27 research outputs found
Growth Hormone Is Necessary for the p53-Mediated, Obesity-Induced Insulin Resistance in Male C57BL/6J Ă— CBA Mice
Insulin resistance is a key marker of both obesity and GH excess. The purpose of the study was to assess the role of GH on p53-mediated insulin resistance of male mice with obesity due to a high-fat diet. C57BL/6J CBA male mice fed on a high-fat diet (Obe) were studied; male mice fed a normal diet (Lean) or transgenic mice for bovine GH under the same genetic background (Acro) served as controls. The convergence of p53 and GH pathways was evaluated by Western blot. Obe mice had insulin resistance, which was sustained by a selective increased expression of p53 in adipose tissue. Normal insulin sensitivity was restored, and adipose p53 expression normalized when the GH pathway was blocked. Only the adipose p53 expression was sensitive to the GH blockage, which occurred through the p38 pathway. Adipose tissue of Obe mice had a coordinate overexpres- sion of suppressors of cytokine signal 1–3 and signal transducers and activators of transcrip- tion-1, -3, and -5b, not different from that of Acro mice, suggesting an increased sensitivity of adipose tissue to GH. On the contrary, Lean mice were unaffected by changes of GH action. GH seems to be necessary for the increased adipose p53 expression and for insulin resistance of obese mice
Transgenic Mice Overexpressing Growth Hormone (GH) Have Reduced or Increased Cardiac Apoptosis through Activation of Multiple GH-Dependent or -Independent Cell Death Pathways
REGULATION OF CARDIAC FATTY ACID METABOLISM IN TRANSGENIC MICE OVEREXPRESSING BOVINE GROWTH HORMONE
Cardiac energy metabolism depends mainly on fatty acid
(FA) oxidation; however, regulation of FA metabolism in
acromegalic (Acro) heart is unknown. The aim of the study
was to evaluate cardiac expression of key proteins of FA
metabolism in young and elder transgenic mice overexpressing
bovine GH Acro. Expression of proteins regulating
FA entry into the cells, their uptake by mitochondria and
b-oxidation were evaluated by western blot, while FA
content by Fourier transform infrared microspectrometry.
Regulatory mechanisms of key steps of FA metabolism were
also studied. The expression of plasma-membrane FA carriers
(fatty acid-binding protein and fatty acid transport protein-1)
and acylCoA synthetase was higher in young and lower in
elder Acro than in corresponding controls; likewise,
expression of cytoplasm to mitochondria-1 (CPT-1), the
key enzyme of mitochondrial FA uptake, and that of
medium-chain acyl-CoA dehydrogenase and long-chain
acyl-CoA dehydrogenase, two regulatory b-oxidation
dehydrogenases, followed a similar pattern. FA content was
lower in young and higher in elder Acro than in wild-type,
suggesting an increased utilisation in young animals. GH
regulated expression of key proteins of FA metabolism
through changes in peroxisome proliferator-activated
receptor a (PPARa) expression, which varied accordingly.
GH effect was confirmed by treatment of Acro mice with
a receptor antagonist, which abolished changes in key
proteins of FA metabolism in young Acro. GH increased
phosphorylation of AMP-activated protein kinase and antiacetyl-
CoA-carboxylase, two regulatory kinases, leading to
lower CPT-1 inhibition by malonyl-CoA, and intervened in
regulating PPARa expression through the ERK 1/2 pathway.
In conclusion, chronic GH excess increased FA metabolism in the young age, whereas its action was overwhelmed in elder ages likely by GH-independent mechanisms, leading to
reduced expression of key enzyme of FA metabolis
Reduced colonic apoptosis in mice overexpressing bovine growth hormone occurs through changes in several kinase pathways
Regulation of cardiac fatty acids metabolism in transgenic mice overexpressing bovine GH
Cardiac expression of adenine nucleotide translocase-1 in transgenic mice overexpressing bovine GH
Divergent effects of dioxin- or non- dioxin- Like polychlorinated biphenyls on the apoptosis of primary cell culture from the mouse dioxin pituitary gland
Polychlorinated biphenyls (PCBs) can disrupt the endocrine function, promote neoplasms and regulate apoptosis in some tissues; however, it is unknown whether PCBs can affect the apoptosis of pituitary cells. The study evaluated the effect of PCBs on the apoptosis of normal pituitary cells and the underlying mechanisms. Primary cell cultures obtained from mouse pituitary glands were exposed to Aroclor 1254 or selected dioxin-like (PCB 77, PCB 126) or non-dioxin-like (PCB 153, PCB 180) congeners. Apoptosis was evaluated by Annexin V staining, DNA fragmentation, and TUNEL assay. Both the expression and activity of caspases were analyzed. Selective thyroid hormone receptor (TR) or aryl-hydrocarbon receptor (AhR) or CYP1A1 antagonist were used to explore the mechanisms underlying PCBs action. Our results showed that Aroclor 1254 induced the apoptosis of pituitary cells as well as the final caspase-3 level and activity through the extrinsic pathway, as shown by the increased caspase-8 level and activity. On the other hand, the intrinsic pathway evaluated by measuring caspase-9 expression was silent. The selected non-dioxin- like congeners either increased (PCB 180) or reduced (PCB 153) pituitary cell apoptosis, affecting the extrinsic pathway (PCB 180), or both the extrinsic and intrinsic pathways (PCB 153), respectively. In contrast, the dioxin-like congeners (PCB 77 and PCB 126) did not affect apoptosis. The anti-apoptotic phenotype of PCB 153 was counteracted by a TR or a CYP1A1 antagonist, whereas the pro-apoptotic effect of PCB 180 was counteracted by an AhR antagonist. The induced apoptosis of Aroclor 1254 or PCB 180 was associated with a reduction of cell proliferation, whereas the decreased apoptosis due to PCB 153 increased cell proliferation by 30%. In conclusion, our data suggest that non-dioxin-like PCBs may modulate apoptosis and the proliferation rate of pituitary cells that have either pro- or anti-apoptotic effects depending on the specific congeners. However, the impact of PCBs on the process of pituitary tumorigenesis remains to be elucidated