Therapeutic Roles of Peroxisome Proliferator–Activated Receptor Agonists

Staels, Bart; Fruchart, Jean Charles

doi:10.2337/diabetes.54.8.2460

Cited by 573 publications

(477 citation statements)

References 94 publications

(76 reference statements)

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“…Lactisole is in common use as a food additive for its anti-sweet properties (12). Among these widely used lactisole analogs are fibrates used to treat certain forms of hyperlipidemia (13)(14)(15)(16). Although the therapeutic effect of fibrates on lipid metabolism is mediated via nuclear peroxisome proliferator-activated receptor-α (PPAR-α), our results (10) show that clofibric and bezafibric acids also inhibit TAS1R3 receptors at drug concentrations similar to those needed to activate PPAR-α (14).…”

mentioning

confidence: 60%

“…To determine the effects of pharmacologically blocking the humanized receptor in the double KO background, we placed double KO-mhTas1r3 males and control WT males for a month on a diet containing 5 mg/g clofibrate (13,14,20,43). No adverse health effects were noted with any of the males on the clofibrate diet.…”

Section: Pharmacological Block Of the Mhtas1r3 Receptor Produces Revementioning

confidence: 99%

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Genetic loss or pharmacological blockade of testes-expressed taste genes causes male sterility

Mosinger

Redding

Parker

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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TAS1R taste receptors and their associated heterotrimeric G protein gustducin are involved in sugar and amino acid sensing in taste cells and in the gastrointestinal tract. They are also strongly expressed in testis and sperm, but their functions in these tissues were previously unknown. Using mouse models, we show that the genetic absence of both TAS1R3, a component of sweet and amino acid taste receptors, and the gustducin α-subunit GNAT3 leads to malespecific sterility. To gain further insight into this effect, we generated a mouse model that expressed a humanized form of TAS1R3 susceptible to inhibition by the antilipid medication clofibrate. Sperm formation in animals without functional TAS1R3 and GNAT3 is compromised, with malformed and immotile sperm. Furthermore, clofibrate inhibition of humanized TAS1R3 in the genetic background of Tas1r3 −/− , Gnat3 −/− doubly null mice led to inducible male sterility. These results indicate a crucial role for these extraoral "taste" molecules in sperm development and maturation. We previously reported that blocking of human TAS1R3, but not mouse TAS1R3, can be achieved by common medications or chemicals in the environment. We hypothesize that even low levels of these compounds can lower sperm count and negatively affect human male fertility, which common mouse toxicology assays would not reveal. Conversely, we speculate that TAS1R3 and GNAT3 activators may help infertile men, particularly those that are affected by some of the mentioned inhibitors and/or are diagnosed with idiopathic infertility involving signaling pathway of these receptors.phenoxy compounds | spermiogenesis

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mentioning

confidence: 60%

Section: Pharmacological Block Of the Mhtas1r3 Receptor Produces Revementioning

confidence: 99%

Genetic loss or pharmacological blockade of testes-expressed taste genes causes male sterility

Mosinger

Redding

Parker

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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“…Within the therapeutic and supra-therapeutic range of plasma PIO concentrations, this thiazolidinedione does not manifest any PPAR-α activity [32], whereas FENO is a pure PPAR-α agonist [33,34]. While the PPAR-α effect of FENO is considered to be moderate, it is the only fibrate (along with gemfibrozil) approved for use in humans.…”

Section: Discussionmentioning

confidence: 99%

Effects of peroxisome proliferator-activated receptor (PPAR)-α and PPAR-γ agonists on glucose and lipid metabolism in patients with type 2 diabetes mellitus

