20-Hydroxyecdysone decreases weight and hyperglycemia in a diet-induced obesity mice model

Kizelsztein, Pablo; Govorko, Dmitry; Komarnytsky, Slavko; Evans, Alysa; Wang, Zhong; Cefalu, William T.; Raskin, Ilya

doi:10.1152/ajpendo.90772.2008

Cited by 94 publications

(96 citation statements)

References 33 publications

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“…To demonstrate that the HFHC diet did have an effect on body weight in our Ins2Cre:Znt8loxP/loxP mice, we compared the weight gain of our mice to previous studies examining control mice fed a normal chow diet. A previous study showed that 19-wk-old C57Bl/6J mice fed a chow diet had gained on average 21% of their original 6-wk-old body weight (27). By comparison, our 19-wk-old Ins2Cre and Ins2Cre:Znt8loxP/loxP mice fed the HFHC diet gained 84 and 73% of their 6-wk-old body weight, respectively.…”

Section: Cre-:znt8mentioning

confidence: 48%

Effects of high-fat diet feeding on Znt8-null mice: differences between β-cell and global knockout of Znt8

Hardy¹,

Wijesekara²,

Genkin³

et al. 2012

American Journal of Physiology-Endocrinology and Metabolism

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Section: Cre-:znt8mentioning

confidence: 48%

Effects of high-fat diet feeding on Znt8-null mice: differences between β-cell and global knockout of Znt8

Hardy¹,

Wijesekara²,

Genkin³

et al. 2012

American Journal of Physiology-Endocrinology and Metabolism

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“…Indeed, much as seen with Nos up-regulation, ecdysone supplementation in vertebrates results in decreased appetite, cholesterol synthesis, and weight gain, while at the same time increasing muscle mass and endurance (Lafont and Dinan 2003;Dinan and Lafont 2006;Kizelsztein et al 2009). Given these apparent abilities to switch fat cell activity from lipid storage to lipid mobilization, a better understanding of the signals and mechanisms underlying NO and ecdysone-mediated effects should provide new insights and possible uses in metabolism based disorders.…”

Section: Nonautonomous Actions On Lipid Metabolismmentioning

confidence: 99%

Nitric oxide coordinates metabolism, growth, and development via the nuclear receptor E75

Cáceres¹,

Necakov²,

Schwartz³

et al. 2011

Genes Dev.

124

173

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Nitric oxide gas acts as a short-range signaling molecule in a vast array of important physiological processes, many of which include major changes in gene expression. How these genomic responses are induced, however, is poorly understood. Here, using genetic and chemical manipulations, we show that nitric oxide is produced in the Drosophila prothoracic gland, where it acts via the nuclear receptor ecdysone-induced protein 75 (E75), reversing its ability to interfere with its heterodimer partner, Drosophila hormone receptor 3 (DHR3). Manipulation of these interactions leads to gross alterations in feeding behavior, fat deposition, and developmental timing. These neuroendocrine interactions and consequences appear to be conserved in vertebrates.[Keywords: E75; DHR3; nitric oxide; Drosophila; metamorphosis; ecdysone; metabolism] Supplemental material is available for this article. In previous work, we showed that ecdysone-induced protein 75 (E75, also known as Eip75B; NR1D3) (Tweedie et al. 2009) contains heme constitutively bound to its ligand-binding domain (LBD), and that amino acids coordinately bound to the heme iron can be displaced in vitro by changes in redox state or the presence of nitric oxide (NO) gas (Pardee et al. 2004;Reinking et al. 2005;Marvin et al. 2009). In turn, these structural changes negate the ability of E75 to repress transcription and to reverse the positive transcriptional activity of its heterodimer partner, Drosophila hormone receptor 3 (DHR3; also known as DHR46, NR1F4) (Tweedie et al. 2009). Here, we look to see whether these interactions are relevant in vivo and, if so, what their roles are.One of the best-characterized roles of E75 and DHR3 in vivo is within the nuclear receptor (NR) transcriptional hierarchy that controls, and responds to, the production of the metamorphosis-inducing hormone ecdysone (diagrammed in Supplemental Fig. 1A). Upon binding ecdysone, the ecdysone receptor (EcR) acts as a heterodimer with a second NR, ultraspiracle (USP), to activate transcription of DHR3 and the E75 isoform E75A (Koelle et al. 1991;Lam et al. 1997Lam et al. , 1999White et al. 1997;Bialecki et al. 2002). DHR3 then promotes its own continued expression as well as that of the E75 splice variant E75B and the downstream NR gene bFtz-F1. bFTZ-F1, in turn, activates the expression of ecdysone synthetic enzyme genes (Lavorgna et al. 1993;Woodard et al. 1994;Broadus et al. 1999), resulting in another round of ecdysone production. The major site of larval ecdysone production is the prothoracic gland (PG) (diagrammed in Supplemental Fig. 1B). The PG is also a major site of NO synthase (Nos) expression (Wildemann and Bicker 1999). Hence, we looked to see whether E75 and NO are present and interactive in this tissue, with the hypothesis that activation of bFtz-F1 transcription by DHR3 requires inactivation of E75 isoforms by NO. As predicted, all of the above-listed genes are expressed in the PG toward the end of third instar development, and disruption of their expression or activity leads to molec...

