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The Role of Lipocalin 2 in White Adipose Tissue Beiging and Metabolic Healthspan
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The Role of Lipocalin 2 in White Adipose Tissue Beiging and Metabolic Healthspan
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Dissertation
The Role of Lipocalin 2 in White Adipose Tissue Beiging and Metabolic Healthspan
2017
Overview
Adipose tissue dysfunction in response to obesity or aging is a major underlying factor in the development of metabolic diseases. Therefore, identifying mechanisms that promote adipose tissue health in the face of metabolic challenges is essential for preventing further deterioration of whole-body metabolic homeostasis. Lipocalin 2 (Lcn2) is an adipose tissue-derived secreted protein that has previously been shown to play a role in diet-induced obesity, metabolic disease, and brown adipose tissue (BAT) thermogenesis. This thesis project addresses two main questions: 1) whether Lcn2 regulates thermogenic activation, or beiging, of inguinal white adipose tissue (iWAT) and 2) whether overexpression of Lcn2 promotes whole-body metabolic homeostasis and healthspan. In the first project, we found Lcn2 deficient inguinal adipocytes have decreased expression of thermogenic genes and reduced mitochondrial capacity under basal conditions. Further, Lcn2 is necessary for retinoic acid (RA) induction of beiging markers in inguinal adipocytes, particularly in the presence of insulin. Lcn2 is required for insulin-stimulated localization of the retinoic acid receptor-alpha (RAR-) to the plasma membrane. Together, this suggests Lcn2 promotes RA-induced thermogenesis, possibly through regulation of RAR- at the plasma membrane. In the second project, we further investigated the role of Lcn2 in WAT beiging and energy metabolism in vivo. Utilizing an ap2-promoter-driven Lcn2 transgenic (Tg) mouse model, we determined whether overexpression of Lcn2 in adipose tissue is sufficient to promote beiging/thermogenesis. We found overexpression of Lcn2 in adipose tissue leads to improved cold adaptation and an increase in beiging markers in iWAT, including uncoupling protein 1 (Ucp1) gene expression. Lcn2 Tg mice had a trend towards increased fat utilization, alongside increased oxidative gene expression and decreased adipocyte size in iWAT. In the third project, we investigated the role of Lcn2 in adipose tissue function and metabolic healthspan. We determined whether overexpression of Lcn2 in adipose tissue can prevent the age-associated decline in adipogenesis, serum metabolic parameters, and liver function. Following aging, Lcn2 Tg mice maintained higher levels of adipogenic markers and reduced adipocyte size in iWAT relative to WT mice, suggesting improved adipose tissue health. Aged Lcn2 Tg mice had decreased serum triglycerides, significantly better maintenance of glucose tolerance, and protection from liver lipid accumulation resulting in decreased markers of liver inflammation and steatosis. In conclusion, Lcn2 has a novel role in promoting WAT beiging and adipose tissue health, protecting against age-related metabolic deterioration, and improving metabolic healthspan.
