The induction of peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC-1alpha), a key regulator of mitochondriogenesis, is well-established under multiple physical exercise regimens, including, endurance, resistance, and sprint training. We wanted to determine if increased expression of PGC-1alpha in muscle is sufficient to improve performance during exercise in vivo. We demonstrate that muscle-specific expression of PGC-1alpha improves the performance during voluntary as well as forced exercise challenges. Additionally, PGC-1alpha transgenic mice exhibit an enhanced performance during a peak oxygen uptake exercise test, demonstrating an increased peak oxidative capacity, or whole body oxygen uptake. This increased ability to perform in multiple exercise paradigms is supported by enhanced mitochondrial function as suggested by increased mitochondrial gene expression, mitochondrial DNA, and mitochondrial enzyme activity. Thus this study demonstrates that upregulation of PGC-1alpha in muscle in vivo is sufficient to greatly improve exercise performance under various exercise paradigms as well as increase peak oxygen uptake.

Subjected research on Ivey's (1971) microcounseling program to a comprehensive meta-analytic review. A multistage sampling procedure resulted in the identification of 81 admissible studies. Glass's (1976) effect size (ES) statistic was used to estimate average effects for each study and across all studies, and the relation between ES and the sampling distribution of several important methodological and substantive characteristics was assessed. The most conservative overall ES statistic fell in the large-effect category. ESs were influenced differentially by the populations from which the subjects were drawn and by the type of client that subjects interviewed when data for ratings on dependent measures were acquired. There was some evidence that the dependent measures used in microcounseling research are limited, which led to a conclusion that research on the teaching of more complex skills may be delayed. The microcounseling program has made a contribution to counseling training and may have pointed the way to new training models.

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High DGAT1 expression levels in the small intestine highlight the critical role this enzyme plays in nutrient absorption. Identification of inhibitors which predominantly inhibit DGAT1 in the gut is an attractive drug discovery strategy with anticipated benefits of reduced systemic toxicity. In this report we describe our discovery and optimization of DGAT1 inhibitors whose plasma exposure is minimized by the action of transporters, including the P-glycoprotein transporter. The impact of this unique absorption profile on efficacy in rat and dog efficacy models is presented. KEYWORDS: DGAT1, triglyceride synthesis, efflux O rally ingested triglycerides (TG) undergo hydrolysis and then are reassembled within enterocytes into TG-rich chylomicrons destined for systemic circulation. The final committed step in triglyceride biosynthesis is known to be mediated by at least two distinct intracellular acyl-coA diacylglycerol acyltransferases (DGATs), namely DGAT1 1 and DGAT2. 2 Since the development of whole-body knockout models of these enzymes, there has been intense evaluation of pharmacological approaches to modulate their activity. 3−8 For DGAT1, this interest is inspired by the favorable metabolic phenotype of DGAT1 −/− mice, 9 which are resistant to dietinduced body weight gain, 10 are more insulin-sensitive relative to wild-type littermates, 11 and exhibit a reduced rate of chylomicrons formation when challenged with lipid nutrients. 12 Interestingly, all aspects of this phenotype are lost when DGAT1 is reintroduced via a tissue-specific promoter into the intestines of female DGAT1 −/− mice, implying that intestinal DGAT1 plays a crucial role in the effects observed in the whole-body knockout model. 13 Indeed, DGAT1 mRNA expression levels have been shown to be high in regions of the small intestine in mice and humans. 14,15 Selective inhibition of intestinal DGAT1 therefore becomes an intriguing drug discovery approach to recapitulate aspects of the DGAT1 −/− mouse, especially if this gut-specific inhibition reduces the potential risk of on-and off-target activity for candidate molecules. Particularly relevant for DGAT1 pharmacological inhibition is the observation of functional and morphological abnormalities in the fur and sebaceous glands of DGAT1 −/− mice. 16 In this report we describe a novel approach to specifically inhibit intestinal DGAT1, and demonstrate the potential viability of this strategy with regard to efficacy and safety in multiple preclinical models.High-throughput screening efforts using recombinant human DGAT1 enzyme identified the benzimidazole 1 (DGAT1 IC 50 = 1.3 μM; DGAT2 IC 50 > 20 μM; Figure 1) as a potential starting point for optimization. Initial structural modifications demonstrated that both the ethyl carbamate and the 2,6-dichlorophenyl substituents on the benzimidazole core could be replaced without substantial loss of activity (i.e., 2, DGAT1 IC 50 = 1.4 μM), and in fact introducing an additional substituent at the 4-position of the 2,6-dimethylphenyl ring led to an im...

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