The RXR agonist LG100268 causes hepatomegaly, improves glycaemic control and decreases cardiovascular risk and cachexia in diabetic mice suffering from pancreatic beta-cell dysfunction

Lenhard, James M.; Lancaster, Mary E.; Paulik, Mark; Weiel, James E.; Binz, Jane G; Sundseth, Scott S.; Gaskill, Betty; Lightfoot, Ruth M.; Brown, H. Roger

doi:10.1007/s001250051193

Cited by 83 publications

(76 citation statements)

References 42 publications

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“…The reason for a decreased response to LG100268 compared with rosiglitazone remains unclear. In mouse models of diabetes, Lenhard et al (32) showed that LG100268 was less effective than rosiglitazone at decreasing serum triglycerides and nonesterified fatty acids and increasing inscapular brown adipose tissue and body weight. LG100268 could be stabilizing RXR/RXR homodimers thereby sequestering RXR and reducing the number of available PPAR␥/RXR heterodimers.…”

Section: Discussionmentioning

confidence: 99%

“…In agreement, Tontonoz et al (35) showed that liposarcoma cell differentiation, characterized by an increase in intracellular lipid accumulation, is enhanced by both rosiglitazone and LG100268 and that simultaneous treatment with both ligands results in an additive stimulation. In mouse models of obesity and type 2 diabetes, antidiabetic activity was enhanced by combination treatment with LG100268 and rosiglitazone (22,32). The cooperative effects of PPAR␥-and RXR-specific ligands may occur at the level of selective coactivator recruitment.…”

Section: Discussionmentioning

confidence: 99%

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Regional Differences in the Response of Human Pre-Adipocytes to PPARγ and RXRα Agonists

et al. 2002

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We have previously reported that omental (OM) preadipocytes respond less well to the prodifferentiating effects of thiazolidinediones than do preadipocytes from subcutaneous (SC) depots. This finding is consistent with in vivo alterations in fat distribution that occur in humans treated with thiazolidinediones. To explore these site-related differences further, we used real-time RT-PCR to quantify the specific mRNAs encoding peroxisome proliferator-activated receptor (PPAR) ␥1 and ␥2 and found that both isoforms were more highly expressed in SC than in OM preadipocytes. After 10 days of thiazolidinedione treatment, preadipocytes from both depots showed a small and comparable increase in expression of PPAR␥1 mRNA (1.7 ؎ 0.2-fold [P ‫؍‬ 0.007]) and 1.3 ؎ 0.1-fold [P ‫؍‬ 0.008] increase for SC and OM, respectively). There was a much larger increase in PPAR␥2 expression, which was significantly greater in SC compared with OM preadipocytes (11.1 ؎ 2.8-fold [P ‫؍‬ 0.0003] and 5.5 ؎ 1.7-fold [P ‫؍‬ 0.0003], respectively; P ‫؍‬ 0.014 for SC versus OM). To establish whether the refractoriness of OM preadipocytes to differentiation was unique to activators of the PPAR␥ pathway, we examined the effects of the retinoid X receptor (RXR) ligand LG100268. As assessed by glycerol-3-phosphate dehydrogenase activity, LG100268 had a greater effect on the differentiation of SC compared with OM preadipocytes when examined alone (SC ‫؍‬ 5.7 ؎ 1.7-fold vs. OM ‫؍‬ 1.9 ؎ 0.6-fold; P < 0.05) or in combination with rosiglitazone (SC ‫؍‬ 27.0 ؎ 7.5 vs. OM ‫؍‬ 10.6 ؎ 3.6-fold; P < 0.05). Consistent with this, RXR␣ mRNA levels were also higher in SC than in OM preadipocytes. In summary, the previously reported insensitivity of OM preadipocytes to the differentiating effects of thiazolidinediones may relate to their lower basal levels of PPAR␥1 and ␥2 mRNA and their diminished capacity to upregulate PPAR␥2 expression in response to ligand. That omentally derived cells also show reduced responsiveness to the prodifferentiating actions of an RXR ligand and a lower expression of RXR␣ in the undifferentiated state suggests that they may have a more generalized resistance to differentiation. Diabetes 51:718 -723, 2002

