Lipocalin 2 is a selective modulator of peroxisome proliferator‐activated receptor‐γ activation and function in lipid homeostasis and energy expenditure

Jin, Daozhong; Guo, Hong; Bu, So Young; Zhang, Yuanyuan; Hannaford, J.; Mashek, Douglas G.; Chen, Xiaoli

doi:10.1096/fj.10-165175

Cited by 78 publications

(63 citation statements)

References 39 publications

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“…Our previous studies have demonstrated that Lcn2 deficiency significantly impairs thermogenesis and lipid homeostasis in male and female mice without affecting ␤-adrenergic signaling activation (25)(26)(27)50). In this study, we explored the potential non-adrenergic mechanism by which Lcn2 regulates energy and lipid metabolism in obesity.…”

Section: Discussionmentioning

confidence: 99%

Lipocalin 2, a Regulator of Retinoid Homeostasis and Retinoid-mediated Thermogenic Activation in Adipose Tissue

Guo¹,

Foncea

O’Byrne

et al. 2016

Journal of Biological Chemistry

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We have recently characterized the role of lipocalin 2 (Lcn2) as a new adipose-derived cytokine in the regulation of adaptive thermogenesis via a non-adrenergic pathway. Herein, we explored a potential non-adrenergic mechanism by which Lcn2 regulates thermogenesis and lipid metabolism. We found that Lcn2 is a retinoic acid target gene, and retinoic acid concurrently stimulated UCP1 and Lcn2 expression in adipocytes. Lcn2 KO mice exhibited a blunted effect of all-trans-retinoic acid (ATRA) on body weight and fat mass, lipid metabolism, and retinoic acid signaling pathway activation in adipose tissue under the high fat diet-induced obese condition. We further demonstrated that Lcn2 is required for the full action of ATRA on the induction of UCP1 and PGC-1␣ expression in brown adipocytes and the restoration of cold intolerance in Lcn2 KO mice. Interestingly, we discovered that Lcn2 KO mice have decreased levels of retinoic acid and retinol in adipose tissue. The protein levels of STRA6 responsible for retinol uptake were significantly decreased in adipose tissue. The retinol transporter RBP4 was increased in adipose tissue but decreased in the circulation, suggesting the impairment of RBP4 secretion in Lcn2 KO adipose tissue. Moreover, Lcn2 deficiency abolished the ATRA effect on RBP4 expression in adipocytes. All the data suggest that the decreased retinoid level and action are associated with impaired retinol transport and storage in adipose tissue in Lcn2 KO mice. We conclude that Lcn2 plays a critical role in regulating metabolic homeostasis of retinoids and retinoidmediated thermogenesis in adipose tissue.Adipose tissue plays a central role in metabolic homeostasis, inflammation, and insulin resistance. The main functions of white adipose tissue (WAT) 5 are to regulate lipid storage and mobilization, glucose homeostasis, and inflammation; many WAT functions in metabolism and insulin sensitivity are exerted by adipose-derived adipokines and cytokines (1). In contrast to WAT, brown adipose tissue (BAT) burns fat to generate heat via the uncoupling protein 1 (UCP1)-mediated nonshivering thermogenic mechanism (2). Recent discovery of metabolically active BAT in adult humans suggests a potential alternative mechanism for metabolic regulation (3). A decline in adipose tissue thermogenic activity has been associated with metabolic dysregulation in obesity and diabetes. Thus, activating thermogenic function of adipose tissue is an attractive therapeutic approach for obesity and obesity-related metabolic complications in humans. UCP1 is fully responsible for thermogenesis in brown adipocytes (4). It is well established that the ␤-adrenergic-cAMP-PKA pathway is an important mediator of sympathetic activation of UCP1 transcription and thermogenesis. The activation of p38 MAPK (p38 mitogen-activated protein kinases), a key component of adrenergic pathway, is essential for PGC-1␣ and UCP1 expression by adrenergic stimulation. Increasing sympathetic nervous system tone is known as one of the therapeutic approaches to acti...

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Section: Discussionmentioning

confidence: 99%

Lipocalin 2, a Regulator of Retinoid Homeostasis and Retinoid-mediated Thermogenic Activation in Adipose Tissue

Guo¹,

Foncea

O’Byrne

et al. 2016

Journal of Biological Chemistry

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“…RGS14 KO and WT mice that had been acclimatized to thermoneutrality (30°C) for 4–10 days were transferred to 4°C with full access to water and food (Jin et al., 2011; Vila‐Bedmar et al., 2012). Rectal temperature of the mice was measured every hour.…”

