Prohibitin/annexin 2 interaction regulates fatty acid transport in adipose tissue
Ahmad Salameh, … , Wadih Arap, Mikhail G. Kolonin
Ahmad Salameh, … , Wadih Arap, Mikhail G. Kolonin
Published July 7, 2016
Citation Information: JCI Insight. 2016;1(10):e86351. https://doi.org/10.1172/jci.insight.86351.
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Research Article Metabolism Vascular biology

Prohibitin/annexin 2 interaction regulates fatty acid transport in adipose tissue

Abstract

We have previously identified prohibitin (PHB) and annexin A2 (ANX2) as proteins interacting on the surface of vascular endothelial cells in white adipose tissue (WAT) of humans and mice. Here, we demonstrate that ANX2 and PHB also interact in adipocytes. Mice lacking ANX2 have normal WAT vascularization, adipogenesis, and glucose metabolism but display WAT hypotrophy due to reduced fatty acid uptake by WAT endothelium and adipocytes. By using cell culture systems in which ANX2/PHB binding is disrupted either genetically or through treatment with a blocking peptide, we show that fatty acid transport efficiency relies on this protein complex. We also provide evidence that the interaction between ANX2 and PHB mediates fatty acid transport from the endothelium into adipocytes. Moreover, we demonstrate that ANX2 and PHB form a complex with the fatty acid transporter CD36. Finally, we show that the colocalization of PHB and CD36 on adipocyte surface is induced by extracellular fatty acids. Together, our results suggest that an unrecognized biochemical interaction between ANX2 and PHB regulates CD36-mediated fatty acid transport in WAT, thus revealing a new potential pathway for intervention in metabolic diseases.

Authors

Ahmad Salameh, Alexes C. Daquinag, Daniela I. Staquicini, Zhiqiang An, Katherine A. Hajjar, Renata Pasqualini, Wadih Arap, Mikhail G. Kolonin

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Figure 3

Deficient WAT lipid uptake in ANX2-null mice.

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Deficient WAT lipid uptake in ANX2-null mice. (A) Triglyceride blood con...
(A) Triglyceride blood concentration analysis upon i.v. Intralipid infusion into prestarved mice shows a delay in clearance for ANX2-null compared with WT mice (n = 4). (B) Abdominal fluorescence of lauric acid boron-dipyrromethene conjugate (BODIPY-FL-C12) measured 15 min. after injection. As quantified for 4 abdominal locations (C), a significantly lower signal is observed for Anxa2–/– mice compared with WT mice. (D) Analysis of individual organs from WT and Anxa2–/– mice 15 min. after injection of palmitic acid (C16) labeled with IRDye-680CW (left) or an equimolar amount of uncoupled IRDye-680 (right). (E) Quantification of D showing a significant reduction of FA localization to s.c. and i.p. WAT of Anxa2–/– mice compared with WT mice (n = 4). FA (but not free fluorophore) accumulation in the liver is higher in Anxa2–/– than in WT mice, while kidney and skeletal muscle accumulation is comparable. (F) SVF from i.p. WAT of WT and Anxa2–/– mice with vascular structures (arrows) were incubated with 0.3 μM BODIPY-FL-C12 (red) and then washed. Note FA uptake (arrows) in WT but not Anxa2–/– endothelium. (G) One hour after red BODIPY-FL-C12 i.v injection into WT and Anxa2–/– mice, adipocytes were isolated after WAT disaggregation using collagenase. Note FA accumulation (arrows) inside WT but not Anxa2–/– nucleated adipocytes. Insets: bright field (BF) images. In A, C, and E, error bars ± SEM; *P<0.05 (Student’s t test, WT vs. Anxa2–/–). Nuclei are blue. Scale bars: 50 μm.