Endothelial Prohibitin Mediates Bi-directional Long Chain Fatty Acid Transport in White and Brown Adipose Tissues
Authors: Gao Zhanguo , Daquinag Alexes C. , Yu Yongmei , Kolonin Mikhail G. 
Published: May 2022

<p><strong>The</strong> <strong>function</strong> <strong>of</strong> <strong>Prohibitin-1</strong> <strong>(PHB1)</strong> <strong>in</strong> <strong>adipocyte</strong> <strong>mitochondrial</strong> <strong>respiration,</strong> <strong>adaptive</strong> <strong>thermogenesis, and long chain fatty acid (LCFA) metabolism has been reported. While</strong> <strong>intracellular</strong> <strong>PHB1</strong> <strong>expression</strong> <strong>is</strong> <strong>ubiquitous,</strong> <strong>cell</strong> <strong>surface</strong> <strong>PHB1</strong> <strong>localization</strong> <strong>is</strong> <strong>selective</strong> <strong>for</strong> <strong>adipocytes and endothelial cells of adipose tissue. The importance of PHB1 in adipose</strong> <strong>endothelium</strong> <strong>has</strong> <strong>not</strong> <strong>been</strong> <strong>investigated</strong> <strong>and</strong> <strong>its</strong> <strong>vascular</strong> <strong>cell</strong> <strong>surface</strong> <strong>function</strong> <strong>has</strong> <strong>remained</strong> <strong>unclear. Here, we generated</strong> <strong>and analyzed mice with PHB1 knock-out specifically in</strong> <strong>endothelial cells (PHB1 EC-KO). Despite the lack of endothelial PHB1, mice developed</strong> <strong>normally and had normal vascularizatoin in both white adipose tissue (WAT) and brown</strong> <strong>adipose tissue (BAT). Tumor and ex vivo explant angiogenesis assays also have not</strong> <strong>detected a functional defect in PHB1 KO endothelium. No metabolic phenotype was</strong> <strong>observed in PHB1 EC-KO mice raised on regular diet. We show that both male and female</strong> <strong>PHB1 EC-KO mice have normal body composition and adaptive thermogenesis. However,</strong> <strong>PHB1 EC-KO mice displayed higher insulin sensitivity and increased glucose clearance</strong> <strong>when fed high fat diet. We demonstrate that the efficacy of long chain fatty acid (LCFA)</strong> <strong>deposition by adipocytes is decreased by PHB1 EC KO, in particular in brown adipose</strong> <strong>tissue</strong> <strong>(BAT).</strong> <strong>Consistent</strong> <strong>with</strong> <strong>that,</strong> <strong>EC-KO</strong> <strong>mice</strong> <strong>have</strong> <strong>a</strong> <strong>defect</strong> <strong>in</strong> <strong>clearing</strong> <strong>triglycerides</strong> <strong>from</strong> <strong>systemic</strong> <strong>circulation.</strong> <strong>Free</strong> <strong>fatty</strong> <strong>acid</strong> <strong>release</strong> <strong>upon</strong> <strong>lipolysis</strong> <strong>induction</strong> <strong>was</strong> <strong>also</strong> <strong>found</strong> <strong>to</strong> <strong>be</strong> <strong>reduced in PHB1 EC-KO mice. Our results demonstrate that PHB1 in endothelial cells</strong> <strong>regulates</strong> <strong>bi-directional</strong> <strong>LCFA</strong> <strong>transport</strong> <strong>and</strong> <strong>thereby</strong> <strong>suppresses</strong> <strong>glucose</strong> <strong>utilization.</strong></p>