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

Yuqi Zhao,Jessica Minnier,Nathalie Pamir,Deanna L Plubell,Xia Yang,Jay W Heinecke,Phillip A Wilmarth,Paige Bergstrom,Alexandra M Fenton

doi:10.1038/s41598-018-29250-8

Abstract

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 < 0.05). Lack of GM-CSF driven myeloid cells lead to reduced adipose tissue 2-oxoglutarate dehydrogenase complex (DHTKD1) levels and subsequent increase in plasma 2-aminoadipate (2-AA) levels, both of which are reported to correlate with insulin resistance. Tissue DHTKD1 levels were >4-fold upregulated and plasma 2-AA levels were >2 fold reduced in Csf2−/− mice (p < 0.05). GM-CSF driven myeloid cells link peripheral insulin sensitivity to adiposity via lysine metabolism involving DHTKD1/2-AA axis in a diet independent manner.

Highlights

Diets high in fat and cholesterol accelerate expansion of adipose tissue and lead to structural and molecular changes within adipose tissue accompanied with an array of metabolic consequences such as insulin resistance, diabetes and cardiovascular disease[1]
Through unbiased three-dimensional integration of proteome profiles, metabolic profiles, and gene regulatory networks, we have identified unique sets of proteins and gene networks that are modulated by granulocyte macrophage–colony stimulating factor (GM-CSF) driven myeloid cells and that characterize the changes within adipose tissue in response to high fat or high fat plus cholesterol feeding
Our studies reveal a divergent role for adipose tissue GM-CSF driven myeloid cells: While they protect from adiposity they participate in diet-independent insulin sensitivity via the lysine metabolism involving the Dhtkd1/2-AA axis

Summary

Introduction

Diets high in fat and cholesterol accelerate expansion of adipose tissue (obesity) and lead to structural and molecular changes within adipose tissue accompanied with an array of metabolic consequences such as insulin resistance, diabetes and cardiovascular disease[1]. Mice lacking GM-CSF (Csf2−/− mice) have fewer CD11C+ cells in their atherosclerotic plaques and white adipose tissue of lean mice indicating that GM-CSF modulates tissue levels of CD11C+ cells in vivo without major changes in other myeloid populations[11,12] These mice display improved peripheral insulin sensitivity in spite of increased adiposity by reducing inflammation in adipose tissue[12,13]. Mice lacking GM-CSF have increased adiposity in both lean[12] and obese states[13] despite favorable insulin sensitivity They provide a model to study the biochemical mechanisms that underlie the functional properties of “healthy” adipose tissue and can help explain the difference between obese individuals with normal glucose tolerance and those with type 2 diabetes

Methods

Results

Conclusion