GDP binding to brown-adipose-tissue mitochondria of diabetic--obese (db/db) mice. Decreased binding in both the obese and pre-obese states.
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ABSTRACT:
SUBMITTER: Goodbody AE
PROVIDER: S-EPMC1162842 | biostudies-other | 1981 Mar
REPOSITORIES: biostudies-other
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Project description:Corticotropin stimulated brown adipose tissue mitochondrial GDP binding of young obese rats to the levels seen in lean rats. This effect was attenuated by chronic increases in corticosterone. The stimulatory response to corticotropin was absent from lean rats unless endogenous secretion of corticosterone was prevented.
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Project description:GDP binding to brown-adipose-tissue mitochondria of young obese Zucker rats (fa/fa) was significantly lower than in lean control rats, as a result of a decrease in the number of binding sites. Adrenalectomy of fa/fa rats restored GDP binding to control values. Corticosterone replacement suppressed GDP binding in adrenalectomized obese rats.
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Project description:GDP binding to brown-adipose-tissue mitochondria of obese Zucker-rat (fa/fa) pups aged 2-14 days was significantly less than in lean control rats. Scatchard analysis in 10-day-old pups suggests that there was a large decrease in GDP-binding sites. However, a significant increase in fat content in brown adipose tissue of 2-day-old pre-obese pups raised the question of the sequential order and causal relationship between these two derangements.
| S-EPMC1144025 | biostudies-other
Project description:BACKGROUND AND PURPOSE: Hyperglycaemia induces overproduction of mitochondrial reactive oxygen species (ROS) in endothelial cells, which is believed to be a major molecular mechanism underlying complications of diabetes, including diabetic nephropathy. Impairment of endothelium-dependent vasodilatation is found in type 2 diabetes. Urocortin is a 40 amino-acid peptide related to the corticotrophin-releasing factor (CRF) family, which suppresses production of ROS in endothelial cells and sustains endothelium-dependent relaxations of rat coronary artery. However, it is not clear if urocortin has any effect on diabetic nephropathy. EXPERIMENTAL APPROACH: Possible mechanisms underlying the effects of urocortin on diabetic nephropathy were investigated in db/db mice and cultured rat mesangial cells. KEY RESULTS: Urocortin decreased body weight, plasma levels of advanced glycation end-products, blood urea nitrogen and creatinine levels. However, food intake, plasma insulin and glucose levels remained unaffected. Superoxide dismutase activity was increased markedly, whereas malonaldehyde levels in kidney homogenate and sorbitol concentrations in red blood cells were decreased significantly in urocortin-treated mice. Urocortin significantly decreased glomerular extracellular matrix expansion and accumulation in kidney. Moreover, urocortin inhibited the overexpression of transforming growth factor-beta 1 and connective tissue growth factor in rat mesangial cells induced by 25 mM glucose. All the effects of urocortin, except sorbitol accumulation, were abolished by the non-selective CRF receptor blocker, astressin. CONCLUSION AND IMPLICATIONS: Urocortin could significantly ameliorate diabetic nephropathy and this effect was mediated via the CRF receptor.
| S-EPMC2451047 | biostudies-other
Project description:1. The binding of GDP to purified thermogenin protein was studied by using fluorescence spectroscopy and equilibrium dialysis. 2. GDP binding to thermogenin diminished fluorescence emission in a concentration-dependent manner that exhibited saturation. 3. Kd values for binding of nucleoside di- and tri-phosphates were lower than those for nucleoside monophosphates. 4. The GDP-induced fluorescence quenching was decreased by increasing pH, but the apparent Kd was unaltered by pH changes. 5. Equilibrium dialysis showed a Kd change from 3 to 6 microM when the pH was increased from 6.6 to 8.5. 6. The apparent pK of the fluorescence changes induced by pH (8.3) was identical with the apparent pK of the GDP-binding response. 7. The data are consistent with the existence of protonated and non-protonated forms of thermogenin protein that both bind GDP.
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Project description:Cytochrome oxidase activity and mitochondrial GDP binding were decreased in brown adipose tissue of mice treated chronically with corticosterone. These changes occurred both in corticosterone-treated mice fed ad libitum and in treated mice pair-fed to control animals. Although the dietary stimulation of brown-adipose-tissue thermogenesis was suppressed by corticosterone, the acute response to cold was not affected.
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Project description:In 16-day-old conscious Zucker rats, at a time when pre-obese fa/fa rats were not yet hyperinsulinaemic compared with their lean Fa/fa littermates, the whole-body glucose-metabolism rate was decreased by 10% in pre-obese compared with lean pups. The markedly decreased glucose utilization found in brown adipose tissue (BAT) of pre-obese compared with lean pups accounted for at least 70% of the difference in whole-body glucose metabolism observed between the two genotypes. In pre-obese fa/fa rats, the 20% decrease in noradrenaline content of BAT reported in this study is consistent with the diminished glucose utilization by this tissue, and further supports the hypothesis of a defect in the sympathetic-nervous-system regulation of BAT metabolism as one of the primary causes for this genetic obesity.
