Lipocalin-2 deficiency may predispose to the progression of spontaneous age-related adiposity in mice

Abstract

Lipocalin-2 (Lcn2) is an innate immune protein elevated by several orders of magnitude in various inflammatory conditions including aging and obesity. Recent studies have shown that Lcn2 is secreted by adipocytes in response to inflammation and is categorized as a new adipokine cross-linking innate immunity and metabolic disorders including obesity. However, the involvement of Lcn2 and its function during the progression of obesity is largely unknown. Recently, browning of white adipose tissue (WAT) has gained attention as a therapeutic strategy to combat obesity. Herein, we have shown that treatment of mature 3T3-L1 adipocytes with recombinant Lcn2 (rec-Lcn2) resulted in the up-regulation of thermogenic and beige/brown markers (UCP1, PRDM16, ZIC-1 and TBX1) and increased mitochondrial activity. Additionally, global Lcn2 genetic knockout (Lcn2KO) mice exhibited accelerated weight gain and visceral fat deposition with age, when compared to wild type (WT) mice. Taken together, both in vitro and in vivo studies suggest that Lcn2 is a naturally occurring adipokine, and may serve as an anti-obesity agent by upregulating the thermogenic markers resulting in the browning of WAT. Therefore, Lcn2 and its downstream signaling pathways could be a potential therapeutic target for obesity. Obesity is a chronic low-grade inflammatory disorder. With nearly 40% of the adult population in the United States being obese, it is no longer just a problem of uncontrolled weight gain but considered as a chronic disease of epidemic proportions. Obesity increases the risk of several disorders, including type-2 diabetes, cardiovascular disease, stroke and bone loss 1. The expense of treating obesity-related illnesses is also increasing and now accounts for nearly 28% of total health-care costs 2. It is estimated that obesity treatment costs between $147 and 210 billion per year, with another $4.3 billion in lost productivity 3-5. Despite the global burden of the disease, there are limited FDA approved anti-obesity drugs available and their use is tempered by significant adverse side effects 6-8. As obesity is now a national epidemic, there is a critical need for the development of anti-obesity drugs with fewer side effects. Adipose tissue plays a vital role in regulating the metabolic disorders and inflammation. White adipose tissue (WAT) primarily functions as an energy storage unit and is a source for inflammatory mediators 9-12. Dysfunction of WAT leads to progression of obesity and its related metabolic disorders 13. Recent studies have shown that conversion of WAT to brown-like beige adipose tissue, known as browning of WAT, is a promising target for the treatment of obesity and associated metabolic and inflammatory disorders 13. Browning of WAT, accompanied by increased mitochondrial activity and thermogenesis, has been reported to decrease weight gain in the high fat diet (HFD) fed obese mouse models 14. More recently, lipocalin 2 (Lcn2) is categorized as a new adipokine secreted by various cell types including adipocytes. It has al...

Neural Mechanisms of Cancer Cachexia

“…The literature also demonstrates nutrition-independent metabolic effects of LCN2, as white adipose expression of lcn2 was demonstrated to activate brown adipose tissue (BAT) via a norepinephrineindependent pathway, as BAT from lcn2-KO mice is less thermogenically active [96]. A recent report by Meyers and colleagues expanded upon this notion of Lcn2 activating thermogenic programs using an in vitro approach, demonstrating exogenous Lcn2 increases beiging (Tbx1 and Zic1) and thermogenic markers (Ucp1 and Ppar-γ) in cultured 3T3-L1 adipocyte cells [97]. Since LCN2 is demonstrated to mediate appetite and fat metabolism, two important components of cancer cachexia, our lab sought to address if LCN2 influences any of the signs or symptoms of cancer cachexia.…”

Recent advances and future avenues in understanding the role of adipose tissue cross talk in mediating skeletal muscle mass and function with ageing

“…On the other hand, it has recently been argued that rather than being causal of metabolic dysfunction, elevated Lcn2 may instead provide a protective mechanism to mitigate obesity-induced dysregulation and preserve pancreatic β-cell function [210]. Indeed, global Lcn2 knockout in mice was recently shown to accelerate age-dependent weight gain and visceral fat deposition in female mice, although curiously this was not the case in male mice [211].…”

Transcriptome study digs out BMP2 involved in adipogenesis in sheep tails

“…CPT2 was also identified with RNA-seq in Lori-Bakhtiari and Zel sheep [ 2 ]. LCN2 may act as an anti-obesity agent by upregulating thermogenic markers, leading to browning in white adipose tissue [ 43 ]. PPARGC1A plays a role in stimulating mitochondrial biogenesis and regulating glucose and fatty acid metabolism [ 44 , 45 ].…”