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.