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Project description:In this study, we discovered cytosolic and mitochondrial fragments resulting from tRNA and mt-tRNA cleavage, which may act as new regulators of cellular and metabolic functions. We analyzed hundreds of these fragments in the pancreatic islets of db/db mice and compared them to heterozygous control db/+ mice. At 16 weeks of age, db/db mice exhibit obesity, insulin resistance, and glucose intolerance. In our analysis, we identified 3858 tRFs in the islets of db/db mice, among which 342 exhibited significant changes (≥ 2 fold; adjusted p value ≤ 0.05) compared to controls. Of these, 199 tRFs showed increased levels, while 170 tRFs showed decreased levels in the pre-diabetic mice. Notably, a striking majority (147 out of 170) of the tRFs with reduced abundance in the islets of db/db mice were derived from the cleavage of tRNAs encoded by the mitochondrial genome. Our findings reveal a significant reshaping of mitochondrial tRFs in pre-diabetic conditions, coinciding with a well-established mitochondrial metabolic defect under these conditions. Specifically, we demonstrated that a fragment (named mt-tRF-LeuTAA) resulting from the cleavage of mt-tRNA-LeuTAA, encoded by the mitochondrial genome and found to be reduced in the islets of db/db mice, acts as a key regulator of mitochondrial OXPHOS functions, mitochondrial membrane potential, the insulin secretory capacity of ß-cells, and the insulin sensitivity of myotube muscle cells.
2024-05-14 | GSE239786 | GEO
Project description:This study was undertaken to determine whether receptor and non-receptor components of the adenylate cyclase (AC) cascade were altered in brown adipose tissue (BAT) of 14-day-old pre-obese (fa/fa) rats, before endocrine status is strongly modified by fa gene expression. Activity of the AC catalytic subunit did not differ between the two genotypes. In fa/fa rats compared with control Fa/fa rats, there was a 50% decrease in the activity of alpha Gs (stimulated by NaF or guanosine 5'-[gamma-thio]triphosphate) but no change in protein content (Western blotting). alpha Gi function, assessed by the inhibitory action of low concentrations of guanosine 5'-[beta gamma-imido]triphosphate upon 10(-4) M forskolin-stimulated AC activity, was equally low in both genotypes. Analysis of dose-response curves for different beta-agonists revealed that (i) both the basal and the maximally stimulated activity of AC were 2-fold lower in fa/fa rats than in Fa/fa rats; (ii) BRL37344 and CGP12177 (beta 3 agonists) were less potent in fa/fa than in Fa/fa rats (Kact. multiplied by 2); (iii) noradrenaline and isoprenaline (Iso), at the low-affinity site (beta 3-AR), were less potent in fa/fa than in Fa/fa pups (Kact. increased by 30 and 20% respectively). At the high-affinity site (mainly beta 1) these two agonists were more potent in fa/fa than in Fa/fa rats (Kact. decreased by 40 and 80% respectively). In good agreement with the latter result, the beta 1-adrenergic receptor (beta 1-AR)-selective antagonist CGP20712A had more effect on the Iso-stimulated AC activity in pre-obese than in lean pups (2-fold decreased in IC50). Binding experiments with [3H]CGP12177 show that in BAT of suckling rats, beta 3-ARs represent 80% of the total beta-ARs. Bmax values for the two sites were not affected by the genotype, although the beta 3-AR mRNA concentration in BAT (quantitative reverse-transcriptase PCR) was 3-fold lower in fa/fa rats than in Fa/fa pups. In conclusion, these results provide evidence for alterations in beta 1- and beta 3-AR signalling in BAT of 14-day-old suckling pre-obese Zucker rats with a decreased activity of alpha Gs. The impaired AC responsiveness to catecholamines might be a primary contributor to the development of this genetic obesity.
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Project description:Sodium meta-arsenite (SA) is implicated in the regulation of hepatic gluconeogenesis-related genes in vitro; however, the effects in vivo have not been studied. We investigated whether SA has antidiabetic effects in a type 2 diabetic mouse model. Diabetic db/db mice were orally intubated with SA (10?mg?kg(-1) body weight/day) for 8 weeks. We examined hemoglobin A1c (HbA1c), blood glucose levels, food intake, and body weight. We performed glucose, insulin, and pyruvate tolerance tests and analyzed glucose production and the expression of gluconeogenesis-related genes in hepatocytes. We analyzed energy metabolism using a comprehensive animal metabolic monitoring system. SA-treated diabetic db/db mice had reduced concentrations of HbA1c and blood glucose levels. Exogenous glucose was quickly cleared in glucose tolerance tests. The mRNA expressions of genes for gluconeogenesis-related enzymes, glucose 6-phosphatase (G6Pase), and phosphoenolpyruvate carboxykinase (PEPCK) were significantly reduced in the liver of SA-treated diabetic db/db mice. In primary hepatocytes, SA treatment decreased glucose production and the expression of G6Pase, PEPCK, and hepatocyte nuclear factor 4 alpha (HNF-4?) mRNA. Small heterodimer partner (SHP) mRNA expression was increased in hepatocytes dependent upon the SA concentration. The expression of Sirt1 mRNA and protein was reduced, and acetylated forkhead box protein O1 (FoxO1) was induced by SA treatment in hepatocytes. In addition, SA-treated diabetic db/db mice showed reduced energy expenditure. Oral intubation of SA ameliorates hyperglycemia in db/db mice by reducing hepatic gluconeogenesis through the decrease of Sirt1 expression and increase in acetylated FoxO1.
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