Project description:Population based studies have established that androgen deficiency in males correlates with type 2 diabetes, visceral adiposity, and metabolic syndrome. Androgen therapy has been investigated as a possible treatment regime to combat these disorders. However, the molecular mechanism of androgen effects on these diseases still remain poorly understood. The zucker diabetic fatty (ZDF) rat, containing a mutation in the leptin receptor, is a well-investigated model of obesity and type 2 diabetes. Male rats are characterized as androgen deficient and spontaneously develop obese, hyperlipidemia, hyperglycemia and hyperinsulinemia. In this study, we used ZDF male rats as a model of metabolic syndrome to investigate the effects of testosterone administration on the development of the metabolic conditions. Methods: Male ZDF rats at six week of age were randomly divided into two groups and administered testosterone undecanoate(TU) or vehicle alone every three days for three weeks. After three weeks, overnight fasted blood glucose and insulin concentrations were significantly higher and glucose tolerance and insulin sensitivity were impaired in TU treated ZDF rats compared to vehicle controls. Moreover, increased serum triglycerides and VLDL were observed in TU treated rats. To further explore the observed metabolic changes in TU treated ZDF rats, whole-genome microarray analysis were performed on isolated liver mRNA. Results: Array analysis revealed that many hepatic lipogenic genes were increased in male ZDF rat livers treated with TU. Interestingly, SREBP-1c, a key transcriptional activator of lipogenic genes and PGC-1 , an activator of SREBP-1c were induced while small heterodimer partner, a transcriptional inhibitor of lipogenic genes was suppressed by TU treatment. Exploring signaling pathways for these effects, we observed that the hepatic activated forms of STAT3 and AMPK, two known inhibitors of hepatic lipogenesis, were decreased in TU treated rat. Moreover, we observed that DHT could block the induction of STAT3 and AMPK phosphorylation in treated primary human hepatocytes. Preliminarily, in the leptin receptor positive zucker diabetic lean male rats, we observed that TU treatment has an oppose effect on the hepatic lipogenic genes, suggesting that hepatic leptin signaling may influence androgen signaling. Further insight into the relationship between androgen deficiency and the leptin system may help improve treatment of the metabolic syndrome. Population based studies have established that androgen deficiency in males correlates with type 2 diabetes, visceral adiposity, and metabolic syndrome. Androgen therapy has been investigated as a possible treatment regime to combat these disorders. However, the molecular mechanism of androgen effects on these diseases still remain poorly understood. The zucker diabetic fatty (ZDF) rat, containing a mutation in the leptin receptor, is a well-investigated model of obesity and type 2 diabetes. Male rats are characterized as androgen deficient and spontaneously develop obese, hyperlipidemia, hyperglycemia and hyperinsulinemia. In this study, we used ZDF male rats as a model of metabolic syndrome to investigate the effects of testosterone administration on the development of the metabolic conditions. Two-condition experiment. (1) lean ZDF rats (control) vs. lean ZDF rats (testosterone treated). (2) obese ZDF rats (control) vs. obese ZDF rats (testosterone treated). Biological replicates: 4 control replicates, 4 treated replicates.

