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

Abstract

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-1α 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 retinoid-mediated thermogenesis in adipose tissue.

• Authors: Hong Guo, Rocio Foncea, Sheila M O'Byrne, Hongfeng Jiang, Yuanyuan Zhang, Jessica A Deis, William S Blaner, David A Bernlohr, Xiaoli Chen
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 291 Issue 21 Pg. 11216-29 (May 20 2016) ISSN: 1083-351X [Electronic] United States
• PMID: 27008859 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

Chemical References

• Lipocalin-2
• Membrane Proteins
• Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
• Ppargc1a protein, mouse
• Rbp4 protein, mouse
• Retinoids
• Retinol-Binding Proteins, Plasma
• Stra6 protein, mouse
• Ucp1 protein, mouse
• Uncoupling Protein 1
• Lcn2 protein, mouse
• Tretinoin

Topics

• Adipocytes, Brown (drug effects, metabolism)
• Adipocytes, White (drug effects, metabolism)
• Adipose Tissue (drug effects, metabolism)
• Animals
• Homeostasis
• Lipocalin-2 (deficiency, genetics, metabolism)
• Male
• Membrane Proteins (metabolism)
• Mice
• Mice, Knockout
• Obesity (etiology, metabolism, pathology)
• Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha (metabolism)
• Protein Binding
• Retinoids (metabolism)
• Retinol-Binding Proteins, Plasma (metabolism)
• Thermogenesis (genetics, physiology)
• Tretinoin (metabolism, pharmacology)
• Uncoupling Protein 1 (metabolism)