Lipocalin 2 (Lcn2) is a recently identified adipose tissue-derived cytokine which functions in innate immunity, inflammation, and insulin resistance. Nonetheless, the metabolic regulation and function of adipose Lcn2 is not completely understood. Herein, we investigated how adipose Lcn2 expression is regulated by metabolic challenges and nutrient signals, as well as how Lcn2 deficiency affects whole-body energy metabolism and lipid homeostasis. We found that Lcn2 mRNA expression was significantly upregulated during fasting and cold exposure in mice. Insulin stimulated Lcn2 expression and secretion in 3T3-L1 adipocytes in a dose-dependent manner, which was enhanced by glucose and attenuated by aspirin treatment. Multiple fatty acids also induced Lcn2 expression and secretion in adipocytes. The regulation of adipose Lcn2 by metabolic challenges and nutrient signals indicated a potential role of Lcn2 in energy metabolism. Next, we explored the metabolic consequences of Lcn2 deficiency in mice under high fat diet (HFD) conditions. We found that Lcn2 deficiency potentiated diet-induced obesity, dyslipidemia, fatty liver disease, and insulin resistance in mice. Moreover, Lcn2 knockout (KO) mice exhibited impaired adaptive thermogenesis and cold intolerance. Further studies showed that Lcn2 deficiency reduced the efficiency of cold-induced mitochondrial oxidation of lipids and blunted cold-induced activation of Uncoupling Protein 1 and expression of thermogenic and angiogenic genes, leading to lipid accumulation and thermogenic dysfunction of brown adipocytes. Interestingly, the administration of PPARgamma agonist effectively improved HFD-induced insulin resistance in Lcn2 KO mice without increasing body weight, subcutaneous fat mass, or lipid accumulation in liver. PPARgamma agonist administration also fully prevented cold-intolerant phenotype in Lcn2 KO mice. Our results indicate that Lcn2 plays a critical role in the regulation of lipid homeostasis and thermogenic activation via a possible mechanism of modulating PPARgamma activation.
University of Minnesota Ph.D. dissertation. March 2013. Major: Nutrition. Advisor: Dr. Xiaoli Chen. 1 computer file (PDF); viii, 167 pages.
Understanding the role of Lipocalin 2 as an important regulator of energy metabolism.
Retrieved from the University of Minnesota Digital Conservancy,
Content distributed via the University of Minnesota's Digital Conservancy may be subject to additional license and use restrictions applied by the depositor.