Chronic oxidative stress results in decreased responsiveness to insulin, eventually leading to diabetes and cardiovascular disease. Activation of the JNK signaling pathway can mediate many of the effects of stress on insulin resistance through inhibitory phosphorylation of insulin receptor substrate 1. By contrast, exercise, which acutely increases oxidative stress in the muscle, improves insulin sensitivity and glucose tolerance in patients with Type 2 diabetes. To elucidate the mechanism underlying the contrasting effects of acute versus chronic oxidative stress on insulin sensitivity, we used a cellular model of insulin-resistant muscle to induce either chronic or acute oxidative stress and investigate their effects on insulin and JNK signaling. Chronic oxidative stress resulted in increased levels of phosphorylated (activated) JNK in the cytoplasm, whereas acute oxidative stress led to redistribution of JNK-specific phosphatase MKP7 from the nucleus into the cytoplasm, reduction in cytoplasmic phospho-JNK, and a concurrent accumulation of phospho-JNK in the nucleus. Acute oxidative stress restored normal insulin sensitivity and glucose uptake in insulin-resistant muscle cells, and this effect was dependent on MKP7. We propose that the contrasting effects of acute and chronic stress on insulin sensitivity are driven by changes in subcellular distribution of MKP7 and activated JNK.Chronic oxidative stress is one of the major sources of metabolic abnormalities associated with Type 2 diabetes (1-3). High glucose and fatty acid levels lead to increased production of reactive oxygen species (ROS), 2 which can cause insulin resistance in peripheral metabolic tissues. This leads to decreased glucose uptake in muscle and adipose tissue, and eventually, pancreatic  cell failure, glucose intolerance, and frank diabetes (4 -8).The mechanistic link between increased ROS levels and insulin resistance is activation of several signaling pathways, primarily mitogen-activated protein kinases (MAPK) pathways. JNK (Jun N-terminal kinases) are MAP kinases activated by cellular stresses, including oxidative stress, and play a role in apoptosis and survival, stress resistance, and immune response (9). Upstream signaling leading to JNK activation involves stress-induced MAPK kinases MEKK4 and MEKK7, as well as scaffold protein JIP (JNK-interacting protein) (10). Activation of JNK leads to dimerization followed by translocation into the nucleus, where it can phosphorylate its downstream target c-Jun, leading to activation of stress response and apoptotic pathways. JNKs are specifically dephosphorylated and inactivated by MAP kinase phosphatase 7 (MKP7), which also acts as a shuttle protein and was proposed to be involved in JNK nucleocytoplasmic translocation (11).Obesity increases JNK activation in muscle and adipose tissue in mice. Genetic ablation or pharmacological inhibition of JNK results in marked improvement of insulin sensitivity in mouse models of diet-induced obesity and insulin resistance (6, 12, 13). Mechanistically, J...
Studies of long-lived Caenorhabditis elegans mutants have identified several genes that function to limit lifespan, i.e., loss-of-function mutations in these genes promote longevity. By contrast, little is known about genes that normally act to delay aging and that when mutated cause premature aging (progeria). To seek such genes, we performed a genetic screen for C. elegans mutants that age prematurely. We found that loss-of-function mutations of the ketoacyl thiolase gene kat-1 result in an increased accumulation of the lipofuscin-like fluorescent aging pigment, shortened lifespan, early behavioral decline, and other abnormalities characteristic of premature aging. These findings suggest that kat-1 acts to delay C. elegans aging. kat-1 encodes a conserved metabolic enzyme that catalyzes the last step of fatty acid oxidation and was previously shown to regulate fat accumulation in worms. We observed that kat-1 is required for the extension of lifespan and enhanced thermotolerance mediated by extra copies of the deacetylase gene sir-2.1. kat-1 acts independently of other known pathways that affect longevity. Our findings suggest that defects in fatty acid oxidation can limit lifespan and accelerate aging in C. elegans and that kat-1-mediated fatty acid oxidation is crucial for overexpressed sir-2.1 to delay aging.progeria | lipofuscin | fatty acid oxidation | sirtuins | protein deacetylation
Type 2 diabetes (T2D) is caused by loss of pancreatic b-cell mass and failure of the remaining b-cells to deliver sufficient insulin to meet demand. b-Cell glucolipotoxicity (GLT), which refers to combined, deleterious effects of elevated glucose and fatty acid levels on b-cell function and survival, contributes to T2D-associated b-cell failure. Drugs and mechanisms that protect b-cells from GLT stress could potentially improve metabolic control in patients with T2D. In a phenotypic screen seeking lowmolecular-weight compounds that protected b-cells from GLT, we identified compound A that selectively blocked GLT-induced apoptosis in rat insulinoma cells. Compound A and its optimized analogs also improved viability and function in primary rat and human islets under GLT. We discovered that compound A analogs decreased GLT-induced cytosolic calcium influx in islet cells, and all measured b-cell-protective effects correlated with this activity. Further studies revealed that the active compound from this series largely reversed GLTinduced global transcriptional changes. Our results suggest that taming cytosolic calcium overload in pancreatic islets can improve b-cell survival and function under GLT stress and thus could be an effective strategy for T2D treatment.
Diacylglycerol O-acyltransferase 1 (DGAT1) inhibitor Pradigastat (1) was shown to be effective at decreasing postprandial triglyceride levels in a patient population with familial chylomicronemia syndrome (FCS). Although pradigastat does not cause photosensitization in humans at the high clinical dose of 40 mg, a positive signal was observed in preclinical models of phototoxicity. Herein, we describe a preclinical phototoxicity mitigation strategy for diarylamine containing molecules utilizing the introduction of an amide or suitable heterocyclic function. This strategy led to the development of two secondgeneration compounds with low risk of phototoxicity, disparate exposure profiles, and comparable efficacy to 1 in a rodent lipid bolus model for post-prandial plasma triglycerides.
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