Peroxisome Proliferator-Activated Receptor -ß/δ, -γ Agonists and Resveratrol Modulate Hypoxia Induced Changes in Nuclear Receptor Activators of Muscle Oxidative Metabolism.

PPAR-α, PPAR-ß, and PPAR-γ, and RXR in conjunction with PGC-1α and SIRT1, activate oxidative metabolism genes determining insulin sensitivity. In utero, hypoxia is commonly observed in Intrauterine Growth Restriction (IUGR), and reduced insulin sensitivity is often observed in these infants as adults. We sought to investigate how changes in oxygen tension might directly impact muscle PPAR regulation of oxidative genes. Following eight days in culture at 1% oxygen, C(2)C(12) muscle myoblasts displayed a reduction of PGC-1α, PPAR-α, and RXR-α mRNA, as well as CPT-1b and UCP-2 mRNA. SIRT1 and PGC-1α protein was reduced, and PPAR-γ protein increased. The addition of a PPAR-ß agonist (L165,041) for the final 24 hours of 1% treatment resulted in increased levels of UCP-2 mRNA and protein whereas Rosiglitazone induced SIRT1, PGC-1α, RXR-α, PPAR-α, CPT-1b, and UCP-2 mRNA and SIRT1 protein. Under hypoxia, Resveratrol induced SIRT1, RXR-α, PPAR-α mRNA, and PPAR-γ and UCP-2 protein. These findings demonstrate that hypoxia alters the components of the PPAR pathway involved in muscle fatty acid oxidative gene transcription and translation. These results have implications for understanding selective hypoxia adaptation and how it might impact long-term muscle oxidative metabolism and insulin sensitivity.

The effects of low protein during gestation on mouse pancreatic development and beta cell regeneration.

Beta cells are partially replaced in neonatal rodents after deletion with streptozotocin (STZ). Exposure of pregnant rats to a low protein (LP) diet impairs endocrine pancreas development in the offspring, leading to glucose intolerance in adulthood. Our objective was to determine whether protein restriction has a similar effect on the offspring in mice, and if this alters the capacity for beta cell regeneration after STZ. Pregnant Balb/c mice were fed a control (C) (20% protein) or an isocaloric LP (8% protein) diet during gestation. Pups were given 35 mg/kg STZ (or vehicle) from d 1 to 5 for each dietary treatment. Histologic analysis showed that C-fed offspring had largely replaced beta cell mass (BCM) after STZ by d 30, but this was not sustained over time. Female LP-fed offspring showed an initial increase in BCM by d 14 but developed glucose intolerance by d 130. In contrast, male LP offspring showed no changes in BCM or glucose tolerance. However, LP exposure limited the capacity for recovery of BCM in both genders after STZ treatment.