PGC-1α improves glucose homeostasis in skeletal muscle in an activity-dependent manner.

Metabolic disorders are a major burden for public health systems globally. Regular exercise improves metabolic health. Pharmacological targeting of exercise mediators might facilitate physical activity or amplify the effects of exercise. The peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) largely mediates musculoskeletal adaptations to exercise, including lipid refueling, and thus constitutes such a putative target. Paradoxically, forced expression of PGC-1α in muscle promotes diet-induced insulin resistance in sedentary animals. We show that elevated PGC-1α in combination with exercise preferentially improves glucose homeostasis, increases Krebs cycle activity, and reduces the levels of acylcarnitines and sphingosine. Moreover, patterns of lipid partitioning are altered in favor of enhanced insulin sensitivity in response to combined PGC-1α and exercise. Our findings reveal how physical activity improves glucose homeostasis. Furthermore, our data suggest that the combination of elevated muscle PGC-1α and exercise constitutes a promising approach for the treatment of metabolic disorders.

Synthesis of monodisperse oligo(1,4-phenyleneethynylene-alt-1,4-triptycyleneethynylene)s.

The synthesis of monodisperse oligo(p-phenyleneethynylene)s 8a(n) with alternating 2,5-dihexyl-1,4-phenylene and 6,14-di-tert-butyl-1,4-triptycylene units and orthogonally protected alkyne end groups is reported. Starting from 6,14-di-tert-butyl-1-(2-triisopropylsilylethynyl)-4-(2-trimethylsilylethynyl)triptycene (5a), 1,4-dihexyl-2,5-diiodobenzene (10), and 1,4-dihexyl-2-iodo-5-(3-hydroxyprop-1-ynyl)benzene (9), oligomers with up to four repeating units, i.e., eight phenyleneethynylene units, were prepared through a partially divergent-convergent route with the alkynyl-aryl (Sonogashira-Hagihara) coupling as the key reaction. The starting compound 5a was prepared from triptycenequinone through a sequence of addition of 2-trialkylsilylethynyllithium, reduction and concomitant elimination of water, conversion of the phenol into a triflate, and finally Pd/Cu-catalyzed coupling with trialkylsilylethyne. A similar access to the key compound for a stringent divergent-convergent route, 6,14-di-tert-butyl-1-(3-hydroxybut-1-ynyl)-4-(2-triisopropylsilylethynyl)triptycene (6), is reported. The optical properties of the oligomers 8a(n) and the corresponding oligo(2,5-dihexyl-1,4-phenyleneethynylene)s in dilute solution are almost identical, whereas they differ significantly for the solid, undiluted compounds.