Thyroid hormone was shown to induce actin cytoskeleton polymerization in hypothyroid astrocytes and osteoblastic cells by a nongenomic mechanism. Polyadenylation of GH mRNA, a process that depends on cytoskeleton-associated proteins, was also shown to be regulated by thyroid hormone. Here we investigated by histochemistry and immunohistochemistry whether acute (100 microg per 100 g body weight, iv, for 30 min) or chronic (5 microg per 100 g body weight, ip, 5 d) administration of T3 to thyroidectomized (Tx) and sham-operated rats affects the somatotrophs F-actin cytoskeleton arrangement and its potential repercussion on GH synthesis and secretion. Thyroidectomy dramatically decreased the amount of somatotrophs F-actin content and induced the disassembly of the actin cytoskeleton. These effects were reversed by acute and chronic administration of T3. In addition, in Tx rat somatotrophs, GH labeling was detected mostly at the cell periphery. After 30 min of T3 administration, GH labeling decreased at periphery and increased in the perinuclear region, suggesting that GH secretion and synthesis were stimulated by T3. No differences were detected in the total actin protein content, although a decrease in the F- and increase in G-actin contents were detected in Tx rat pituitaries, a panorama that was reversed by acute T3 treatment, as shown by Western blotting analysis. The sham-operated animals' somatotrophs were only mildly affected by acute T3 administration. The results indicate that the T3-induced rapid alterations on somatotroph actin cytoskeleton and GH cellular distribution resulted from actin filaments rearrangement, which characterizes a nongenomic action.
PGZ and PGZ+INS improved INS peripheral sensitivity, possibly by decreasing blood free fatty acids, and reduced fat tissue wasting and body weight loss in small tumor-bearing rats. The results suggest clinical benefits of PGZ in preventing INS resistance, adipose tissue wasting and weight loss when the tumor is small, i.e., in less severe cachexia.
Metformin (MET) is widely used in the correction of insulin (INS) resistance and metabolic abnormalities in type 2 diabetes. However, its effect on INS resistance and metabolic disorders associated with cancer cachexia is not established. We investigated the MET effects, isolated or associated with INS, on INS resistance and metabolic changes induced by Walker-256 tumor in rats with advanced cachexia. MET (500 mg·kg, oral) and MET + INS (1.0 IU·kg, s.c.) were administered for 12 days, starting on the day of tumor cell inoculation. Tumor-bearing rats showed adipose and muscle mass wasting, body mass loss, anorexia, decreased Akt phosphorylation in retroperitoneal and mesenteric adipose tissue, peripheral INS resistance, hypoinsulinemia, reduced INS content and secretion from pancreatic islets, and also inhibition of glycolysis, gluconeogenesis, and glycogenolysis in liver. MET and MET + INS treatments did not prevent these changes. It can be concluded that treatments with MET and MET + INS did not prevent the adipose and muscle mass wasting and body mass loss of tumor-bearing rats possibly by not improving INS resistance. Therefore, MET, used for the treatment of INS resistance in type 2 diabetes, is not effective in improving INS resistance in the advanced stage of cancer cachexia, evidencing that the drug does not have the same beneficial effect in these 2 diseases.
The angiotensin II type 1 receptor (AT1R) is involved in the development of cardiac hypertrophy promoted by thyroid hormone. Recently, we demonstrated that triiodothyronine (T 3 ) rapidly increases AT1R mRNA and protein levels in cardiomyocyte cultures. However, the molecular mechanisms responsible for these rapid events are not yet known. In this study, we investigated the T 3 effect on AT1R mRNA polyadenylation in cultured cardiomyocytes as well as on the expression of microRNA-350 (miR-350), which targets AT1R mRNA. The transcriptional and translational actions mediated by T 3 on AT1R levels were also assessed. The total content of ubiquitinated proteins in cardiomyocytes treated with T 3 was investigated. Our data confirmed that T 3 rapidly raised AT1R mRNA and protein levels, as assessed by realtime PCR and western blotting respectively. The use of inhibitors of mRNA and protein synthesis prevented the rapid increase in AT1R protein levels mediated by T 3 . In addition, T 3 rapidly increased the poly-A tail length of the AT1R mRNA, as determined by rapid amplification of cDNA ends poly-A test, and decreased the content of ubiquitinated proteins in cardiomyocytes. On the other hand, T 3 treatment increased miR-350 expression. In parallel with its transcriptional and translational effects on the AT1R, T 3 exerted a rapid posttranscriptional action on AT1R mRNA polyadenylation, which might be contributing to increase transcript stability, as well as on translational efficiency, resulting to the rapid increase in AT1R mRNA expression and protein levels. Finally, these results show, for the first time, that T 3 rapidly triggers distinct mechanisms, which might contribute to the regulation of AT1R levels in cardiomyocytes.