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Regional Differences in the Response of Human Pre-Adipocytes to PPARγ and RXRα Agonists

et al. 2002

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“…Currently, the reports on the effects of PPAR-␥ on insulin secretion are contradictory. PPAR-␥ agonists can decrease insulin secretion in diabetic animal models, whereas activation of PPAR-␥ does not acutely improve insulin secretion in isolated human islets (Table 1) (4,5,30,(33)(34)(35)(36)(37)(38)(39)(40). However, it is reported that PPAR-␥ agonists can protect the ␤-cells from apoptosis and restore the function of ␤-cells, including GSIS (39,41,42).…”

Section: Role Of Ppar-␥ In the Glucose-sensing Apparatus Of Pancreatimentioning

confidence: 99%

Role of Peroxisome Proliferator-Activated Receptor-γ in the Glucose-Sensing Apparatus of Liver and β-Cells

2004

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“…[3][4][5] PPARg directs adipocyte differentiation both in vitro and in vivo in collaboration with other transcription factors of the CCAAT/enhancer binding protein family. 6 In accordance with this role, TZD drugs (including Rosiglitazone, Pioglitazone and Troglitazone, of which the last has been withdrawn because of liver toxicity), despite normalizing glycemia and insulinemia, promote body weight gain both in animals and humans [7][8][9][10][11][12] and adipogenesis in vitro. [13][14][15] This is one of the main side effects of TZD treatment, and current investigation focuses on correcting this undesirable consequence.…”

Section: Introductionmentioning

confidence: 99%

Fenofibrate prevents Rosiglitazone-induced body weight gain in ob/ob mice

et al. 2005

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AIMS/HYPOTHESIS:Fibrates and thiazolidinediones are commonly used for the treatment of dyslipidemia and type 2 diabetes, respectively. The aim of this study was to investigate the effects on body weight as well as on glucose and lipid homeostasis of ligands for PPARa and PPARg, Fenofibrate and Rosiglitazone, alone or in association. METHODS: Ob/ob mice were divided into four groups: control, and mice daily injected (intraperitoneally), either with 10 mg/kg Rosiglitazone, 100 mg/kg Fenofibrate or both molecules. Body weight and food intake were monitored daily. After 13 days of treatment, mice were killed, and blood samples were collected for posterior metabolite quantification. The liver and adipose tissues were dissected and weighed. RESULTS: Body weight was significantly reduced or increased by Fenofibrate and Rosiglitazone, respectively. The effect of Rosiglitazone was prevented by coadministration of Fenofibrate. This was accompanied by a normalization of the daily food efficiency. Compared to those treated with Rosiglitazone, animals treated with Fenofibrate alone or in combination presented a decreased white adipose tissue mass. Fenofibrate or Rosiglitazone alone significantly reduced the levels of plasma lipid parameters. Surprisingly, Fenofibrate also decreased blood glucose levels in ob/ob mice, despite having no effect on insulin levels. By contrast, both glucose and insulin levels were decreased by Rosiglitazone treatment. Coadministration of both drugs improved all parameters as with Rosiglitazone. Fenofibrate restored almost normal hepatocyte morphology and significantly reduced the triglyceride content of the liver. This was accompanied by an increase in fatty acid oxidation in the liver in all groups receiving Fenofibrate. CONCLUSION/INTERPRETATION: These biological effects suggest that combined therapy with a PPARa and a PPARg ligand is more effective in ameliorating, specifically, lipid homeostasis than in activating any of this receptor separately. Furthermore, Fenofibrate prevents one of the most undesirable effects of Rosiglitazone, namely increased adiposity and body weight gain.

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The RXR agonist LG100268 causes hepatomegaly, improves glycaemic control and decreases cardiovascular risk and cachexia in diabetic mice suffering from pancreatic beta-cell dysfunction

Cited by 83 publications

References 42 publications

Regional Differences in the Response of Human Pre-Adipocytes to PPARγ and RXRα Agonists

Regional Differences in the Response of Human Pre-Adipocytes to PPARγ and RXRα Agonists

Role of Peroxisome Proliferator-Activated Receptor-γ in the Glucose-Sensing Apparatus of Liver and β-Cells

Fenofibrate prevents Rosiglitazone-induced body weight gain in ob/ob mice

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