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“…Similarly to HB, 20HE had no effect on food consumption in this model (21). Taken together, these data suggest that plant brassinosteroids and ecdysteroids have similar effects on glucose metabolism and insulin sensitivity in animals; however, the underlying molecular mechanisms and targets may be different.…”

Section: Discussionmentioning

confidence: 62%

“…Whereas animal steroid hormones act through the nuclear receptor family of transcription factors, plant brassinosteroids signal through a cell surface receptor kinase-mediated signal transduction pathway (29,34). At the same time, brassinosteroids share some similarities with ecdysteroids that have a wide array of physiological and pharmacological effects in animals and insects (4), including modulation of protein synthesis (14) and carbohydrate metabolism (21).…”

Section: Discussionmentioning

confidence: 99%

Hypoglycemic effects of brassinosteroid in diet-induced obese mice

Esposito

Kizelsztein

Komarnytsky

et al. 2012

American Journal of Physiology-Endocrinology and Metabolism

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Esposito D, Kizelsztein P, Komarnytsky S, Raskin I. Hypoglycemic effects of brassinosteroid in diet-induced obese mice. Am J Physiol Endocrinol Metab 303: E652-E658, 2012. First published July 11, 2012; doi:10.1152/ajpendo.00024.2012.-The prevalence of obesity is increasing globally, and obesity is a major risk factor for metabolic diseases such as type 2 diabetes. Previously, we reported that oral administration of homobrassinolide (HB) to healthy rats triggered a selective anabolic response that was associated with lower blood glucose. Therefore, the aim of this study was to evaluate the effects of HB administration on glucose metabolism, insulin sensitivity, body composition, and gluconeogenic gene expression profiles in liver of C57BL/6J high-fat diet-induced obese mice. Acute oral administration of 50 -300 mg/kg HB to obese mice resulted in a dose-dependent decrease in fasting blood glucose within 3 h of treatment. Daily chronic administration of HB (50 mg/kg for 8 wk) ameliorated hyperglycemia and improved oral glucose tolerance associated with obesity without significantly affecting body weight or body composition. These changes were accompanied by lower expression of two key gluconeogenic enzymes, phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G-6-Pase), and increased phosphorylation of AMP-activated protein kinase in the liver and muscle tissue. In vitro, HB treatment (1-15 M) inhibited cyclic AMP-stimulated but not dexamethasone-stimulated upregulation of PEPCK and G-6-Pase mRNA levels in H4IIE rat hepatoma cells. Among a series of brassinosteroid analogs related to HB, only homocastasterone decreased glucose production in cell culture significantly. These results indicate the antidiabetic effects of brassinosteroids and begin to elucidate their putative cellular targets both in vitro and in vivo.homobrassinolide; glucose; insulin resistance; diabetes; phosphoenolpyruvate carboxykinase BRASSINOSTEROIDS are plant-specific polyhydroxylated derivatives of 5␣-cholestane, structurally similar to cholesterol-derived animal steroid hormones and ecdysteroids from insects. They are found at low levels in pollen, seeds, leaves, and young vegetative tissues throughout the plant kingdom (2). The first biologically active plant brassinosteroid was isolated from the pollen of rapeseed Brassica napus in 1979 (16). The natural occurrence of more than 50 compounds of this group has been reported following the initial discovery (13). Similar to animal steroid hormones (24), brassinosteroids regulate the expression of specific plant genes and complex physiological responses involved in growth (9) partly via interactions with other hormones setting the frame for brassinosteroid responses (28). Brassinosteroid signaling in plants resembles the Wnt pathway and is mediated by GSK-3-like kinase (18). Moreover, application of brassinosteroids increased sugar and starch content in plants (35), whereas a brassinosteroid-deficient Arabidopsis mutant had an impaired carbohydrate metabolism (32).Very little is...

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20-Hydroxyecdysone decreases weight and hyperglycemia in a diet-induced obesity mice model

Cited by 94 publications

References 33 publications

Effects of high-fat diet feeding on Znt8-null mice: differences between β-cell and global knockout of Znt8

Effects of high-fat diet feeding on Znt8-null mice: differences between β-cell and global knockout of Znt8

Nitric oxide coordinates metabolism, growth, and development via the nuclear receptor E75

Hypoglycemic effects of brassinosteroid in diet-induced obese mice

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