ABSTRACT
Non-shivering thermogenesis takes place in brown and beige adipocytes and facilitates cold tolerance and acclimation. However, thermogenesis in adipose tissue also was found to be activated in metabolic overload states for fast utilization of nutrients excess. This observation spurred research interest in mechanisms of thermogenesis regulation for metabolic overload and obesity prevention. One of proposed regulators of thermogenic efficiency in adipocytes is the dynamics of mitochondria, where thermogenesis takes place. Indeed, brown and beige adipocytes exhibit fragmented round-shaped mitochondria, while white adipocytes have elongated organelles with high ATP synthesis. Mitochondrial morphology can determine uncoupling protein 1 (UCP1) content, efficiency of catabolic pathways and electron transport chain, supplying thermogenesis. This review will highlight the co-regulation of mitochondrial dynamics and thermogenesis and formulate hypothetical ways for excessive nutrients burning in response to mitochondrial morphology manipulation.
Subject(s)
Mitochondria/metabolism , Thermogenesis , Uncoupling Protein 1/metabolism , Adipose Tissue/metabolism , Animals , Energy Metabolism , Humans , Mitochondrial DynamicsABSTRACT
Obesity is accompanied by dyslipidemia, hypoxia, endoplasmic reticulum (ER) stress, and inflammation, representing the major risk factor for the development of insulin resistance (IR) and type 2 diabetes. We modeled these conditions in cultured 3T3-L1 adipocytes and studied their effect on insulin signaling, glucose uptake, and inflammatory response via activation of stress-dependent JNK1/2 kinases. Decreased insulin-induced phosphorylation of the insulin cascade components IRS, Akt, and AS160 was observed under all tested conditions (lipid overloading of cells by palmitate, acute inflammation induced by bacterial lipopolysaccharide, hypoxia induced by Co2+, and ER stress induced by brefeldin A). In all the cases, except the acute inflammation, glucose uptake by adipocytes was reduced, and the kinetics of JNK1/2 activation was bi-phasic exhibiting sustained activation for 24 h. By contrast, in acute inflammation, JNK1/2 phosphorylation increased transiently and returned to the basal level within 2-3 h of stimulation. These results suggest a critical role of sustained (latent) vs. transient (acute) inflammation in the induction of IR and impairment of glucose utilization by adipose tissue. The components of the inflammatory signaling can be promising targets in the development of new therapeutic approaches for preventing IR and type 2 diabetes.
Subject(s)
Inflammation , Insulin Resistance , Obesity/pathology , 3T3-L1 Cells , Adipocytes/cytology , Adipocytes/drug effects , Adipocytes/metabolism , Animals , Endoplasmic Reticulum Stress/drug effects , Fatty Acids, Nonesterified/pharmacology , Inflammation/etiology , Insulin/pharmacology , Lipopolysaccharides/pharmacology , Mice , Mitogen-Activated Protein Kinase 8/metabolism , Mitogen-Activated Protein Kinase 9/metabolism , Obesity/metabolism , Phosphatidylinositol 3-Kinases/metabolism , Phosphorylation/drug effects , Proto-Oncogene Proteins c-akt/metabolism , Signal Transduction/drug effectsABSTRACT
We studied the effect of SIRT1 deacetylase and PPARγ receptor activators on proinflammatory (M1), anti-inflammatory (M2) polarization of RAW264.7 macrophages and their modulating effects on insulin sensitivity of adipocytes. In M1 macrophages, the expression of TNFα and CXCL9, secretion of CXCL11, ROS generation, and content of dendritic-like cells were elevated. In M2 macrophages, expression of IGF-1 and ALOX15 factors was enhanced. SIRT1 activator (DCHC) and PPARγ receptor ligand (rosiglitazone) reduced expression of inflammatory markers TNFα and CXCL9 and increased expression of IGF-1 and ALOX15. SIRT1 inhibitor Ex527 increased the proportion of dendritic cells in macrophage populations. The paracrine effect of M1-macrophage-conditioned media attenuated insulin-dependent phosphorylation of threonine (Thr308) in Akt kinase and enhanced phosphorylation of serine (Ser473). This effect was attenuated by DCHC and rosiglitazone.
Subject(s)
Adipocytes/drug effects , Adipocytes/metabolism , Inflammation/metabolism , Insulin/pharmacology , Macrophages/metabolism , Animals , Arachidonate 15-Lipoxygenase/metabolism , Carbazoles/pharmacology , Chemokine CXCL9/metabolism , Dendritic Cells/drug effects , Insulin-Like Growth Factor I/metabolism , Mice , PPAR gamma/metabolism , RAW 264.7 Cells , Rosiglitazone , Thiazolidinediones/pharmacology , Tumor Necrosis Factor-alpha/metabolismABSTRACT
Obesity and latent inflammation in adipose tissue significantly contribute to the development of insulin resistance (IR) and type 2 diabetes. Here we studied whether the antiinflammatory interleukin-4 (IL-4) can restore insulin sensitivity in cultured 3T3-L1 adipocytes. The activity of key components of the insulin signaling cascade was assessed by immunoblotting using phospho-specific antibodies to insulin receptor substrate IRS1 (Tyr612), Akt (Thr308 and Ser473), and AS160 (Ser318) protein that regulates translocation of the GLUT4 glucose transporter to the plasma membrane. IR was induced in mature adipocytes with albumin-conjugated palmitate. IR significantly reduced phosphorylation levels of all the above-mentioned proteins. Addition of IL-4 to the culturing medium during IR induction led to a dose-dependent stimulation of the insulin-promoted phosphorylation of IRS1, Akt, and AS160. At the optimal concentration of 50 ng/ml, IL-4 fully restored activation of the insulin cascade in IR cells, but it did not affect insulin signaling activation in the control cells. IL-4 neither upregulated expression of key adipogenesis markers GLUT4 and PPARγ nor caused lipid accumulation in the adipocytes. These results demonstrate that IL-4 can restore insulin sensitivity in adipocytes via mechanisms not associated with induced adipogenesis or de novo formation of lipid depots.