Updated project metadata. Adipose tissue dysfunction in obese humans is associated with disrupted metabolic homeostasis, insulin resistance, and type 2 diabetes mellitus (T2DM). In a mouse model 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. Multiple-dimensional liquid chromatography tandem mass spectrometry and extended multiplexing TMT labeling (24 biological samples) was used to analyze proteomes of epididymal adipose tissues isolated from wildtype (Csf2+/+) and GM-CSF driven dendritic cell deficient (Csf2-/-) mice that were fed low fat, high fat, or high fat plus cholesterol diets for 8 weeks. The peripheral 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 metabolism proteins participating in amino acid and branched chain amino acid pathways were altered, between Csf2-/- and Csf2+/+ mice. Tissue DHTKD1 levels were >4-fold upregulated and plasma 2-aminoadipoate (2-AA) levels were >2 fold reduced in Csf2-/- mice. GM-CSF driven dendritic cells play a detrimental role in insulin sensitivity via lysine metabolism involving Dhtkd1/2-AA axis.