The association of chronic low grade inflammation with obesity and type II diabetes is now well established. Moreover, substantial evidence now suggests a link between elevated inflammatory status and the pathogenesis of insulin resistance. Thus, interventions that decrease or prevent specific inflammatory responses improve insulin sensitivity. Based on their importance to understanding the pathogenesis and treatment of insulin resistance, we are currently concentrating our efforts on the identification of mechanisms that may initiate inflammatory responses in obesity. Our work has concentrated on one of these putative mechanisms, namely hyperlipidemia. We have established that one of the principal inflammatory pathways (IKK/IkappaB/NF-kappaB) is activated by saturated fatty acids in skeletal muscle and in preliminary data we demonstrate that one mechanism of action of fatty acids on the IKK/IkappaB/NF-kappaB (NF-kappaB) pathway is to stimulate toll-like receptor (TLR) activity. This work has established one biochemical link between lipids, inflammatory pathway activity and a proximal mediator of the innate immune response (TLR's). The hypothesis to be tested in the current proposal is simply that TLR's play a role in vivo in initiating and maintaining the inflammatory response and associated insulin resistance in obesity, and that one possible driving force of TLR activation is hyperlipidemia. These experiments will increase our understanding of the role of hyperlipidemia in activation of inflammatory pathways, the role of TLR's in mediating the effects of lipids, and the relationship between elevated inflammatory responses and the pathogenesis of insulin resistance. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK058855-06
Application #
7266224
Study Section
Cellular Aspects of Diabetes and Obesity Study Section (CADO)
Program Officer
Laughlin, Maren R
Project Start
2001-02-15
Project End
2010-05-31
Budget Start
2007-06-01
Budget End
2008-05-31
Support Year
6
Fiscal Year
2007
Total Cost
$274,777
Indirect Cost
Name
University of Pittsburgh
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Gusdon, Aaron M; Callio, Jason; Distefano, Giovanna et al. (2017) Exercise increases mitochondrial complex I activity and DRP1 expression in the brains of aged mice. Exp Gerontol 90:1-13
Krishna, Kanthi B; Stefanovic-Racic, Maja; Dedousis, Nikolaos et al. (2016) Similar degrees of obesity induced by diet or aging cause strikingly different immunologic and metabolic outcomes. Physiol Rep 4:
Jiang, Mengxi; He, Jinhan; Kucera, Heidi et al. (2014) Hepatic overexpression of steroid sulfatase ameliorates mouse models of obesity and type 2 diabetes through sex-specific mechanisms. J Biol Chem 289:8086-97
Murphy, Eileen F; Cotter, Paul D; Hogan, Aileen et al. (2013) Divergent metabolic outcomes arising from targeted manipulation of the gut microbiota in diet-induced obesity. Gut 62:220-6
Stefanovic-Racic, Maja; Yang, Xiao; Turner, Michael S et al. (2012) Dendritic cells promote macrophage infiltration and comprise a substantial proportion of obesity-associated increases in CD11c+ cells in adipose tissue and liver. Diabetes 61:2330-9
Mantell, Benjamin S; Stefanovic-Racic, Maja; Yang, Xiao et al. (2011) Mice lacking NKT cells but with a complete complement of CD8+ T-cells are not protected against the metabolic abnormalities of diet-induced obesity. PLoS One 6:e19831
Huang, Wan; Metlakunta, Anantha; Dedousis, Nikolaos et al. (2010) Depletion of liver Kupffer cells prevents the development of diet-induced hepatic steatosis and insulin resistance. Diabetes 59:347-57
Murphy, E F; Cotter, P D; Healy, S et al. (2010) Composition and energy harvesting capacity of the gut microbiota: relationship to diet, obesity and time in mouse models. Gut 59:1635-42
Huang, Wan; Metlakunta, Anantha; Dedousis, Nikolas et al. (2009) Leptin augments the acute suppressive effects of insulin on hepatic very low-density lipoprotein production in rats. Endocrinology 150:2169-74
Liang, Huiyun; Balas, Bogdan; Tantiwong, Puntip et al. (2009) Whole body overexpression of PGC-1alpha has opposite effects on hepatic and muscle insulin sensitivity. Am J Physiol Endocrinol Metab 296:E945-54

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