Lipocalin 2 in inflammation and metabolic control

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DESCRIPTION (provided by applicant): Adipose tissue undergoes remodelling during metabolic adaptations, which is essential for maintaining metabolic homeostasis. The dysregulation of this process has been associated with adipose tissue dysfunction, inflammation, and insulin resistance in obesity. The metabolic activation of brown adipose tissue (BAT) and the recruitment of brown adipocytes in white adipose tissue (WAT) are the important components of the remodelling process under certain physiological conditions such as cold stress and adrenergic stimulation. BAT activation in adult humans and WAT browning has recently gained great recognitions for their role in combating obesity. However, we are far from a full understanding of how this remodelling process is regulated and what factors are involved. Our lab has been characterizing metabolic functions of lipocalin 2 (Lcn2), a newly identified adipokine preferentially abundant in WAT. We have discovered that Lcn2 is a critical regulator of adaptive thermogenesis playing an important role in insulin resistance, dyslipidemia, and fatty liver disease. Lcn2 deficiency led to markedly impaired BAT thermogenic activation by cold exposure and reduced BAT activity and browning of WAT during high fat diet-induced obesity. In addition, we have identified that Lcn2, as a potential circulating retinoid acid (RA) biding protein, is essential for RA action in adipose tissue. We hypothesize that Lcn2 plays a key role in regulating energy expenditure via a peripheral pathway involving BAT activation and WAT browning. WAT is the major source of circulating Lcn2 modulating RA action on thermogenic activity in BAT and WAT. Four specific aims are proposed to test the hypothesis. Aim 1 determines the role of Lcn2 in retinoid metabolism and the delivery and uptake of circulating RA to adipose tissue in mouse and cell models. Aim 2 establishes the role of Stra1 (stimulated by retinoic acid gene 1) as a cell surface receptor for Lcn2 in mediating cellular RA uptake in adipocytes using gain- and loss-of-function approaches. Aim 3 assesses the contribution of adipose-derived Lcn2 to BAT thermogenic activation during metabolic adaptations. Aim 4 assesses the contribution of adipose-derived Lcn2 to the browning of WATs and energy expenditure during metabolic adaptations. This study will identify and establish Lcn2 as a novel circulating RA binding protein that controls RA delivery and uptake, thereby action of RA on BAT and WAT thermogenic activation and energy expenditure.