Cancer‐bearing often exhibits hypoinsulinemia, insulin (INS) resistance and glutamine depletion associated with cachexia. However, INS and glutamine effects on cachexia metabolic abnormalities, particularly on tumor‐affected proteins related to INS resistance, are poorly known. The main purpose of this study was to investigate the effects of INS and glutamine dipeptide (GDP) treatments on phospho‐protein kinase B (p‐Akt), and phospho‐hormone sensitive lipase (p‐HSL) in Walker‐256 tumor‐bearing rats. INS (NPH, 40 UI/kg, subcutaneous), GDP (1.5 g/kg, oral), INS+GDP or vehicle (control rats) were administered for 13 days, once a day, starting at the day of inoculation of tumor cells. The experiments were performed 4 hours after the last treatment to evaluate acute effects of INS and GDP, besides the chronic effects. INS and/or INS+GDP treatments, which markedly increased the insulinemia, increased the p‐Akt: total Akt ratio and prevented the increased p‐HSLSer552: total HSL ratio in the retroperitoneal fat of tumor‐bearing rats, without changing the INS resistance and increased expression of factor tumor necrosis‐α (TNF‐α) in this tissue. INS and INS+GDP also increased the p‐Akt: total Akt ratio, whereas GDP and INS+GDP increased the GLUT4 glucose transporter gene expression, in the gastrocnemius muscle of the tumor‐bearing rats. Accordingly, treatments with INS and INS+GDP markedly reduced glycemia, increased retroperitoneal fat and attenuated the body mass loss of tumor‐bearing rats. In conclusion, hyperinsulinemia induced by high‐dose INS treatments increased Akt phosphorylation and prevented increased p‐HSLSer552: total HSL ratio, overlapping INS resistance. These effects are consistent with increased fat mass gain and weight loss (cachexia) attenuation of tumor‐bearing rats, evidencing that Akt activation is a potential strategy to prevent loss of fat mass in cancer cachexia.
The neonatal period (NP) is a critical phase of the development in which the expression pattern of most genes is established. Thyroid hormones (TH) play a key role in this process and, alterations in its availability in the NP may lead to different patterns of gene expression, which might reflect in the permanent expression of several genes in the adulthood. GH gene expression in the pituitary is greatly dependent on TH in the early postnatal life; thus, modifications of thyroid state in NP might lead to alterations in GH gene expression as well as to physiological repercussions in the adult life. This study aimed to investigate this possibility by means of the induction of a neonatal hyperthyroidism in rats (4 mg of 3,5,30 -triiodo-L-thyronine (T3)/100 g body weight, s.c.) for 5, 15 or 30 days, and further evaluation of GH gene expression, as well as its physiological consequences in adult rats subjected to a transient hyperthyroidism in the first 30 days of life. GH mRNA level was shown to be increased in T3-treated rats for 5 days; when the treatment was extended to 15 or 30 days, the GH mRNA levels were similar to the control group. Moreover, rats treated with T3 for 30 days and killed when 90 days old, i.e., 60 days at the end of the T3 treatment, showed decreased GH mRNA content, body weight, bone mineral density, and lean body mass. In conclusion: (1) T3 effects on GH gene expression depend on the period of life in which the hyperthyroidism is set and on the length of T3 treatment in the NP and (2) transient neonatal hyperthyroidism leads to a lower GH mRNA expression in adult life accompanied by physiological repercussions indicative of GH deficiency.
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