Lipocalin-2 derived from adipose tissue mediates aldosterone-induced renal injury

Sun, Wenxue; Bai, Bo; Luo, Cuiting; Yang, Keli; Li, Dahui; Wu, Donghai; Félétou, Michel; Villeneuve, Nicole; Zhou, Yang; Yang, Junwei; Xu, Aimin; Vanhoutte, Paul M.; Wang, Yudong

doi:10.1172/jci.insight.120196

Cited by 26 publications

(29 citation statements)

References 89 publications

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“…They also demonstrate that incubating recombinant LCN2 with adipose tissues (≥16hr incubation) from LCN2KO mice resulted in removal of polyamination [65]. Further, the same group demonstrated that adipose-derived LCN2 can also mediate both acute and chronic renal injuries and that this is independent of kidney-derived LCN2 [67]. In contrast, cell-type-resolved liver proteomics revealed that LCN2 is predominantly secreted by Kupffer cells (hepatic macrophages) and not the hepatocytes, implying that increased LCN2 expression in the liver signifies an inflammatory environment in response to obesity [68].…”

Section: Resultsmentioning

confidence: 99%

Sex-specific metabolic functions of adipose Lipocalin-2

Krishnan

Sabir

Shum

et al. 2019

Molecular Metabolism

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ObjectiveLipocalin-2 (LCN2) is a secreted protein involved in innate immunity and has also been associated with several cardiometabolic traits in both mouse and human studies. However, the causal relationship of LCN2 to these traits is unclear, and most studies have examined only males.MethodsUsing adeno-associated viral vectors we expressed LCN2 in either adipose or liver in a tissue specific manner on the background of a whole-body Lcn2 knockout or wildtype mice. Metabolic phenotypes including body weight, body composition, plasma and liver lipids, glucose homeostasis, insulin resistance, mitochondrial phenotyping, and metabolic cage studies were monitored.ResultsWe studied the genetics of LCN2 expression and associated clinical traits in both males and females in a panel of 100 inbred strains of mice (HMDP). The natural variation in Lcn2 expression across the HMDP exhibits high heritability, and genetic mapping suggests that it is regulated in part by Lipin1 gene variation. The correlation analyses revealed striking tissue dependent sex differences in obesity, insulin resistance, hepatic steatosis, and dyslipidemia. To understand the causal relationships, we examined the effects of expression of LCN2 selectively in liver or adipose. On a Lcn2-null background, LCN2 expression in white adipose promoted metabolic disturbances in females but not males. It acted in an autocrine/paracrine manner, resulting in mitochondrial dysfunction and an upregulation of inflammatory and fibrotic genes. On the other hand, on a null background, expression of LCN2 in liver had no discernible impact on the traits examined despite increasing the levels of circulating LCN2 more than adipose LCN2 expression. The mechanisms underlying the sex-specific action of LCN2 are unclear, but our results indicate that adipose LCN2 negatively regulates its receptor, LRP2 (or megalin), and its repressor, ERα, in a female-specific manner and that the effects of LCN2 on metabolic traits are mediated in part by LRP2.ConclusionsFollowing up on our population-based studies, we demonstrate that LCN2 acts in a highly sex- and tissue-specific manner in mice. Our results have important implications for human studies, emphasizing the importance of sex and the tissue source of LCN2.

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Section: Resultsmentioning

confidence: 99%

Sex-specific metabolic functions of adipose Lipocalin-2

Krishnan

Sabir

Shum

et al. 2019

Molecular Metabolism

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“…It is produced by adipocytes at high levels in mice and humans in response to inflammatory stimuli and the impact of age on this proinflammatory adipokine is unknown ( 95 , 96 ). However, adipose tissue-derived LCN2 has been shown to promote the pathogenesis of renal injury, a condition that is more prevalent in aged individuals with type 2 diabetes ( 97 , 98 ). In addition, it may also play an important proinflammatory role in adipose tissue remodeling during visceral fat expansion ( 99 ).…”

