Rapid and Weight-Independent Improvement of Glucose Tolerance Induced by a Peptide Designed to Elicit Apoptosis in Adipose Tissue Endothelium

Abstract

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 acylcamitines were distinctive in HF-PP compared with HF-V or HF-PF. Microarray analysis in AT revealed that pathways involved in mitochondria] 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. Diabetes 61:2299-2310, 2012