Abstract

Skeletal muscle resistance is a major contributor to the hyperglycemia, hyperinsulinemia and dyslipidemia associated with type II diabetes and obesity. Recent work has implicated leptin, the adipocyte-derived hormone, in improving insulin sensitivity. Thus, leptin administration to leptin-deficient ob/ob mice corrects hyperglycemia and hyperinsulinemia, while elevating leptin in normal rats increases insulin sensitivity. Based on these observations the effects of leptin on the metabolic abnormalities of the high-fat fed rat, a model of diet-induced obesity that more closely resembles human obesity than monogenetic obesity models, were investigated. These studies, performed by the P.I. and discussed in this proposal, demonstrate that a gene therapy intervention that elevates plasma leptin levels reverses the skeletal muscle insulin resistance and other metabolic abnormalities associated with diet-induced obesity. However, the mechanisms underlying these effects are unknown. This proposal, therefore, focuses on identification of the mechanisms underlying leptin-induced reversal of skeletal muscle insulin resistance in diet-induced obesity.
Three specific aims will test the hypotheses that skeletal muscle insulin resistance by leptin. These variables have been implicated in the pathogenesis of insulin resistance and the determination of muscle insulin sensitivity, and are altered by leptin. Identification of the mechanisms mediating leptin-induced reversal of muscle insulin resistance may serve as a platform for the rational design of pharmaceutical or genetic therapy of insulin resistance in human obesity and type II diabetes.
Specific Aims : 1. To determine the role of altered lipid metabolism in mediating leptin-induced improvements in insulin sensitivity. 2. To determine the role of altered activity of the insulin signaling pathway in mediating leptin-induced improvements in insulin sensitivity. 3. To determine the role of altered metabolic gene expression in mediating leptin-induced improvements in insulin sensitivity.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK058855-03
Application #
6628600
Study Section
Endocrinology Study Section (END)
Program Officer
Laughlin, Maren R
Project Start
2001-02-15
Project End
2005-01-31
Budget Start
2003-02-01
Budget End
2004-01-31
Support Year
3
Fiscal Year
2003
Total Cost
$217,831
Indirect Cost

  Institution

Name
University of Pittsburgh
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213

  Publications

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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