Section: Effects Of Aging On Adipose Tissue Adipokine Secretionmentioning

confidence: 99%

The Impact of Aging on Adipose Function and Adipokine Synthesis

2019

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During the last 40 years, there has been a world-wide increase in both the prevalence of obesity and an increase in the number of persons over the age of 60 due to a decline in deaths from infectious disease and the nutrition transition in low and middle income nations. While the increase in the elderly population indicates improvements in global public health, this population may experience a diminished quality of life due to the negative impacts of obesity on age-associated inflammation. Aging alters adipose tissue composition and function resulting in insulin resistance and ectopic lipid storage. A reduction in brown adipose tissue activity, declining sex hormones levels, and abdominal adipose tissue expansion occur with advancing years through the redistribution of lipids from the subcutaneous to the visceral fat compartment. These changes in adipose tissue function and distribution influence the secretion of adipose tissue derived hormones, or adipokines, that promote a chronic state of low-grade systemic inflammation. Ultimately, obesity accelerates aging by enhancing inflammation and increasing the risk of age-associated diseases. The focus of this review is the impact of aging on adipose tissue distribution and function and how these effects influence the elaboration of pro and anti-inflammatory adipokines.

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“…As such, increased circulating LCN2 is often used as a pathological biomarker such as acute kidney injury [ 102 ]. In pathological conditions, it was shown that two other forms of LCN2—R81E and deamidated LCN2—were expressed at least in WAT [ 95 , 103 ]. Thus, pathological forms of LCN2 probably display diverse ligand-binding and post-translation modifications, depending on the different tissue/cell sources, further complicating their causal roles in acute and chronic diseases.…”

Section: Chronic Inflammation During the Development Of Type 2 Diabetmentioning

confidence: 99%

Roles of bone-derived hormones in type 2 diabetes and cardiovascular pathophysiology

Lin

Onda

Yang

et al. 2020

Molecular Metabolism

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Background Emerging evidence demonstrates that bone is an endocrine organ capable of influencing multiple physiological and pathological processes through the secretion of hormones. Recent research suggests complex crosstalk between the bone and other metabolic and cardiovascular tissues. It was uncovered that three of these bone-derived hormones—osteocalcin, lipocalin 2, and sclerostin—are involved in the endocrine regulations of cardiometabolic health and play vital roles in the pathophysiological process of developing cardiometabolic syndromes such as type 2 diabetes and cardiovascular disease. Chronic low-grade inflammation is one of the hallmarks of cardiometabolic diseases and a major contributor to disease progression. Novel evidence also implicates important roles of bone-derived hormones in the regulation of chronic inflammation. Scope of review In this review, we provide a detailed overview of the physiological and pathological roles of osteocalcin, lipocalin 2, and sclerostin in cardiometabolic health regulation and disease development, with a focus on the modulation of chronic inflammation. Major conclusions Evidence supports that osteocalcin has a protective role in cardiometabolic health, and an increase of lipocalin 2 contributes to the development of cardiometabolic diseases partly via pro-inflammatory effects. The roles of sclerostin appear to be complicated: It exerts pro-adiposity and pro-insulin resistance effects in type 2 diabetes and has an anti-calcification effect during cardiovascular disease. A better understanding of the actions of these bone-derived hormones in the pathophysiology of cardiometabolic diseases will provide crucial insights to help further research develop new therapeutic strategies to treat these diseases.

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Lipocalin-2 derived from adipose tissue mediates aldosterone-induced renal injury

Cited by 26 publications

References 89 publications

Sex-specific metabolic functions of adipose Lipocalin-2

Sex-specific metabolic functions of adipose Lipocalin-2

The Impact of Aging on Adipose Function and Adipokine Synthesis

Roles of bone-derived hormones in type 2 diabetes and cardiovascular pathophysiology

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