Lipocalin-2, a mitokine that mediates white to brown fat crosstalk

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Project Summary/Abstract One third of American adults are suffering from obesity. Obesity significantly contributes to the prevalence of numerous other life-threatening diseases, such as type 2 diabetes, cardiovascular diseases, cancers, etc. Although substantial resources have been invested to resolve this major public health threat, the fact is that, currently, only limited methods of pharmacological therapeutics have been developed to treat obesity. An in- depth understanding of the reasons for obesity is urgently needed to facilitate finding more effective therapeutics. There are two types of fat tissue in humans: white and brown adipose tissue. They have different morphologies and perform distinct functions. While white fat stores excessive energy in the form of lipids, brown fat consumes excessive energy through adaptive thermogenesis (i.e., generating heat). A common phenomenon in human obesity is the conversion of brown fat into white fat, a process identified as whitening. Reversing brown fat whitening activates brown fat function and exerts anti-obesity effects. The overarching goal of this study is to investigate the role of lipocalin 2 (LCN-2), a potential factor that promotes brown fat whitening. The applicant recently performed a series of screenings in his adipocyte mitochondrial dysfunction model. LCN-2 was suggested to be a leading factor that drives the white to brown adipose tissue crosstalk to induce brown fat whitening. Therefore, this proposal is set out to evaluate the central hypotheses: LCN-2, a secreting factor from the white fat, is induced by mitochondrial distress and promotes brown fat whitening. In Aim 1, cell culture systems (in vitro) will be utilized to demonstrate that LCN-2 is required in brown fat whitening. In Aim 2, evidence from mice (in vivo) will be provided to further evaluate the role of LCN-2 in brown fat whitening and metabolic consequences (i.e., cold intolerance and obesity). This study will fill a knowledge gap through defining a novel whitening factor in understanding how the brown adipose tissue becomes whitened. Furthermore, this study has translational merits because either neutralization of LCN-2 per se or inhibition of the LCN-2 receptor holds an enormous potential to ameliorate brown AT whitening and, in turn, to identify innovative therapeutics that alleviate obesity.