Metabolism
Selective Insulin Resistance in Adipocytes
Aside from glucose metabolism, insulin regulates a variety of pathways in peripheral tissues. Under insulin-resistant conditions, it is well known that insulin-stimulated glucose uptake is impaired, and many studies attribute this to a defect in Akt signaling. Here we make use of several insulin resistance models, including insulin-resistant 3T3-L1 adipocytes and fat explants prepared from high fat-fed C57BL/6J and ob/ob mice, to comprehensively distinguish defective from unaffected aspects of insulin signaling and its downstream consequences in adipocytes.Increasing Adipocyte Lipoprotein Lipase Improves Glucose Metabolism in High Fat Diet-induced Obesity
Lipid accumulation in liver and skeletal muscle contributes to co-morbidities associated with diabetes and obesity. We made a transgenic mouse in which the adiponectin (Adipoq) promoter drives expression of lipoprotein lipase (LPL) in adipocytes to potentially increase adipose tissue lipid storage. These mice (Adipoq-LPL) have improved glucose and insulin tolerance as well as increased energy expenditure when challenged with a high fat diet (HFD). To identify the mechanism(s) involved, we determined whether the Adipoq-LPL mice diverted dietary lipid to adipose tissue to reduce peripheral lipotoxicity, but we found no evidence for this.Insulin and Insulin-like Growth Factor 1 (IGF-1) Modulate Cytoplasmic Glucose and Glycogen Levels but Not Glucose Transport across the Membrane in Astrocytes
Background: Astrocytes contain glycogen, an energy buffer in the brain.Results: Stimulation with insulin and IGF-1 decreases cytosolic glucose concentration in astrocytes without affecting glucose entry across the astrocyte plasma membrane.Conclusion: Insulin and IGF-1 boost the process of glycogen formation.Significance: This is the first high temporal resolution measurement of the decrease of glucose levels in astrocytes resulting from insulin and IGF-1 stimulation.ATP6AP2/(Pro)renin Receptor Contributes to Glucose Metabolism via Stabilizing the Pyruvate Dehydrogenase E1 β Subunit
Background: The mechanism of efficient energy generation in the highly evolved mammalian retina remains incompletely understood.Results: ATP6PA2 interacts with the E1 β subunit of pyruvate dehydrogenase, a key enzyme in aerobic energy generation, controlling its protein stability.Conclusion: ATP6AP2 contributes to glucose metabolism together with oxidative stress.Significance: The present data provide a novel insight into the biological function of ATP6AP2 in the retina. Aerobic glucose metabolism is indispensable for metabolically active cells; however, the regulatory mechanism of efficient energy generation in the highly evolved mammalian retina remains incompletely understood.MicroRNA-214 Suppresses Gluconeogenesis by Targeting Activating Transcriptional Factor 4
Background: miR-214 targets ATF4 involved in glucose metabolism; however, the role of miR-214 and ATF4 in hepatic gluconeogenesis is unknown.Results: Overexpression of miR-214 suppresses gluconeogenesis in hepatocytes in vitro and in vivo via the ATF4-dependent pathway.Conclusion: miR-214 suppresses gluconeogenesis via targeting ATF4.Significance: Our studies reveal that the miR-214-ATF4 axis is a novel pathway for the regulation of hepatic gluconeogenesis.Tumor Necrosis Factor (TNF)-α-induced Repression of GKAP42 Protein Levels through cGMP-dependent Kinase (cGK)-Iα Causes Insulin Resistance in 3T3-L1 Adipocytes
Insulin receptor substrates (IRSs) have been shown to be major mediators of insulin signaling. Recently, we found that IRSs form high-molecular weight complexes, and here, we identify by yeast two-hybrid screening a novel IRS-1-associated protein: a 42-kDa cGMP-dependent protein kinase-anchoring protein (GKAP42). GKAP42 knockdown in 3T3-L1 adipocytes suppressed insulin-dependent IRS-1 tyrosine phosphorylation and downstream signaling, resulting in suppression of GLUT4 translocation to plasma membrane induced by insulin.
