The Structure−Activity Relationship between Peroxisome Proliferator-Activated Receptor γ Agonism and the Antihyperglycemic Activity of Thiazolidinediones

Willson, Timothy M.; Cobb, Jeff E.; Cowan, David J.; Wiethe, Robert W.; Correa, Itzela D.; Prakash, Shimoga R.; Beck, Kelli D.; Moore, Linda B.; Kliewer, Steven A.; Lehmann, Jürgen

doi:10.1021/jm950395a

Cited by 630 publications

(373 citation statements)

References 26 publications

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“…First, the clinical potencies of the various TZDs correlate closely with their in vitro potency in PPAR binding or transactivation assays [58,59]. Second, non-TZD PPAR agonists also improve insulin sensitivity in vivo with potencies that correlate with in vitro PPAR binding affinity [60].…”

Section: Ppar and Insulin Resistancementioning

confidence: 99%

PPARs and adipocyte function

Christodoulides

Vidal-Puig

2010

Molecular and Cellular Endocrinology

112

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Abstract:For long viewed as passive lipid storage depots, adipocytes are now recognised as key players in the pathogenesis of insulin resistance and metabolic disease. In parallel, the last two decades of research have seen the emergence of transcription factors of the peroxisome proliferator-activated receptor (PPAR) family as central regulators of lipid and glucose homeostasis and molecular targets for drugs to treat hyper-lipidaemia and type 2 diabetes mellitus. In this review we discuss the characteristics of PPARs and the role of the different isotypes in adipocyte biology.

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Section: Ppar and Insulin Resistancementioning

confidence: 99%

PPARs and adipocyte function

Christodoulides

Vidal-Puig

2010

Molecular and Cellular Endocrinology

112

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“…Currently, two PPAR agonist classes are in widespread use, the thiazolidinediones (TZDs) which activate PPAR and increase insulin sensitivity, and the fibrates (gemfibrozil, fenofibrate) which activate PPAR to reduce hepatic triglyceride production and increase hepatic fatty acid oxidation (Harris and Kletzien 1994;Forman et al 1995;Lehmann et al 1995;Willson et al 1996a). In vivo, PPAR and ligands appear to be naturally occurring fatty acids and eicosanoid arachidonic acid metabolites (Forman et al 1997).…”

Section: Pparsmentioning

confidence: 99%

Nuclear receptors, mitochondria and lipid metabolism

2008

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Lipid metabolism is a continuum from emulsification and uptake of lipids in the intestine to cellular uptake and transport to compartments such as mitochondria. Whether fats are shuttled into lipid droplets in adipose tissue or oxidized in mitochondria and peroxisomes depends on metabolic substrate availability, energy balance and endocrine signaling of the organism. Several members of the nuclear hormone receptor superfamily are lipid-sensing factors that affect all aspects of lipid metabolism. The physiologic actions of glandular hormones (e.g. thyroid, mineralocorticoid and glucocorticoid), vitamins (e.g. vitamins A and D) and reproductive hormones (e.g. progesterone, estrogen and testosterone) and their cognate receptors are well established. The peroxisome proliferator activated receptors (PPARs) and Liver X receptors (LXRs), acting in concert with PPARγ Coactivator 1α (PGC-1α), have been shown to regulate insulin sensitivity and lipid handling. These receptors are the focus of intense pharmacologic studies to expand the armamentarium of small molecule ligands to treat diabetes and the metabolic syndrome (hypertension, insulin resistance, hyperglycemia, dyslipidemia, and obesity). Recently, additional partners of PGC-1α have moved to the forefront of metabolic research, the Estrogen-related Receptors (ERRs). Although no endogenous ligands for these receptors have been identified, phenotypic analyses of knockout mouse models demonstrate an important role for these molecules in substrate sensing and handling as well as mitochondrial function.

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“…Experiments were carried out in accordance with ethical guidelines from the Comité d'Ethique en Expériementation Animale de la Region Nord-Pas de Calais. Six-to 8-week-old mice were sensitized by means of intraperitoneal injection of ovalbumin (OVA; 50 lg, Sigma) in 100 lL of alum (Imject, Pierce) or received alum only and were challenged for 20 minutes on days 14,15,16,18,19, and 20 by means of aerosol nebulization with OVA (1% in PBS) by using an ultrasonic nebulizer (System). Ciglitazone (5 3 10 ÿ5 mol/L, Alexis) in PBS or ciglitazone (5 3 10 ÿ5 mol/L) and GW9662 (5 3 10 ÿ5 mol/L, Cayman) in PBS (or vehicle) were administered by means of nebulization for 20 minutes immediately before and during each OVA challenge.…”

Section: Murine Asthma Modelmentioning

confidence: 99%

“…18 One group of synthetic PPAR-c agonistic ligands is the glitazones, drugs used in the treatment of diabetic patients. 19 Several studies have clearly demonstrated that PPAR-c plays an important role in the control of inflammatory responses, 20,21 acting on T cells, 22,23 macrophages, dendritic cells, 24 and mast cells. 25 In monocytes and macrophages PPAR-c agonists inhibit the expression of proinflammatory cytokines, such as TNF-a, IL-1b, and IL-6.…”

mentioning

confidence: 99%