23]who used a ribonuclease protection assay to study whole-liver tissue mRNA. These investigators reported decreased IGF-I and IGF-IB mRNA levels in 6- and 11-week-old fa/fa rats as compared with lean controls.…”

Section: Discussioncontrasting

confidence: 99%

IGF-I Transcript Levels in Whole-Liver Tissue, in Freshly Isolated Hepatocytes, and in Cultured Hepatocytes from Lean and Obese Zucker Rats

et al. 2003

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Background: The mechanisms underlying the maintenance of normal to high rates of linear growth and plasma insulin-like growth factor I (IGF-I) levels in spite of a low growth hormone secretion in obese children remain unknown. Among the animal models of early-onset obesity, obese Zucker (fa/fa) rats (which are homozygous for an inactivating missense mutation in the leptin receptor) are particularly appropriate, because their linear growth shows this growth hormone independence. Methods: To study the regulation of IGF-I synthesis in this model, we have established primary cultures of hepatocytes derived from 12-week-old Zucker male obese and lean rats. The rat IGF-I gene contains six exons, and alternative splicing generates different mRNAs, one of which (called IGF-1B) has been shown to be decreased by fasting. We report steady state mRNA levels for IGF-I (all transcripts) and for IGF-IB in hepatocytes after 3 days in culture, in freshly isolated hepatocytes, and in whole-liver tissue. RT-PCRs using primers specific for IGF-I or IGF-IB were performed with two different internal competitors for quantification. Results: In primary cultures of hepatocytes, the IGF-IB mRNA was increased by >50-fold (p = 0.01) in cells derived from obese animals as compared with cells from lean animals. However, these transcript levels were not significantly different when measured in freshly isolated hepatocytes or in whole-liver tissue. Conclusions: Increased IGF-IB transcription could be an intrinsic characteristic of cultured hepatocytes harbouring leptin receptors that bear the fa mutation. However, the modulation of this characteristic by cell-cell interactions and by in vivo hormone and metabolic status remains to be studied.

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“…The factors which may regulate diminished Akt activation during hyperglycemia will require further experimentation. Similarly, it is also possible that reduced availability of circulating growth factors, decreased expression of local growth factors or alterations in cytokine levels may also play a role regulating Akt signaling 31. This latter possibility is an intriguing alternative that we are actively pursuing.…”

Section: Discussionmentioning

confidence: 99%

Lean and obese Zucker rats exhibit different patterns of p70s6 kinase regulation in the tibialis anterior muscle in response to high‐force muscle contraction

Katta¹,

Karkala²,

Wu³

et al. 2009

Muscle and Nerve

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Increased phosphorylation of the 70 kDa ribosomal S6 kinase (p70s6k) signaling is strongly correlated with the degree of muscle adaptation following exercise. Here, we compare the phosphorylation of p70s6k, Akt and mTOR in the tibialis anterior (TA) muscles of lean and obese Zucker rats following a bout of eccentric exercise. Exercise increased p70S6k (Thr 389) phosphorylation immediately after (33.3 ± 7.2%) and during recovery [1-hr; (24.0 ± 14.9%), and 3-hr (24.6 ± 11.3%)], in the lean TA and at 3-hr (33.5 ± 8.0%) in the obese TA. mTOR (Ser 2448) phosphorylation was elevated in the lean TA immediately after exercise (96.5 ± 40.3%) but remained unaltered in the obese TA. Exercise increased Akt (Thr 308) and Akt (Ser 473) phosphorylation in the lean but not the obese TA. These results suggest that insulin resistance is associated with alterations in the ability of muscle to activate p p70s6k signaling following an acute bout of exercise.

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Tissue-specific response of IGF-I mRNA expression to obesity-associated GH decline in the male Zucker fatty rat

Cited by 9 publications

References 48 publications

Insulin-Like Growth Factor 1 Alleviates High-Fat Diet–Induced Myocardial Contractile Dysfunction

Insulin-Like Growth Factor 1 Alleviates High-Fat Diet–Induced Myocardial Contractile Dysfunction

IGF-I Transcript Levels in Whole-Liver Tissue, in Freshly Isolated Hepatocytes, and in Cultured Hepatocytes from Lean and Obese Zucker Rats

Lean and obese Zucker rats exhibit different patterns of p70s6 kinase regulation in the tibialis anterior muscle in response to high‐force muscle contraction

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