BACKGROUND AND PURPOSE: FD technology enables reconstructive repair of otherwise difficult-totreat intracranial aneurysms. These stentlike devices may induce progressive aneurysm thrombosis without additional implants and may initiate complete reverse vessel remodeling. The associated vascular biologic processes are as yet only partially understood.

BACKGROUND AND PURPOSE:Transverse sinus stenosis is common in patients with IIH. While the role of transverse sinus stenosis in IIH pathogenesis remains controversial, modeling studies suggest that stent placement within a transverse sinus stenosis with a significant pressure gradient should decrease cerebral venous pressure, improve CSF resorption in the venous system, and thereby reduce intracranial (CSF) pressure, improving the symptoms of IIH and reducing papilledema. We aimed to determine if IIH could be reliably treated by stent placement in transverse sinus stenosis.

Since the description of O-linked N-acetylglucosamine (OGlcNAc)1 as an abundant modification in murine lymphocytes (1), a myriad of cytoplasmic and nuclear proteins in all metazoans have been found to carry this modification. Such proteins cover a broad range, including many transcription factors, RNA polymerase II, oncogenes, nuclear pore proteins, viral proteins, and tumor repressors (for details, see Refs. 2 and 3 and citations within). Unlike classic O-or N-linked protein glycosylations, the O-GlcNAc modification involves only a single GlcNAc moiety linked to the hydroxyl group of Ser/Thr residues, generally is not elongated, and is found exclusively in the cytoplasm and nucleoplasm.Protein O-GlcNAcylation is highly dynamic, and the cycle of addition/removal of the sugar moiety is rapid, analogous to protein phosphorylation/dephosphorylation catalyzed by kinases and phosphatases (2). Indeed, existing evidence suggests that this modification has a "yin-yang" relationship with pro-

The transcriptional coactivator peroxisome proliferator-activated receptor ␥ coactivator-1␣ (PGC-1␣) has been identified as an inducible regulator of mitochondrial function. Skeletal muscle PGC-1␣ expression is induced post-exercise. Therefore, we sought to determine its role in the regulation of muscle fuel metabolism. Studies were performed using conditional, musclespecific, PGC-1␣ gain-of-function and constitutive, generalized, loss-of-function mice. Forced expression of PGC-1␣ increased muscle glucose uptake concomitant with augmentation of glycogen stores, a metabolic response similar to postexercise recovery. Induction of muscle PGC-1␣ expression prevented muscle glycogen depletion during exercise. Conversely, PGC-1␣-deficient animals exhibited reduced rates of muscle glycogen repletion post-exercise. PGC-1␣ was shown to increase muscle glycogen stores via several mechanisms including stimulation of glucose import, suppression of glycolytic flux, and by down-regulation of the expression of glycogen phosphorylase and its activating kinase, phosphorylase kinase ␣. These findings identify PGC-1␣ as a critical regulator of skeletal muscle fuel stores.Glucose and fatty acids are the chief fuel sources for skeletal muscle. During prolonged bouts of low intensity exercise, muscle energy needs are met through utilization of both substrates with mitochondrial fatty acid oxidation serving a "glucose sparing" function (1, 2). During acute high intensity exercise, glucose derived from hepatic and muscle glycogen stores serves as the chief energy source (reviewed in Refs. 3-5). Rapid glycogen repletion following a bout of exhausting intense exercise is an important adaptive response, preparing the muscle for subsequent bouts of activity. With endurance exercise training, the capacity for mitochondrial oxidation of fatty acids is augmented and muscle glycogen reserves increase (2). In disease states such as diabetes and heart failure, the capacity for muscle energy substrate utilization is reduced due to alterations in glucose metabolism and derangements in mitochondrial function (6, 7) (reviewed in Ref. 8).The molecular regulatory mechanisms involved in the control of muscle fuel metabolism are incompletely understood. Recent evidence implicates the transcriptional coactivator, peroxisome proliferator-activated receptor (PPAR) 5 -␥ coactivator 1␣ (PGC-1␣), in the regulation of striated muscle energy metabolism and function (9 -13). PGC-1␣ levels are rapidly induced in skeletal muscle following bouts of activity in rodents and humans (14 -22). PGC-1␣ coactivates multiple transcription factors involved in mitochondrial biogenesis, oxidative phosphorylation, and fatty acid oxidation, including the estrogen-related receptor ␣, PPAR␣, and nuclear respiratory factors 1 and 2 (6, 23-26). PGC-1␣ gain-and loss-of-function studies conducted in cells and in mice have demonstrated that PGC-1␣ stimulates gene regulatory programs that augment mitochondrial oxidative capacity in tissues with high energy demands, such as heart and ske...

Insulin resistance and ␤ cell toxicity are key features of type 2 diabetes. One leading hypothesis suggests that these abnormalities result from excessive flux of nutrients through the UDPhexosamine biosynthetic pathway leading to ''glucose toxicity.'' How the products of the hexosamine pathway mediate these effects is not known. Here, we show that transgenic overexpression of an enzyme using UDP-GlcNAc to modify proteins with O-GlcNAc produces the type 2 diabetic phenotype. Even modest overexpression of an isoform of O-GlcNAc transferase, in muscle and fat, leads to insulin resistance and hyperleptinemia. These data support the proposal that O-linked GlcNAc transferase participates in a hexosamine-dependent signaling pathway that is linked to insulin resistance and leptin production.