TNF, but not hyperinsulinemia or hyperglycemia, is a key driver of obesity-induced monocytosis revealing that inflammatory monocytes correlate with insulin in obese male mice.

Jessica A Breznik,Kevin P Foley,Jonathan D Schertzer,Dessi Loukov,Trevor C Lau,Christian Schulz,Dawn M E Bowdish,Avee Naidoo,Deborah M Sloboda

doi:10.14814/phy2.13937

Abstract

Inflammation contributes to obesity‐related hyperinsulinemia and insulin resistance, which often precede type 2 diabetes. Inflammation is one way that obesity can promote insulin resistance. It is not clear if the extent of obesity, hyperinsulinemia, or hyperglycemia, underpins changes in cellular immunity during diet‐induced obesity. In particular, the requirement for obesity or directionality in the relationship between insulin resistance and monocyte characteristics is poorly defined. Inflammatory cytokines such as tumor necrosis factor (TNF) can contribute to insulin resistance. It is unclear if TNF alters monocytosis or specific markers of cellular immunity in the context of obesity. We measured bone marrow and blood monocyte characteristics in WT and TNF −/− mice that were fed obesogenic, high fat (HF) diets. We also used hyperglycemic Akita mice and mice implanted with insulin pellets in order to determine if glucose or insulin were sufficient to alter monocyte characteristics. We found that diet‐induced obesity in male mice increased the total number of monocytes in blood, but not in bone marrow. Immature, inflammatory (Ly6Chigh) monocytes decreased within the bone marrow and increased within peripheral blood of HF‐fed mice. We found that neither hyperinsulinemia nor hyperglycemia was sufficient to induce the observed changes in circulating monocytes in the absence of diet‐induced obesity. In obese HF‐fed mice, antibiotic treatment lowered insulin and insulin resistance, but did not alter circulating monocyte characteristics. Fewer Ly6Chigh monocytes were present within the blood of HF‐fed TNF −/− mice in comparison to HF‐fed wild‐type (WT) mice. The prevalence of immature Ly6Chigh monocytes in the blood correlated with serum insulin and insulin resistance irrespective of the magnitude of adipocyte or adipose tissue hypertrophy in obese mice. These data suggest that diet‐induced obesity instigates a TNF‐dependent increase in circulating inflammatory monocytes, which predicts increased blood insulin and insulin resistance independently from markers of adiposity or adipose tissue expansion.

Highlights

Obesity is associated with chronic, low-grade systemic inflammation that impacts endocrine control of metabolism (McPhee and Schertzer 2015)
We observed that mice implanted with insulin pellets had decreased circulating neutrophils (Fig. 2L). These results suggest that overt hyperglycemia, and chronic hyperinsulinemia are not sufficient to account for the increase in circulating immature, inflammatory Ly6Chigh monocytes that we observed in high fat (HF) diet-fed mice
In this study we examined the effects of diet-induced obesity on monocyte prevalence and phenotype

Summary

Introduction

Obesity is associated with chronic, low-grade systemic inflammation that impacts endocrine control of metabolism (McPhee and Schertzer 2015). Using TNFÀ/À male mice as a model of reduced systemic inflammation, we demonstrated that despite diet-induced obesity in TNFÀ/À mice there was a reduction in circulating Ly6Chigh inflammatory monocytes and macrophage accumulation in adipose tissue in comparison to WT mice. This discovery allowed for an assessment of insulin resistance characteristics in obese mice that had different levels of circulating Ly6Chigh monocytes. We determined that during diet-induced obesity the TNFdependent prevalence of blood monocytes, and inflammatory Ly6Chigh monocytes in particular, were better predictors of indices of insulin resistance than body weight or parameters of adiposity, such as adipocyte size.

Results

SHAM INSULIN

Discussion