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Adrenergic receptor (AR) activation increases expression of peroxisome proliferator-activated receptor (PPAR)-gamma coactivator 1alpha (PGC-1alpha) mRNA, which may promote mitochondrial biogenesis in skeletal muscles. An AR-activated increase in PGC-1alpha mRNA was observed in exercise. PGC-1alpha mRNA is considered a single transcript (PGC-1alpha-a); however, a transcript search of PGC-1alpha in expressed sequence tag libraries revealed that two novel isoforms of PGC-1alpha mRNA, named PGC-1alpha-b and PGC-1alpha-c, were expressed in mice tissues. Compared with PGC-1alpha-a mRNA (a previously described isoform), PGC-1alpha-b or PGC-1alpha-c mRNA was transcribed by a different exon 1 of the PGC-1alpha gene and produced slightly smaller-sized proteins. PGC-1alpha-b or PGC-1alpha-c protein was functional; both isoforms possessed transcriptional activity and could coactivate PPARs, similar to those in PGC-1alpha-a in vitro. Transgenic mice overexpressing PGC-1alpha-b or PGC-1alpha-c in skeletal muscles showed increased gene expression related to mitochondrial biogenesis and fatty acid oxidation. In C57BL/6J mice, injection of the beta2-AR agonist clenbuterol increased PGC-1alpha-b and PGC-1alpha-c mRNA expression more than 350-fold, but not PGC-1alpha-a, in skeletal muscle. A single bout of exercise also increased PGC-1alpha-b and PGC-1alpha-c mRNAs, but not PGC-1alpha-a, in skeletal muscles. The increases in skeletal muscles in response to exercise were inhibited by pretreatment with the beta2-AR-specific inhibitor ICI 118,551. However, in liver, fasting increased PGC-1alpha-a mRNA, but not PGC-1alpha-b and PGC-1alpha-c mRNAs. These data indicate that AR activation is a major mechanism of an increase in PGC-1alpha expression in skeletal muscles, and the increase in PGC-1alpha mRNAs was isoform specific.

Sterol regulatory element binding protein 1c (SREBP1c) is a master regulator of lipogenic gene expression in liver and adipose tissue, where its expression is regulated by a heterodimer of nuclear receptor-type transcription factors retinoid X receptor-alpha (RXRalpha) and liver X receptor-alpha (LXRalpha). Despite the potential importance of SREBP1c in skeletal muscle, little is known about the regulation of SREBP1c in that setting. Here we report that gene expression of RXRgamma is markedly decreased by fasting and is restored by refeeding in mouse skeletal muscle, in parallel with changes in gene expression of SREBP1c. RXRgamma or RXRalpha, together with LXRalpha, activate the SREBP1c promoter in vitro. Moreover, transgenic mice overexpressing RXRgamma specifically in skeletal muscle showed increased gene expression of SREBP1c with increased triglyceride content in their skeletal muscles. In contrast, transgenic mice overexpressing the dominant-negative form of RXRgamma showed decreased SREBP1c gene expression. The expression of Forkhead-O1 transcription factor (FOXO1), which can suppress the function of multiple nuclear receptors, is negatively correlated to that of SREBP1c in skeletal muscle during nutritional change. Moreover, transgenic mice overexpressing FOXO1 specifically in skeletal muscle exhibited decreased gene expression of both RXRgamma and SREBP1c. In addition, FOXO1 suppressed RXRalpha/LXRalpha-mediated SREBP1c promoter activity in vitro. These findings provide in vivo and in vitro evidence that RXR/LXR up-regulates SREBP1c gene expression and that FOXO1 antagonizes this effect of RXR/LXR in skeletal muscle.

A single bout of exercise increases expression of peroxisome proliferator-activated receptor-gamma coactivator (PGC)-1alpha mRNA, which may promote mitochondrial biogenesis in skeletal muscle. In brown adipose tissue, cold exposure up-regulates PGC-1alpha expression via adrenergic receptor (AR) activation. Because exercise also activates the sympathetic nervous system, we examined whether exercise-induced increase in PGC-1alpha mRNA expression in skeletal muscle was mediated via AR activation. In C57BL/6J mice, injection of the beta2-AR agonist clenbuterol, but not alpha-, beta1-, or beta3-AR agonists, increased PGC-1alpha mRNA expression more than 30-fold in skeletal muscle. The clenbuterol-induced increase in PGC-1alpha mRNA expression in mice was inhibited by pretreatment with the beta-AR antagonist propranolol. In ex vivo experiments, direct exposure of rat epitrochlearis to beta2-AR agonist, but not alpha-, beta1-, and beta3-AR agonist, led to an increase in levels of PGC-1alpha mRNA. Injection of beta2-AR agonist did not increase PGC-1alpha mRNA expression in beta1-, beta2-, and beta3-AR knockout mice (beta-less mice). PGC-1alpha mRNA in gastrocnemius was increased 3.5-fold in response to running on a treadmill for 45 min. The exercise-induced increase in PGC-1alpha mRNA was inhibited by approximately 70% by propranolol or the beta2-AR-specific inhibitor ICI 118,551. The exercise-induced increase in PGC-1alpha mRNA in beta-less mice was also 36% lower than that in wild-type mice. These data indicate that up-regulation of PGC-1alpha expression in skeletal muscle by exercise is mediated, at least in part, by beta-ARs activation. Among ARs, beta2-AR may mediate an increase in PGC-1alpha by exercise.

The relation between blood taurine (2-aminoethanesulfonic acid) concentrations and obesity was investigated. Taurine is supplied to the body by dietary ingestion as well as by de novo synthesis; it is anabolized by cysteine dioxygenase (CDO), which is abundantly expressed in liver and white adipose tissue. Overexpression of CDO in 3T3-L1 preadipocytes caused a decrease in the level of cysteine (precursor of taurine) and an increase in the level of taurine in the culture medium, suggesting that CDO is involved in biosynthesis and secretion of taurine in white adipose tissue. In high-fat diet-induced and/or genetically obese mice, a decrease in the blood taurine concentration was observed along with a decrease in CDO expression in adipose tissue but not in liver. Dietary taurine supplementation prevented high-fat diet-induced obesity with increased resting energy expenditure. Thus, taurine deficiency observed in association with obesity may create a vicious circle promoting obesity. Dietary taurine supplementation interrupts this vicious circle and may prevent obesity.