SUMMARY The benefits of endurance exercise on general health make it desirable to identify orally active agents that would mimic or potentiate the effects of exercise to treat metabolic diseases. Although certain natural compounds, such as reseveratrol, have endurance-enhancing activities, their exact metabolic targets remain elusive. We therefore tested the effect of pathway-specific drugs on endurance capacities of mice in a treadmill running test. We found that PPARβ/δ agonist and exercise training synergistically increase oxidative myofibers and running endurance in adult mice. Because training activates AMPK and PGC1α, we then tested whether the orally active AMPK agonist AICAR might be sufficient to overcome the exercise requirement. Unexpectedly, even in sedentary mice, 4 weeks of AICAR treatment alone induced metabolic genes and enhanced running endurance by 44%. These results demonstrate that AMPK-PPARδ pathway can be targeted by orally active drugs to enhance training adaptation or even to increase endurance without exercise.

Obesity is a growing threat to global health by virtue of its association with insulin resistance, glucose intolerance, hypertension, and dyslipidemia, collectively known as the metabolic syndrome or syndrome X. The nuclear receptors PPARα and PPARγ are therapeutic targets for hypertriglyceridemia and insulin resistance, respectively, and drugs that modulate these receptors are currently in clinical use. More recent work on the less-described PPAR isotype PPARδ has uncovered a dual benefit for both hypertriglyceridemia and insulin resistance, highlighting the broad potential of PPARδ in the treatment of metabolic disease. PPARδ enhances fatty acid catabolism and energy uncoupling in adipose tissue and muscle, and it suppresses macrophage-derived inflammation. Its combined activities in these and other tissues make it a multifaceted therapeutic target for the metabolic syndrome with the potential to control weight gain, enhance physical endurance, improve insulin sensitivity, and ameliorate atherosclerosis. IntroductionThe prevalence of adult obesity has increased an alarming 75% since 1980, rendering a third of men and women obese in the US (1). This unabated rise has spawned proportionate increases in obesity-associated metabolic disorders, including glucose intolerance, insulin resistance, dyslipidemia, and hypertension, that are well-established risk factors for cardiovascular disease. Known as the metabolic syndrome or syndrome X, this dangerous cluster of pathologies accounts for 6-7% of all-cause mortality and is an expanding health threat. In fact, it is predicted that life expectancy will plateau or decline in the US within the first half of this century because of the magnitude of obesity-associated conditions and the increased rates of obesity in younger populations, particularly children (2, 3). The global obesity problem will require complex solutions, including public health efforts to diminish portion sizes, improve food choices, increase physical activity levels, and raise public awareness. In addition to social and behavioral changes, however, pharmacological interventions to diminish diabetic and cardiovascular complications of the metabolic syndrome are urgently needed.The pathophysiology underlying the metabolic syndrome is incompletely understood, but insulin resistance appears to be an important component (4, 5). Insulin resistance is marked by hyperinsulinemia, enhanced hepatic gluconeogenesis, and impaired insulin-stimulated glucose uptake into skeletal muscle and fat. Elevated levels of circulating FFAs, associated with obesity and insulin resistance, increase fat accumulation in insulin target tissues and contribute to defective insulin action. Indeed, intramuscular fat, based on NMR spectroscopy, correlates strongly with insulin resistance (6). Obese adipose tissue-derived inflammation and altered adipokine secretion may also inhibit insulin signals and affect systemic metabolism (7). The resulting hyperglycemia, dyslipidemia, and hypertension of the metabolic syndrome cause endothelial...

Retinoid X receptor (RXR) belongs to a family of ligandactivated transcription factors that regulate many aspects of metazoan life. A class of nuclear receptors requires RXR as heterodimerization partner for their function. This places RXR in the crossroad of multiple distinct biological pathways. This and the fact that the debate on the endogenous ligand requirement for RXR is not yet settled make RXR still an enigmatic transcription factor. Here, we review some of the biology of RXR. We place RXR into the evolution of nuclear receptors, review structural details and ligands of the receptor. Then processes regulated by RXR are discussed focusing on the developmental roles deduced from studies on knockout animals and metabolic roles in diseases such as diabetes and atherosclerosis deduced from pharmacological studies. Finally, aspects of RXR's involvement in myeloid differentiation and apoptosis are summarized along with issues on RXR's suitability as a therapeutic target.

How type I skeletal muscle inherently maintains high oxidative and vascular capacity in absence of exercise in unclear. We show that nuclear receptor ERRγ is highly expressed in type I muscle and when transgenically expressed in anaerobic type II muscles (ERRGO mice), dually induces metabolic and vascular transformation in absence of exercise. ERRGO mice show increased expression of genes promoting fat metabolism, mitochondrial respiration and type I fiber specification. Muscles in ERRGO mice also display an activated angiogenic program marked by myofibrillar induction and secretion of pro-angiogenic factors, neo-vascularization and a 100% increase in running endurance. Surprisingly, the induction of type I muscle properties by ERRγ does not involve PGC1α. Instead, ERRγ genetically activates the energy sensor AMPK, in mediating the metabo-vascular changes in the ERRGO mice. Therefore, ERRγ represents a previously unrecognized determinant that specifies intrinsic vascular and oxidative metabolic features that distinguish type I from type II muscle.