et al. 2007

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Aims/hypothesis The aim of the study was to examine the effects of pioglitazone (PIO), a peroxisome proliferatoractivated receptor (PPAR)-γ agonist, and fenofibrate (FENO), a PPAR-α agonist, as monotherapy and in combination on glucose and lipid metabolism. Subjects and methods Fifteen type 2 diabetic patients received FENO (n=8) or PIO (n=7) for 3 months, followed by the addition of the other agent for 3 months in an openlabel study. Subjects received a 4 h hyperinsulinaemiceuglycaemic clamp and a hepatic fat content measurement at 0, 3 and 6 months. Results Following PIO, fasting plasma glucose (FPG) (p<0.05) and HbA 1c (p<0.01) decreased, while plasma adiponectin (AD) (5.5±0.9 to 13.8±3.5 μg/ml [SEM], p<0.03) and the rate of insulin-stimulated total-body glucose disposal (R d ) (23.8 ± 3.8 to 40.5 ± 4.4 μmol kg −1 min −1 , p < 0.005) increased. After FENO, FPG, HbA 1c , AD and R d did not change. PIO reduced fasting NEFA (784±53 to 546± 43 μmol/l, p<0.05), triacylglycerol (2.12±0.28 to 1.61± 0.22 mmol/l, p<0.05) and hepatic fat content (20.4±4.8 to 10.2±2.5%, p<0.02). Following FENO, fasting NEFA and hepatic fat content did not change, while triacylglycerol decreased (2.20± 0.14 to 1.59± 0.13 mmol/l, p<0.01).Addition of FENO to PIO had no effect on R d , FPG, HbA 1c , NEFA, hepatic fat content or AD, but triacylglycerol decreased (1.61±0.22 to 1.00±0.15 mmol/l, p<0.05). Addition of PIO to FENO increased R d (24.9±4.4 to 36.1± 2.2 μmol kg −1 min −1 , p<0.005) and AD (4.1±0.8 to 13.1± 2.5 μg/ml, p<0.005) and reduced FPG (p<0.05), HbA 1c (p<0.05), NEFA (p<0.01), hepatic fat content (18.3±3.1 to 13.5±2.1%, p<0.03) and triacylglycerol (1.59±0.13 to 0.96±0.9 mmol/l, p<0.01). Muscle adenosine 5′-monophosphate-activated protein kinase (AMPK) activity did not change following FENO; following the addition of PIO, muscle AMPK activity increased significantly (phosphorylated AMPK:total AMPK ratio 1.2±0.2 to 2.2±0.3, p<0.01). Conclusions/interpretation We conclude that PPAR-α therapy has no effect on NEFA or glucose metabolism and that addition of a PPAR-α agonist to a PPAR-γ agent causes a further decrease in plasma triacylglycerol, but has no effect on NEFA or glucose metabolism.

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“…For example, binding of the PPARa receptor results in transcription of genes involved in fatty acid uptake and oxidation, inflammation and vascular function, whereas PPARg binding upregulates genes involved in fatty acid uptake and storage, inflammation and glucose homeostasis. 93 …”

Section: Dyslipidemiamentioning

confidence: 99%

Atypical antipsychotic-induced metabolic side effects: insights from receptor-binding profiles

2007

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Atypical antipsychotic drugs offer several notable benefits over typical antipsychotics, including greater improvement in negative symptoms, cognitive function, prevention of deterioration, and quality of life, and fewer extrapyramidal symptoms (EPS). However, concerns about EPS have been replaced by concerns about other side effects, such as weight gain, glucose dysregulation and dyslipidemia. These side effects are associated with potential long-term cardiovascular health risks, decreased medication adherence, and may eventually lead to clinical deterioration. Despite a greater understanding of the biochemical effects of these drugs in recent years, the pharmacological mechanisms underlying their various therapeutic properties and related side effects remain unclear. Besides dopamine D 2 receptor antagonism, a characteristic feature of all atypical antipsychotic drugs, these agents also bind to a range of non-dopaminergic targets, including serotonin, glutamate, histamine, a-adrenergic and muscarinic receptors. This review examines the potential contribution of different receptors to metabolic side effects associated with atypical antipsychotic treatment for all seven agents currently marketed in the United States (risperidone, olanzapine, quetiapine, ziprasidone, aripiprazole, paliperidone and clozapine) and another agent (bifeprunox) in clinical development at the time of this publication.

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Therapeutic Roles of Peroxisome Proliferator–Activated Receptor Agonists

Cited by 573 publications

References 94 publications

Genetic loss or pharmacological blockade of testes-expressed taste genes causes male sterility

Genetic loss or pharmacological blockade of testes-expressed taste genes causes male sterility

Effects of peroxisome proliferator-activated receptor (PPAR)-α and PPAR-γ agonists on glucose and lipid metabolism in patients with type 2 diabetes mellitus

Atypical antipsychotic-induced metabolic side effects: insights from receptor-binding profiles

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