Project description:Population based studies have established that androgen deficiency in males correlates with type 2 diabetes, visceral adiposity, and metabolic syndrome. Androgen therapy has been investigated as a possible treatment regime to combat these disorders. However, the molecular mechanism of androgen effects on these diseases still remain poorly understood. The zucker diabetic fatty (ZDF) rat, containing a mutation in the leptin receptor, is a well-investigated model of obesity and type 2 diabetes. Male rats are characterized as androgen deficient and spontaneously develop obese, hyperlipidemia, hyperglycemia and hyperinsulinemia. In this study, we used ZDF male rats as a model of metabolic syndrome to investigate the effects of testosterone administration on the development of the metabolic conditions. Methods: Male ZDF rats at six week of age were randomly divided into two groups and administered testosterone undecanoate(TU) or vehicle alone every three days for three weeks. After three weeks, overnight fasted blood glucose and insulin concentrations were significantly higher and glucose tolerance and insulin sensitivity were impaired in TU treated ZDF rats compared to vehicle controls. Moreover, increased serum triglycerides and VLDL were observed in TU treated rats. To further explore the observed metabolic changes in TU treated ZDF rats, whole-genome microarray analysis were performed on isolated liver mRNA. Results: Array analysis revealed that many hepatic lipogenic genes were increased in male ZDF rat livers treated with TU. Interestingly, SREBP-1c, a key transcriptional activator of lipogenic genes and PGC-1 , an activator of SREBP-1c were induced while small heterodimer partner, a transcriptional inhibitor of lipogenic genes was suppressed by TU treatment. Exploring signaling pathways for these effects, we observed that the hepatic activated forms of STAT3 and AMPK, two known inhibitors of hepatic lipogenesis, were decreased in TU treated rat. Moreover, we observed that DHT could block the induction of STAT3 and AMPK phosphorylation in treated primary human hepatocytes. Preliminarily, in the leptin receptor positive zucker diabetic lean male rats, we observed that TU treatment has an oppose effect on the hepatic lipogenic genes, suggesting that hepatic leptin signaling may influence androgen signaling. Further insight into the relationship between androgen deficiency and the leptin system may help improve treatment of the metabolic syndrome. Population based studies have established that androgen deficiency in males correlates with type 2 diabetes, visceral adiposity, and metabolic syndrome. Androgen therapy has been investigated as a possible treatment regime to combat these disorders. However, the molecular mechanism of androgen effects on these diseases still remain poorly understood. The zucker diabetic fatty (ZDF) rat, containing a mutation in the leptin receptor, is a well-investigated model of obesity and type 2 diabetes. Male rats are characterized as androgen deficient and spontaneously develop obese, hyperlipidemia, hyperglycemia and hyperinsulinemia. In this study, we used ZDF male rats as a model of metabolic syndrome to investigate the effects of testosterone administration on the development of the metabolic conditions.

Project description:Patients with long-duration diabetes develop cardiovascular complications resulting in highly increased mortality and complications which affect the kidneys, eyes and peripheral nerves associated with high morbidity. Among the diabetic complications, damage in the eye, diabetic retinopathy, is the most common microvascular complication of diabetes. Diabetic retinopathy is a leading cause of vision-loss globally. It is characterized by a number of different patho-mechanisms including changes in vascular permeability, capillary degeneration, and finally at a late stage overshooting formation of new blood vessels. This expression analysis focused on the use of different experimental models for Diabetes Mellitus and its complications (for a review see 1: Al-Awar et al: Experimental Diabetes Mellitus in Different Animal Models. J Diabetes Res. 2016; doi: 10.1155/2016/9051426). By that, we wanted to uncover the relative contributions of systemic hyperinsulinaemia and/or hyperglycemia to molecular regulations. The following models have been used: As insulinopenic, hyperglycemic model reflecting Type 1 diabetes, male STZ-Wistar rats (60mg/kg BW; i.p.) were used. Wistar rats without STZ injection served as non-diabetic controls. Male obese ZDF rats (Fa/Fa) were used as type-2 diabetes model characterized by persisting hyperglycemia and transient hyperinsulinemia. Male lean ZDF rats (Fa/-) served as non-diabetic controls. Male obese ZF rats (Fa/Fa) hyperglycemia were used reflecting euglycemia and severe insulin resistance. Male lean ZF rats (Fa/-) served as controls. ZDF and ZF rats were obtained in two genotypes, obese (genotype fa/fa) and lean littermates (genotype Fa/?). All rats were housed in standard cages under a normal light-dark cycle for 16 weeks. All animals had free access to food and water. ZF and Wistar rats received a standard chow (Ssniff R/M) and ZDF rats received Purina 5008 chow. A group size of n=8 were used for all study groups. Wistar rats were rendered type-1 like hyperglycemic and hypoinsulinemic via a single injection of streptocotocin (STZ, 60mg/kg; i.p.) at 7 weeks of age. Obese ZDF rats (fa/fa) develop spontaneously a type-2 diabetes phenotype with persisting hyperglycemia and transient hyperinsulinemia (hyperglycemic, hypoinsulinemic). Obese ZF rats (fa/fa) develop insulin resistance with permanent hyperinsulinemia without concomitant hyperglycemia and no overt diabetes phenotype. Non STZ treated Wistar rats, lean ZDF littermates (Fa/?), and lean ZF littermates (Fa/?) served as controls. All groups were kept for 12 weeks on respective conditions together with appropriate age-matched controls. Unbiased gene expression analysis was performed per group using Affymetrix gene arrays.

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Transcriptomic profiling of diabetic rats treated with peripherical focused ultrasound (pFUS)

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