Ablation of peroxisome proliferator activated receptor (PPAR) ␣, a lipid-activated transcription factor that regulates expression of ␤-oxidative genes, results in profound metabolic abnormalities in liver and heart. In the present study we used PPAR␣ knockout (KO) mice to determine whether this transcription factor is essential for regulating fuel metabolism in skeletal muscle. When animals were challenged with exhaustive exercise or starvation, KO mice exhibited lower serum levels of glucose, lactate, and ketones and higher nonesterified fatty acids than wild type (WT) littermates. During exercise, KO mice exhausted earlier than WT and exhibited greater rates of glycogen depletion in liver but not skeletal muscle. Fatty acid oxidative capacity was similar between muscles of WT and KO when animals were fed and only 28% lower in KO muscles when animals were starved. Exercise-induced regulation and starvation-induced regulation of pyruvate-dehydrogenase kinase 4 and uncoupling protein 3, two classical and robustly responsive PPAR␣ target genes, were similar between WT and KO in skeletal muscle but markedly different between genotypes in heart. Real time quantitative PCR analyses showed that unlike in liver and heart, in mouse skeletal muscle PPAR␦ is severalfold more abundant than either PPAR␣ or PPAR␥. In both human and rodent myocytes, the highly selective PPAR␦ agonist GW742 increased fatty acid oxidation about 2-fold and induced expression of several lipid regulatory genes, including pyruvate-dehydrogenase kinase 4 and uncoupling protein 3, responses that were similar to those elicited by the PPAR␣ agonist GW647. These results show redundancy in the functions of PPARs ␣ and ␦ as transcriptional regulators of fatty acid homeostasis and suggest that in skeletal muscle high levels of the ␦-subtype can compensate for deficiency of PPAR␣.Peroxisome proliferator activated receptors (PPARs) 1 ␣, ␦, and ␥ comprise a family of nuclear hormone receptors that regulate systemic fatty acid metabolism via ligand-dependent transcriptional activation of target genes (1). Strong evidence indicates that their endogenous ligands consist of fatty acids and/or lipid metabolites and that they function to mediate adaptive metabolic responses to changes in systemic fuel availability (1, 2). PPAR␣, which is expressed most abundantly in tissues that are characterized by high rates of fatty acid oxidation (FAO), is considered the primary subtype that mediates lipid-induced activation of FAO genes (3). This premise is based largely on studies of PPAR␣ knockout (KO) mice, which, compared with wild type (WT) littermates, exhibit low rates of ␤-oxidation and abnormal accumulation of neutral lipids in both cardiac and hepatic tissues (4, 5). The metabolic phenotype of KO mice is associated with decreased expression of FAO genes and failure of liver and heart to induce ␤-oxidative pathways in response to physiological or pharmacological perturbations in lipid metabolism (4 -6). Taken together, these studies indicate that, at least in rodents,...

An acute bout of exercise increases muscle GLUT4 mRNA in mice, and denervation decreases GLUT4 mRNA. AMP-activated protein kinase (AMPK) activity in skeletal muscle is also increased by exercise, and GLUT4 mRNA is increased in mouse skeletal muscle after treatment with AMPK activator 5-aminoimidazole-4-carboxamide-1-␤-D-ribofuranoside (AICAR). These findings suggest that AMPK activation might be responsible for the increase in GLUT4 mRNA expression in response to exercise. To investigate the role of AMPK in GLUT4 regulation in response to exercise and denervation, transgenic mice with a mutated AMPK ␣-subunit (dominant negative; AMPK-DN) were studied. GLUT4 did not increase in AMPK-DN mice that were treated with AICAR, demonstrating that muscle AMPK is inactive. Exercise (two 3-h bouts of treadmill running separated by 1 h of rest) increased GLUT4 mRNA in both wild-type and AMPK-DN mice. Likewise, denervation decreased GLUT4 mRNA in both wild-type and AMPK-DN mice. GLUT4 mRNA was also increased by AICAR treatment in both the innervated and denervated muscles. These data demonstrate that AMPK is not required for the response of GLUT4 mRNA to exercise and denervation. adenosine 5Ј-monophosphate; glucose transporter isoform 4; denervation; exercise EXERCISE TRAINING has been shown to increase total GLUT4 protein in skeletal muscle in both rats and humans (2,5,10,13,30,31). One exercise session increased GLUT4 protein content 50% in epitrochlearis. After a second session, rats exhibited a twofold increase in GLUT4 protein (29). In studies with trained and sedentary men, the GLUT4 protein content of the trained group was roughly twofold greater than that of the sedentary group (11). After 1 wk of cycle ergometer training there was a 2.8-fold increase in muscle GLUT4 protein content in sedentary males (12).One week of training significantly increased GLUT4 protein content (1.7-fold increase), although there was no significant increase in message 24 h after the last training bout. Transcription of the GLUT4 gene was significantly increased at 3 h after exercise in both the trained and untrained groups; however, the increase in GLUT4 gene transcription in the untrained rats was lower (1.4-fold) compared with the trained rats (1.8-fold). No increase in transcription was seen at 30 min or 24 h after exercise (24). This suggests that exercise transiently increased GLUT4 gene transcription, whereas the level of GLUT4 mRNA is increased each day after exercise and returns to baseline. However, GLUT4 protein increases each day during endurance exercise training because of the transient increase in GLUT4 mRNA. A more recent study using transgenic mice confirmed the increases in GLUT4 gene transcription (20). An acute exercise bout resulted in a significant increase in endogenous mRNA (20). Work with transgenic mice demonstrated that 895 bp of the human GLUT4 promoter were sufficient for normal GLUT4 response to exercise (20). Numerous other studies have shown an increase in GLUT4 gene expression in skeletal muscle due to physic...

These data suggest that inhibition of lipolysis by adenosine has the potential to be greater in obese AAW, and this could possibly be one explanation for the observation that obese AAW have more difficulty in losing weight than obese CAW.