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Lipocalin‐2 Is Required for Retinoic Acid‐Induced Beiging of White Adipocytes and Insulin‐Stimulated Plasma Membrane Localization of RAR‐α
Author(s) -
Deis Jessica,
Guo Hong,
Bernlohr David,
Chen Xiaoli
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.44.2
Subject(s) - medicine , endocrinology , thermogenin , white adipose tissue , adipocyte , retinoic acid , thermogenesis , biology , adipogenesis , adipose tissue , brown adipose tissue , biochemistry , gene
Beiging of white adipose tissue (WAT) has therapeutic value for treating obesity and metabolic disease. Lipocalin‐2 (Lcn2) is a protein secreted from adipose tissue that is necessary for cold adaptation and non‐adrenergic activation of brown adipose tissue. In this study, we sought to determine whether and how Lcn2 regulates beiging of WAT. Lcn2 −/− inguinal adipocytes have impaired p38 mitogen‐activated protein kinase (p38MAPK) signaling and thermogenic gene expression in response to insulin. This is accompanied by mitochondrial dysfunction as shown by significantly reduced basal/maximal respiration, proton leak, and NAD+/NADH ratio. Hormone sensitive lipase and p38MAPK signaling in response to norepinephrine is normal in Lcn2 −/− inguinal adipocytes, suggesting Lcn2 promotes thermogenesis by a non‐adrenergic mechanism. Recruitment of beige adipocytes by rosiglitazone treatment during the entire differentiation period results in similar levels of uncoupling protein‐1 (UCP‐1) in wild‐type (WT) and Lcn2 −/− inguinal adipocytes. However, retinoic acid (RA) induction of thermogenic genes and UCP‐1 protein is attenuated in rosiglitazone‐treated Lcn2 −/− inguinal adipocytes and chronic treatment of mice with retinoic acid resulted in lower UCP‐1 protein levels in inguinal WAT of Lcn2 −/− mice when compared to WT. Further, the synergistic effect of insulin and RA on UCP‐1 and peroxisome proliferator‐activated receptor gamma coactivator 1α (PGC‐1α) expression is markedly reduced in Lcn2 −/− inguinal adipocytes. Short‐term RA treatment is able to phosphorylate p38MAPK, and this is blunted in Lcn2 −/− inguinal adipocytes. We found that retinoic acid receptor‐α (RAR‐α) and Lcn2 are present in the plasma membrane fraction of adipocytes isolated from inguinal and brown adipocytes, suggesting a possible mechanism for rapid phosphorylation of p38MAPK by non‐genomic RAR‐α activation. Interestingly, insulin treatment increased RAR‐α levels to a greater extent than RA in the plasma membrane of WT adipocytes, and this effect was not seen in Lcn2 −/− adipocytes. Taken together, our data suggests a model where Lcn2 regulates RA‐induced activation of beige adipocytes through modulating insulin‐stimulated plasma membrane translocation of RAR‐α and non‐genomic action of RAR‐α on phosphorylation of p38MAPK. Support or Funding Information This study was supported by the NIDDK‐funded Minnesota Obesity Center (P30DK050456), and NIDDK‐funded traineeship (T32DK083250) to J.D.