OBJECTIVE-Skeletal muscle-specific LPL knockout mouse (SMLPL Ϫ/Ϫ ) were created to study the systemic impact of reduced lipoprotein lipid delivery in skeletal muscle on insulin sensitivity, body weight, and composition. RESEARCH DESIGN AND METHODS-Tissue-specific insulin sensitivity was assessed using a hyperinsulinemic-euglycemic clamp and 2-deoxyglucose uptake. Gene expression and insulinsignaling molecules were compared in skeletal muscle and liver of SMLPL Ϫ/Ϫ and control mice.RESULTS-Nine-week-old SMLPL Ϫ/Ϫ mice showed no differences in body weight, fat mass, or whole-body insulin sensitivity, but older SMLPL Ϫ/Ϫ mice had greater weight gain and whole-body insulin resistance. High-fat diet feeding accelerated the development of obesity. In young SMLPL Ϫ/Ϫ mice, insulin-stimulated glucose uptake was increased 58% in the skeletal muscle, but was reduced in white adipose tissue (WAT) and heart. Insulin action was also diminished in liver: 40% suppression of hepatic glucose production in SMLPL Ϫ/Ϫ vs. 90% in control mice. Skeletal muscle triglyceride was 38% lower, and insulin-stimulated phosphorylated Akt (Ser473) was twofold greater in SMLPL Ϫ/Ϫ mice without changes in IRS-1 tyrosine phosphorylation and phosphatidylinositol 3-kinase activity. Hepatic triglyceride and liver X receptor, carbohydrate response element-binding protein, and PEPCK mRNAs were unaffected in SMLPL Ϫ/Ϫ mice, but peroxisome proliferator-activated receptor (PPAR)-␥ coactivator-1␣ and interleukin-1 mRNAs were higher, and stearoyl-coenzyme A desaturase-1 and PPAR␥ mRNAs were reduced. CONCLUSIONS-LPL deletion in skeletal muscle reduces lipid storage and increases insulin signaling in skeletal muscle without changes in body composition. Moreover, lack of LPL in skeletal muscle results in insulin resistance in other key metabolic tissues and ultimately leads to obesity and systemic insulin resistance. Diabetes 58:116-124, 2009 L ipoprotein lipase (LPL) (European Commission no. 3.1.1.34) is a key enzyme in lipid metabolism and is described as a "gatekeeper" for its role in partitioning lipoprotein-derived free fatty acids (FFAs) between tissues (1). Once hydrolyzed, the lipoprotein-derived FFAs are available for uptake and use by extrahepatic tissues for either storage or oxidation. LPL is most abundant in heart, adipose tissue, and skeletal muscle (2,3). The importance of LPL in fuel partitioning and utilization is underscored by observations that tissuespecific perturbations in LPL activity result in dramatic shifts in body composition and lipid and glucose metabolism (4), particularly in heart and skeletal muscle.We and others previously showed that mice with musclespecific lipoprotein lipase overexpression are insulin resistant (5,6). Insulin resistance developed selectively in muscle, while insulin sensitivity in the liver was not affected. Overexpression of LPL in the skeletal muscle also led to excessive intramyocellular lipid deposition, suggestive of the relationship between lipid storage and insulin sensitivity.To further investigate...
SIRT3, the primary mitochondrial deacetylase, plays a significant role in enhancing the function of mitochondrial proteins. Downregulation of SIRT3 is a key component of metabolic syndrome, a precondition for obesity, diabetes and cardiovascular diseases. In this study, we examined the effects of brain mitochondrial protein hyperacetylation in western diet-fed Sirt3−/− mice, a model for metabolic syndrome. Brain mitochondrial proteins were hyperacetylated, following western diet feeding and Sirt3 deletion. To identity these hyperacetylated proteins, we performed a comprehensive acetylome analysis by label-free tandem mass spectrometry. Gene ontology pathway analysis revealed Sirt3 deletion-mediated downregulation of enzymes in several metabolic pathways, including fatty acid oxidation and tricarboxylic acid cycle. Mitochondrial respiration was impaired at multiple states, along with lower levels of mitochondrial fission proteins Mfn1 and Mfn2. Cleavage of procaspase-1 suggested inflammasome formation. Assembly of inflammasomes with caspase-1 and NLRP3 was detected as shown by proximity ligation assay. Markers of neuroinflammation including microgliosis and elevated brain IL-1β expression were also observed. Importantly, these findings were further exacerbated in Sirt3−/− mice when fed a calorie-rich western diet. The observations of this study suggest that SIRT3 deficiency-induced brain mitochondrial dysfunction and neuroinflammation in metabolic syndrome may play a role in late-life cognitive decline.
Miller MW, Knaub LA, Olivera-Fragoso LF, Keller AC, Balasubramaniam V, Watson PA, Reusch JE. Nitric oxide regulates vascular adaptive mitochondrial dynamics. Am J Physiol Heart Circ Physiol 304: H1624 -H1633, 2013. First published April 12, 2013 doi:10.1152/ajpheart.00987.2012.-Cardiovascular disease risk factors, such as diabetes, hypertension, dyslipidemia, obesity, and physical inactivity, are all correlated with impaired endothelial nitric oxide synthase (eNOS) function and decreased nitric oxide (NO) production. NO-mediated regulation of mitochondrial biogenesis has been established in many tissues, yet the role of eNOS in vascular mitochondrial biogenesis and dynamics is unclear. We hypothesized that genetic eNOS deletion and 3-day nitric oxide synthase (NOS) inhibition in rodents would result in impaired mitochondrial biogenesis and defunct fission/fusion and autophagy profiles within the aorta. We observed a significant, eNOS expression-dependent decrease in mitochondrial electron transport chain (ETC) protein subunits from complexes I, II, III, and V in eNOS heterozygotes and eNOS null mice compared with age-matched controls. In response to NOS inhibition with N G -nitro-L-arginine methyl ester (L-NAME) treatment in Sprague Dawley rats, significant decreases were observed in ETC protein subunits from complexes I, III, and IV as well as voltagedependent anion channel 1. Decreased protein content of upstream regulators of mitochondrial biogenesis, cAMP response elementbinding protein and peroxisome proliferator-activated receptor-␥ coactivator-1␣, were observed in response to 3-day L-NAME treatment. Both genetic eNOS deletion and NOS inhibition resulted in decreased manganese superoxide dismutase protein. L-NAME treatment resulted in significant changes to mitochondrial dynamic protein profiles with decreased fusion, increased fission, and minimally perturbed autophagy. In addition, L-NAME treatment blocked mitochondrial adaptation to an exercise intervention in the aorta. These results suggest that eNOS/NO play a role in basal and adaptive mitochondrial biogenesis in the vasculature and regulation of mitochondrial turnover.endothelial nitric oxide synthase; vascular mitochondria THE VASCULATURE IS A COMPLEX tissue with a cellular architecture that permits specific contractile profiles for optimal tissue perfusion and adaptation to physiological demands. One of the primary regulators of physiological vasomotion is nitric oxide (NO), generated enzymatically by a family of nitric oxide synthases (NOS): endothelial NOS (eNOS), neuronal NOS (nNOS), and inducible NOS. In addition to the regulation of blood flow, NO modulates vascular structure and function through direct signaling to vascular endothelium, vascular smooth muscle cells, and inflammatory and adventitial cells (reviewed in Ref. 11). Endothelium-derived NO is a physiologically significant vasodilator and inhibitor of platelet aggregation and adhesion. Vascular NO also prevents leukocyte adhesion to the endothelium and inhibits proliferation of vas...
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