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.
Highlights
Adipose tissue plays a central role in metabolic homeostasis, inflammation, and insulin resistance
To determine how retinoic acid regulates lipocalin 2 (Lcn2) and uncoupling protein 1 (UCP1) expression in adipose tissue, we investigated the regulation of Ucp1 and Lcn2 expression by all-trans-retinoic acid (ATRA) in differentiated brown and white adipocytes
We found that ATRA stimulated much higher levels of Ucp1 gene expression than norepinephrine did in differentiated brown adipocytes (Fig. 1A)
Summary
Four-week-old Lcn2-deficient male mice were housed with a 12-h light-dark cycle and fed a HFD (fat calories, 60%; Bio-Serv F3282; New Brunswick, NJ) for 12 weeks. At 16 weeks of age, HFD-fed WT and Lcn KO mice were treated with all-trans-retinoic acid (ATRA) (Sigma) at a dose of 50 mg/kg body weight via gavage daily for 24 days based on previous publications [31,32,33,34]. Chow diet-fed WT and Lcn KO mice at 14 weeks of age were subjected to gavage of ATRA (10 mg/kg body weight/day; ATRA was dissolved in 1% ethanol and 99% water) for 2 weeks. Mice treated with the vehicle (1% ethanol in water) served as controls. Mice were sacrificed immediately; blood and tissue samples were collected for various assessments
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