Rapid and weight-independent improvement of glucose tolerance induced by a peptide designed to elicit apoptosis in adipose tissue endothelium.
A peptide designed to induce apoptosis of endothelium in white adipose tissue (WAT) decreases adiposity. The goal of this work is to determine whether targeting of WAT endothelium results in impaired glucose regulation as a result of impaired WAT function. Glucose tolerance tests were performed on days 2 and 3 of treatment with vehicle (HF-V) or proapoptotic peptide (HF-PP) and mice pair-fed to HF-PP (HF-PF) in obese mice on a high-fat diet (HFD). Serum metabolic variables, including lipid profile, adipokines, individual fatty acids, and acylcarnitines, were measured. Microarray analysis was performed in epididymal fat of lean or obese mice treated with vehicle or proapoptotic peptide (PP). PP rapidly and potently improved glucose tolerance of obese mice in a weight- and food intake-independent manner. Serum insulin and triglycerides were decreased in HF-PP relative to HF-V. Levels of fatty acids and acylcarnitines were distinctive in HF-PP compared with HF-V or HF-PF. Microarray analysis in AT revealed that pathways involved in mitochondrial dysfunction, oxidative phosphorylation, and branched-chain amino acid degradation were changed by exposure to HFD and were reversed by PP administration. These studies suggest a novel role of the AT vasculature in glucose homeostasis and lipid metabolism.
Department of Pharmacology, Korea University College of Medicine, Seoul, Republic of Korea.
Dong-Hoon
DH
Kim
Maureen A
MA
Sartor
James R
JR
Bain
Darleen
D
Sandoval
Robert D
RD
Stevens
Mario
M
Medvedovic
Christopher B
CB
Newgard
Stephen C
SC
Woods
Randy J
RJ
Seeley
D052436:Adipose Tissue, White / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001786:Blood Glucose / Q000378:metabolism*; D002331:Carnitine / Q000031:analogs & derivatives / Q000097:blood; D059305:Diet, High-Fat; D002149:Energy Intake; D005951:Glucose Tolerance Test; D006706:Homeostasis / Q000187:drug effects; D036341:Intercellular Signaling Peptides and Proteins; D050356:Lipid Metabolism; D008297:Male; D053858:Metabolic Networks and Pathways / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D010455:Peptides / Q000494:pharmacology*; D014280:Triglycerides / Q000097:blood
D001786:Blood Glucose; C576018:CKGGRAKDC-GG-D(KLAKLAK)2; D036341:Intercellular Signaling Peptides and Proteins; D010455:Peptides; D014280:Triglycerides; C116917:acylcarnitine; D002331:Carnitine