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Nuclear Receptors in Physiology and Disease
Summary: The discovery of steroid receptors and, subsequently, the family of orphan nuclear receptors provides a molecular approach to the study of metabolic regulation by fat-soluble hormones, vitamins, and dietary lipids. Ronald Evans is interested in understanding the molecular genetics of metabolic disease and inflammation (including atherosclerosis and diabetes) and cancer and using this information to devise cures for their treatment.
The concept of fat—a single word expressing the melding of nutrition, physiology, energy metabolism, diet, and disease—is simple to grasp. While an abundance of food may be perceived to be good, there is little to be achieved in its excess. The association between excess weight (obesity) and a tetrad of medical problems—hypertension, cardiovascular disease, hyperlipidemia, and diabetes—has come to be known as metabolic syndrome or syndrome X. The peroxisome proliferator-activated receptor (PPAR) family of orphan receptors comprises three related gene products, each of which uniquely contributes to the etiology and potential treatment of this syndrome.
Obesity and Metabolic Syndrome
The PPARs are a class of orphan receptors that are the product of the closely related α, γ, and δ genes. The γ isoform, which functions as an adipocyte differentiation factor, is the target of the antidiabetic drugs Actos and Avandia. In mature adipose cells or macrophages, activation of PPARγ promotes lipid uptake and storage. PPARγ expression in human monocytes and in lipid-accumulating foam cells in the coronary artery directly contributes to atherosclerosis. Activation of PPARγ by antidiabetic drugs promotes expression of the oxycholesterol receptor LXRα, which in turn induces the efflux pump ABC-A1, resulting in cholesterol removal from the foam cell macrophages. Despite this knowledge, it is not known how PPARγ contributes to diabetes and how thiazolidinediones (TZDs) act therapeutically. In the body, PPARγ is expressed at its highest levels in brown and white adipose tissue, suggesting an important role for fat in the etiology and treatment of insulin resistance. We are employing chromatin immunoprecipitation (ChIP) to identify key direct target genes by hybridization to DNA promoter chips (ChIP on Chip).
The PPARδ isoform behaves very differently than its γ relative. It is not required for adipogenesis and promotes fat burning rather than fat storage. Despite this opposing activity, PPARγ also acts as a novel insulin sensitizer in obese animal models of insulin resistance. Unexpectedly, it does this by action in the liver and not in adipose tissue. The use of an orally active synthetic PPARγ agonist lowers blood glucose and free fatty acid levels. Gene array studies confirm that PPARγ exerts broad control on the enzymatic families controlling glucogen and pyruvate metabolism.
Losing Weight by Increasing Metabolism
In Western cultures, excess adipose mass, or obesity, has reached epidemic proportions, resulting in metabolic syndrome, typified by type II diabetes, cardiovascular disease, and hyperlipidemia. In contrast to the well-established roles of PPARγ and PPARα in lipid metabolism, little is known about PPARδ in this process. We have recently demonstrated that targeted activation of PPARδ in adipose tissue specifically induces expression of genes required for fatty acid oxidation and energy dissipation, which then leads to improved lipid profiles and reduced adiposity. Importantly, these animals are completely resistant to weight gain on a high-fat diet. As predicted, acute treatment of obese mice with a synthetic PPARδ agonist also prevents lipid accumulation. In parallel, PPARδ-deficient mice challenged with a high-fat diet show reduced energy expenditure and are prone to obesity. In the LDL (low-density lipoprotein) receptor–deficient mouse, we show that the PAPRγ agonist dramatically slows atherogenic lesion progression. Our findings suggest that PPARδ serves as a widespread regulator of fat burning and is a potential therapeutic target in the treatment of obesity, diabetes, and heart disease.
The Marathon Mouse
Endurance exercise training can promote an adaptive muscle fiber transformation and an increase of mitochondrial biogenesis by triggering scripted changes in gene expression. Exercise also improves metabolic profiles by lowering glucose and raising HDL (high-density lipoprotein). However, no transcription factor has yet been identified that explains the molecular basis of these observations. PPARδ's ability to promote oxidative phosphorylation in adipose tissue led us to speculate that PPARδ may be the common link. To address this problem, we engineered a mouse capable of continuous running of up to twice the distance of a wild-type littermate. This feat was achieved by targeted expression of an activated form of PPARδ in skeletal muscle, which resulted in a dramatic increase in "nonfatiguing" type I muscle fibers. Moreover, these genetically generated fibers confer resistance to obesity, even in the absence of exercise. This work demonstrates that complex physiologic properties such as fatigue, endurance, and running capacity can be genetically manipulated. The dramatic impact of PPARδ on normal muscle leads us to speculate on its potential benefit to mice harboring genetic defects that mimic human muscular dystrophies.
These projects have been partially supported by grants from the National Institute of Diabetes and Digestive and Kidney Diseases and the National Institute of Child Health and Human Development.
Last updated: May 1, 2008
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