LKB1 is a tumor suppressor that may also be fundamental to cell metabolism, since LKB1 phosphorylates and activates the energy sensing enzyme AMPK. We generated muscle-specific LKB1 knockout (MLKB1KO) mice, and surprisingly, found that a lack of LKB1 in skeletal muscle enhanced insulin sensitivity, as evidenced by decreased fasting glucose and insulin concentrations, improved glucose tolerance, increased muscle glucose uptake in vivo, and increased glucose utilization during a hyperinsulinemic-euglycemic clamp. MLKB1KO mice had increased insulin-stimulated Akt phosphorylation and a >80% decrease in muscle expression of TRB3, a recently identified Akt inhibitor. Akt/TRB3 binding was present in skeletal muscle, and overexpression of TRB3 in C2C12 myoblasts significantly reduced Akt phosphorylation. These results demonstrate that skeletal muscle LKB1 is a negative regulator of insulin sensitivity and glucose homeostasis. LKB1-mediated TRB3 expression provides a novel link between LKB1 and Akt, critical kinases involved in both tumor genesis and cell metabolism.LKB1 is a serine/threonine kinase that links a diverse array of cellular processes, including cancer, cellular polarity, and metabolism. Originally identified as the tumor suppressor protein mutated in Peutz-Jeghers syndrome (17, 21), LKB1 has since been shown to regulate polarity in a number of systems, including Caenorhabditis elegans (48), Drosophila melanogaster (28), Xenopus (33), and mammalian cells (3). Biochemically, LBK1 can phosphorylate and activate at least 13 members of the AMP-activated protein kinase (AMPK) subfamily of protein kinases (20, 27) when associated with two regulatory proteins essential for catalytic activity, STE20-related adapter protein and mouse protein 25 (MO25) (15). AMPK, the most studied of LKB1's downstream substrates, is a conserved serine/threonine kinase that functions in the regulation of energy metabolism (16,18,29). Studies with cell culture (15,40,51) or conditional knockouts of LKB1 in skeletal muscle (38), cardiac muscle (39), or liver (41) have found that LKB1 regulates AMPK activity both in vitro and in vivo. Other than AMPK and the microtubule affinity-regulating kinase (MARK) proteins, which have been implicated in the control of cellular polarity (9), relatively little is known about the function of the AMPK-related kinases. The well-established role of AMPK in metabolism, however, directly implicates LKB1 in the maintenance of energy balance.The protein kinase Akt functions both in the control of cell proliferation and as a critical node in insulin signaling, appearing to mediate most of the metabolic effects of insulin (44). Akt is activated by phosphorylation of Thr 308 within the T loop of the catalytic domain and Ser 473 , located in a C-terminal, noncatalytic region of the enzyme (1). A mammalian homolog of D. melanogaster tribbles, TRB3, was recently identified as a negative regulator of Akt activity in human embryonic kidney 293 (HEK293) cells and mouse liver (10). In HEK293 cells and liver, TRB3 bind...

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RYGBP can decrease the prescription medication requirements, resulting in significant cost-savings in the treatment of obesity-related hypertension and diabetes. This study found a 77.3% reduction in total cost of diabetic and anti-hypertensive medications.

The goal of the present study was to determine if supraspinal pathways are necessary for inhibition of bladder reflex activity induced by activation of somatic afferents in the pudendal or tibial nerve. Cats anesthetized with α-chloralose were studied after acute spinal cord transection at the thoracic T9/T10 level. Dilute (0.25%) acetic acid was used to irritate the bladder, activate nociceptive afferent C-fibers, and trigger spinal reflex bladder contractions (amplitude: 19.3 ± 2.9 cmH2O). Hexamethonium (a ganglionic blocker, intravenously) significantly (P < 0.01) reduced the amplitude of the reflex bladder contractions to 8.5 ± 1.9 cmH2O. Injection of lidocaine (2%, 1-2 ml) into the sacral spinal cord or transection of the sacral spinal roots and spinal cord further reduced the contraction amplitude to 4.2 ± 1.3 cmH2O. Pudendal nerve stimulation (PNS) at frequencies of 0.5-5 Hz and 40 Hz but not at 10-20 Hz inhibited reflex bladder contractions, whereas tibial nerve stimulation (TNS) failed to inhibit bladder contractions at all tested frequencies (0.5-40 Hz). These results indicate that PNS inhibition of nociceptive afferent C-fiber-mediated spinal reflex bladder contractions can occur at the spinal level in the absence of supraspinal pathways, but TNS inhibition requires supraspinal pathways. In addition, this study shows, for the first time, that after acute spinal cord transection reflex bladder contractions can be triggered by activating nociceptive bladder afferent C-fibers using acetic acid irritation. Understanding the sites of action for PNS or TNS inhibition is important for the clinical application of pudendal or tibial neuromodulation to treat bladder dysfunctions.