GM-CSF driven myeloid cells in adipose tissue link weight gain and insulin resistance via formation of 2-aminoadipate

• Published in: Scientific reports 2018-07, Vol.8 (1), p.11485-12, Article 11485
• Main Authors: Plubell, Deanna L., Fenton, Alexandra M., Wilmarth, Phillip A., Bergstrom, Paige, Zhao, Yuqi, Minnier, Jessica, Heinecke, Jay W., Yang, Xia, Pamir, Nathalie
• Format: Article
• Language: English
• Subjects: 13; 631/114/2784; 64/60; 692/163/2743/2037; 82; 82/58; 96/31; a-Ketoglutaric acid; Adipose tissue; Adipose Tissue - metabolism; Adiposity - physiology; Animals; Body weight; Body Weight - physiology; Cholesterol; Cholesterol - metabolism; Diet; Diet, High-Fat; Dietary Fats; Energy Metabolism - physiology; Genotypes; Glucose - metabolism; Glucose tolerance; Granulocyte-macrophage colony-stimulating factor; Granulocyte-Macrophage Colony-Stimulating Factor - metabolism; High cholesterol diet; High fat diet; Humanities and Social Sciences; Insulin; Insulin - metabolism; Insulin resistance; Insulin Resistance - physiology; Ketone Oxidoreductases - metabolism; Lipid Metabolism - physiology; Liquid chromatography; Low fat diet; Lysine; Male; Mass spectroscopy; Metabolism; Mice; Mitochondria; multidisciplinary; Myeloid cells; Myeloid Cells - metabolism; Oxoglutarate dehydrogenase (lipoamide); Phospholipids; Proteomes; Science; Science (multidisciplinary); Triglycerides; Triglycerides - metabolism; Weight Gain - physiology
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-018-29250-8

In a GM-CSF driven myeloid cell deficient mouse model ( Csf2 −/− ) that has preserved insulin sensitivity despite increased adiposity, we used unbiased three-dimensional integration of proteome profiles, metabolic profiles, and gene regulatory networks to understand adipose tissue proteome-wide changes and their metabolic implications. Multi-dimensional liquid chromatography mass spectrometry and extended multiplex mass labeling was used to analyze proteomes of epididymal adipose tissues isolated from Csf2 +/+ and Csf2 −/− mice that were fed low fat, high fat, or high fat plus cholesterol diets for 8 weeks. The metabolic health (as measured by body weight, adiposity, plasma fasting glucose, insulin, triglycerides, phospholipids, total cholesterol levels, and glucose and insulin tolerance tests) deteriorated with diet for both genotypes, while mice lacking Csf2 were protected from insulin resistance. Regardless of diet, 30 mostly mitochondrial, branch chain amino acids (BCAA), and lysine metabolism proteins were altered between Csf2 −/− and Csf2 +/+ mice (FDR 4-fold upregulated and plasma 2-AA levels were >2 fold reduced in Csf2 −/− mice (p