Section: Methodsmentioning

confidence: 99%

Enhanced longevity and metabolism by brown adipose tissue with disruption of the regulator of G protein signaling 14

et al. 2018

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SummaryDisruption of the regulator for G protein signaling 14 (RGS14) knockout (KO) in mice extends their lifespan and has multiple beneficial effects related to healthful aging, that is, protection from obesity, as reflected by reduced white adipose tissue, protection against cold exposure, and improved metabolism. The observed beneficial effects were mediated by improved mitochondrial function. But most importantly, the main mechanism responsible for the salutary properties of the RGS14 KO involved an increase in brown adipose tissue (BAT), which was confirmed by surgical BAT removal and transplantation to wild‐type (WT) mice, a surgical simulation of a molecular knockout. This technique reversed the phenotype of the RGS14 KO and WT, resulting in loss of the improved metabolism and protection against cold exposure in RGS14 KO and conferring this protection to the WT BAT recipients. Another mechanism mediating the salutary features in the RGS14 KO was increased SIRT3. This mechanism was confirmed in the RGS14 X SIRT3 double KO, which no longer demonstrated improved metabolism and protection against cold exposure. Loss of function of the Caenorhabditis elegans RGS‐14 homolog confirmed the evolutionary conservation of this mechanism. Thus, disruption of RGS14 is a model of healthful aging, as it not only enhances lifespan, but also protects against obesity and cold exposure and improves metabolism with a key mechanism of increased BAT, which, when removed, eliminates the features of healthful aging.

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“…LCN2 increases during adipogenesis, and its expression is sex, age, and depot dependent as well as inducible by LPS, proinflammatory cytokines TNF␣, IL-1␤, and IL-6 and saturated fat (109,205,354,356). Lcn2 knockout mice are cold-intolerant and develop increased body fat mass, show exacerbated adipocyte hypertrophy, dyslipidemia, fatty liver, and insulin resistance on high-fat diet feeding (109,145,358). Obesity and obesity-associated insulin resistance are related to an upregulation of LCN2 that is linked to iron status and inflammation (37,38,205,343).…”

Section: Recruitment Of Proinflammatory Immune Cells In Obesity Perpementioning

confidence: 99%

Revisiting the adipocyte: a model for integration of cytokine signaling in the regulation of energy metabolism

Rodrı́guez

Ezquerro

Méndez‐Giménez

et al. 2015

American Journal of Physiology-Endocrinology and Metabolism

241

186

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Adipose tissue constitutes an extremely active endocrine organ with a network of signaling pathways enabling the organism to adapt to a wide range of different metabolic challenges, such as starvation, stress, infection, and short periods of gross energy excess. The functional pleiotropism of adipose tissue relies on its ability to synthesize and release a huge variety of hormones, cytokines, complement and growth factors, extracellular matrix proteins, and vasoactive factors, collectively termed adipokines. Obesity is associated with adipose tissue dysfunction leading to the onset of several pathologies including type 2 diabetes, dyslipidemia, nonalcoholic fatty liver, or hypertension, among others. The mechanisms underlying the development of obesity and its associated comorbidities include the hypertrophy and/or hyperplasia of adipocytes, adipose tissue inflammation, impaired extracellular matrix remodeling, and fibrosis together with an altered secretion of adipokines. Recently, the potential role of brown and beige adipose tissue in the protection against obesity has been also recognized. In contrast to white adipocytes, which store energy in the form of fat, brown and beige fat cells display energy-dissipating capacity through the promotion of triacylglycerol clearance, glucose disposal, and generation of heat for thermogenesis. Identification of the morphological and molecular changes in white, beige, and brown adipose tissue during weight gain is of utmost relevance for the identification of pharmacological targets for the treatment of obesity and its associated metabolic diseases. white and brown adipogenesis; fat browning; adipocyte hypertrophy and hyperplasia; adipose tissue inflammation; extracellular matrix remodeling THE ADIPOSE ORGAN REPRESENTS a special loose connective tissue containing adipocytes and several cell types surrounded by capillary and innervation networks (47, 79, 82). Adipocytes comprise ϳ35-70% of adipose mass, and the other cell types found in the stroma-vascular fraction include preadipocytes, mesenchymal stem cells, macrophages and other immune cells, and endothelial and smooth muscle cells, among others (79). The classical functions of adipose tissue are the storage of energy in the form of triacylglycerols (TG) and as thermal insulator. Adipocytes were formerly classified into two main types: white adipocytes, which store energy in the form of fat, and brown adipocytes, which induce thermogenesis (82). The current classification scheme includes a third category of adipocytes, termed beige or brite (brown-in-white) adipocytes, which can be considered inducible brown-like cells with thermogenic properties (340). Since the identification of leptin in 1994 (359), adipose tissue has emerged as an extremely active endocrine organ that secretes a huge variety of hormones, cytokines, growth factors, and vasoactive factors that are collectively termed adipokines (67, 81,235,262). Over the last three decades, overwhelming evidence has proven that adipokines not only influence adipobiol...

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Lipocalin 2 is a selective modulator of peroxisome proliferator‐activated receptor‐γ activation and function in lipid homeostasis and energy expenditure

Cited by 78 publications

References 39 publications

Lipocalin 2, a Regulator of Retinoid Homeostasis and Retinoid-mediated Thermogenic Activation in Adipose Tissue

Lipocalin 2, a Regulator of Retinoid Homeostasis and Retinoid-mediated Thermogenic Activation in Adipose Tissue

Enhanced longevity and metabolism by brown adipose tissue with disruption of the regulator of G protein signaling 14

Revisiting the adipocyte: a model for integration of cytokine signaling in the regulation of energy metabolism

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