LIPID METABOLISM IN FAT CELLS
Principal Investigator: Wen Guo
Abstract: Obesity is a major health problem that predisposes to type 2 diabetes and other serious conditions. A more complete understanding of how fat synthesis is regulated in adipocytes is critical to guide rational development of new approaches for treating obesity and its complications. In the last grant period, we demonstrated that medium-chain fatty acids (octanoate) stimulate beta-oxidation and inhibit triglyceride synthesis in adipocytes, mimicking some of the metabolic effects of fasting. Analogous anti-lipogenic effects have been found in adipocytes treated with TNFalpha. We demonstrated that the three stressors,fasting in vivo, octanoate, and TNFalpha in vitro, induce many of the same cellular responses. These include increased generation of reactive oxidative species (ROS), activation of MAP-kinases (MARK) and AMP- activated protein kinase (AMPK), and decreased expression of the nuclear transcription factor PPARgamma and associated lipogenic genes. In light of these findings, we plan to use these three stressorsto manipulate lipogenesis in adipocytes to dissect mechanisms of regulation. We hypothesize that critical signals (ROS or ROS-independent) are generatedas a result of increased beta-oxidation.These signaling molecules activate stress-responsive kinases, which inactivate PPARgamma,attenuating expression of genes necessary for fat synthesis. To test this hypothesis, we propose the following specific aims: (1) to determine whether ROS is crucial for regulation of lipogenesis;(2) to test if changes in beta-oxidation generate critical signals that cause inactivation of PPARgamma;and (3) to determine if PPARgamma is the point at which signals converge that control stress-induced anti-lipogenic effects, what is the mechanism of PPARgamma inactivation, and which metabolic genes are most sensitive to the stress manipulation. Each aim will be addressed with comprehensive and integratedapplication of cell biology and molecular biology in combination with metabolic and biochemical approaches, using culture murine and human adipocytes as well as rodent models. Together, these studies will provide new insights into the stress-induced regulation of lipogenesis in adipocytes, a potentially important avenue for modulating energy balance.
Funding Period: ----------------2000 - ---------------2010-
more information: NIH RePORT
- Fatty acid transport and metabolism in HepG2 cellsWen Guo
Department of Physiology and Biophysics, Boston University School of Medicine, Boston, MA 02118, USA
Am J Physiol Gastrointest Liver Physiol 290:G528-34. 2006..Our results show that natural fatty acids rapidly bind to, and diffuse through, the plasma membrane without hindrance by metabolic inhibitors or by an inhibitor of putative membrane-bound fatty acid transporters...
- AAV-mediated administration of myostatin pro-peptide mutant in adult Ldlr null mice reduces diet-induced hepatosteatosis and arteriosclerosisWen Guo
Department of Medicine, Boston University School of Medicine, Boston, Massachusetts, USA
PLoS ONE 8:e71017. 2013..Cultured aortic endothelial cells responded to myostatin with a reduction in eNOS phosphorylation and an increase in ICAM-1 and VCAM-1 expression...
- Effects of dihydrotestosterone on differentiation and proliferation of human mesenchymal stem cells and preadipocytesVandana Gupta
Department of Medicine, Boston University, School of Medicine, Boston Medical Center, Boston, MA 02118, USA
Mol Cell Endocrinol 296:32-40. 2008..DHT stimulated forskolin-stimulated lipolysis in subcutaneous and mesenteric preadipocytes and inhibited incorporation of fatty acid into triglyceride in adipocytes differentiated from preadipocytes from all fat depots...
- The effects of myostatin on adipogenic differentiation of human bone marrow-derived mesenchymal stem cells are mediated through cross-communication between Smad3 and Wnt/beta-catenin signaling pathwaysWen Guo
Section of Endocrinology, Diabetes, and Nutrition, Boston University School of Medicine, Boston Medical Center, 670 Albany Street, Boston, MA 02118, USA
J Biol Chem 283:9136-45. 2008..These effects were mediated, in part, by activation of Smad3 and cross-communication of the TGFbeta/Smad signal to Wnt/beta-catenin/TCF4 pathway, leading to down-regulation of PPARgamma...
- Oleate-induced formation of fat cells with impaired insulin sensitivityWeisheng Xie
Obesity Research Center, Boston University School of Medicine, Boston, Massachusetts 02118, USA
Lipids 41:267-71. 2006....
- DNA extraction procedures meaningfully influence qPCR-based mtDNA copy number determinationWen Guo
Department of Internal Medicine, Boston University School of Medicine, Section of Endocrinology, Boston, MA 02118, USA
Mitochondrion 9:261-5. 2009..We conclude genomic DNA sample preparation can meaningfully influence mtDNA copy number determination by qPCR...
- Acipimox, an inhibitor of lipolysis, attenuates atherogenesis in LDLR-null mice treated with HIV protease inhibitor ritonavirWen Guo
Section of Endocrinology, Boston University School of Medicine, 670 Albany Street, Second Floor, Boston, MA 02118, USA
Arterioscler Thromb Vasc Biol 29:2028-32. 2009..The purpose of this study was to test the hypothesis that inhibition of adipose lipolysis will retard atherogenic lesion development induced by the antiviral protease inhibitors...
- Respiration in adipocytes is inhibited by reactive oxygen speciesTong Wang
Obesity Research Center, Department of Medicine, Boston University School of Medicine, Boston, Massachusetts, USA
Obesity (Silver Spring) 18:1493-502. 2010..Stimulating fuel oxidation in adipocytes by decreasing ROS may provide a novel means to shift the balance from fuel storage to fuel burning...
- High glucose disrupts mitochondrial morphology in retinal endothelial cells: implications for diabetic retinopathyKyle Trudeau
Department of Medicine, Boston University School of Medicine, 650 Albany Street, Boston 02118, USA
Am J Pathol 177:447-55. 2010....
- High glucose induces mitochondrial morphology and metabolic changes in retinal pericytesKyle Trudeau
Department of Medicine, Boston University School of Medicine, Boston, Massachusetts 02118, USA
Invest Ophthalmol Vis Sci 52:8657-64. 2011..In this study, the effects of HG on mitochondrial morphology, membrane potential, and metabolic changes and whether they could contribute to HG-induced apoptosis in retinal pericytes were investigated...
- Genetic disruption of myostatin reduces the development of proatherogenic dyslipidemia and atherogenic lesions in Ldlr null micePowen Tu
Department of Molecular Medicine, Boston University School of Medicine, Boston, Massachusetts, USA
Diabetes 58:1739-48. 2009..In this study, we determined whether Mstn disruption could prevent the development of insulin resistance, proatherogenic dyslipidemia, and atherogenesis...