Obesity is a major risk for developing insulin resistance and metabolic diseases. Adipose tissue plays a critical role as an endocrine organ and a major source of chronic low-grade inflammation in the regulation of insulin action and energy metabolism. Dysfunctional adipose tissue characterized by abnormal production of adipokines/cytokines has been linked to obesity and its associated inflammation, insulin resistance, and metabolic dysregulation. However, which adipokines/cytokines mediate this linkage and the mechanisms involved during obesity remain largely unknown. Lack of such knowledge is a critical problem as it is the key to solve the molecular puzzle of obesity and its related metabolic syndrome. Our long-term goal is to elucidate the role and mechanisms of adipose-derived factors in the regulation of inflammation and metabolic homeostasis. Through the proteomics and microarray screening, we recently identified lipocalin 2 (LCN2) as a new adipokine that potentially connects obesity and insulin resistance. LCN2 belongs to the lipocalin subfamily members that are small secreted proteins with a structural similarity to fatty acid binding proteins (FABPs) and the ability to bind small hydrophobic molecules such as FFA and retinoic acid (RA). LCN2 promoter possesses NF-(B and C/EBP binding sites and glucocorticoid response element;and LCN2 secretion is highly regulated by LPS and TNF(. In our previous studies, the level of LCN2 expression is up-regulated in adipose tissue and liver of genetically obese animals. This increase is significantly reversed by TZD administration. LCN2 appears to potentiate insulin action and antagonize TNF( effects on glucose metabolism, PPAR( gene expression and insulin resistance in 3T3- L1 adipocytes. Moreover, LCN2 suppresses TNF(- and LPS-induced cytokine/chemokine production in adipocytes as well as macrophages. Most strikingly, LCN2 regulates the adipocyte production of leptin and adiponectin. Our results lead to the hypothesis that LCN2 homeostatically regulates inflammatory response and insulin action in adipocytes by a negative feedback regulatory mechanism, and that LCN2 deficiency causes a proinflammatory state, dysregulation of adipose secretion, and ultimately systemic insulin resistance. We further hypothesize that LCN2 exerts its biological functions in adipocytes via the ligand binding and receptor-mediated transport mechanism. This proposal uses LCN2 null mice, LCN2 knockdown 3T3-L1 adipocytes, and mutants of LCN2 that lack ligand binding ability to test three specific aims.
Aim 1 investigates the regulation of LCN2 in inflammation, insulin action, adipocyte metabolism, and adipokine/cytokine production.
Aim 2 defines the ligand binding and functional properties of LCN2.
Aim 3 assesses the impact of LCN2 deficiency on inflammatory response, insulin action, and metabolic homeostasis in mice.

Public Health Relevance

Increasing evidence supports the role of adipose tissue inflammation, lipid metabolic defects, and endocrine dysfunction in obesity and insulin resistance. This proposal aims at identifying and characterizing the role and mechanism of lipocalin 2, a new adipose-derived factor, in the regulation of inflammation, insulin action, and adipocyte lipid/glucose metabolism in cell-based as well as animal studies. The knowledge obtained will provide the key to solve the molecular puzzle of obesity and lead to the identification of novel strategies for preventive and therapeutic interventions.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK080743-05
Application #
8245172
Study Section
Cellular Aspects of Diabetes and Obesity Study Section (CADO)
Program Officer
Haft, Carol R
Project Start
2008-04-01
Project End
2013-03-31
Budget Start
2012-04-01
Budget End
2013-03-31
Support Year
5
Fiscal Year
2012
Total Cost
$284,014
Indirect Cost
$87,994
Name
University of Minnesota Twin Cities
Department
Nutrition
Type
Schools of Earth Sciences/Natur
DUNS #
555917996
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
Zhang, Yuanyuan; Foncea, Rocio; Deis, Jessica A et al. (2014) Lipocalin 2 expression and secretion is highly regulated by metabolic stress, cytokines, and nutrients in adipocytes. PLoS One 9:e96997
Zhang, Yuanyuan; Guo, Hong; Deis, Jessica A et al. (2014) Lipocalin 2 regulates brown fat activation via a nonadrenergic activation mechanism. J Biol Chem 289:22063-77
Guo, Hong; Jin, Daozhong; Chen, Xiaoli (2014) Lipocalin 2 is a regulator of macrophage polarization and NF-?B/STAT3 pathway activation. Mol Endocrinol 28:1616-28
Guo, Hong; Bazuine, Merlijn; Jin, Daozhong et al. (2013) Evidence for the regulatory role of lipocalin 2 in high-fat diet-induced adipose tissue remodeling in male mice. Endocrinology 154:3525-38
Hannaford, Jennifer; Guo, Hong; Chen, Xiaoli (2013) Involvement of cathepsins B and L in inflammation and cholesterol trafficking protein NPC2 secretion in macrophages. Obesity (Silver Spring) 21:1586-95
Guo, Hong; Zhang, Yuanyuan; Brockman, David A et al. (2012) Lipocalin 2 deficiency alters estradiol production and estrogen receptor signaling in female mice. Endocrinology 153:1183-93
Jin, Daozhong; Zhang, Yuanyuan; Chen, Xiaoli (2011) Lipocalin 2 deficiency inhibits cell proliferation, autophagy, and mitochondrial biogenesis in mouse embryonic cells. Mol Cell Biochem 351:165-72
Zhang, Yuanyuan; Chen, Xiaoli (2011) Reducing selenoprotein P expression suppresses adipocyte differentiation as a result of increased preadipocyte inflammation. Am J Physiol Endocrinol Metab 300:E77-85
Jin, Daozhong; Guo, Hong; Bu, So Young et al. (2011) Lipocalin 2 is a selective modulator of peroxisome proliferator-activated receptor-gamma activation and function in lipid homeostasis and energy expenditure. FASEB J 25:754-64
Guo, Hong; Jin, Daozhong; Zhang, Yuanyuan et al. (2010) Lipocalin-2 deficiency impairs thermogenesis and potentiates diet-induced insulin resistance in mice. Diabetes 59:1376-85

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