Obesity-induced inflammation in adipose tissue (AT) and liver have been proposed to play a key role in the development of insulin resistance. However, it is not clear whether inflammation is a cause or consequence of obesity and/or insulin resistance. To further investigate this we examined the temporal relationship between insulin resistance and inflammation by performing extensive high fat feeding (HFF) time course studies (1-16 weeks) in male C57BL6 mice. Euglycaemic-hyperinsulinaemic clamps combined with radiolabelled glucose tracers were used to assess whole body and tissue specific insulin sensitivity in conscious mice. These experiments revealed a disassociation between the onset and maintenance of insulin resistance and the development of low-grade metabolic inflammation. Severe local adipose tissue, hepatic and whole body insulin resistance (~25%↓ in GIR vs. chow) developed as early as one week after HFF, which occurred without any change in classical markers of inflammation or endoplasmic reticulum stress (P-JNK, P-IKK, F480, Cd11c, Tnf-α, Il6, Bip and Chop gene expression, XBP1 splicing and F4/80 immunohistochemistry). While insulin resistance did not deteriorate beyond 3 weeks of HFF (~55%↓ in GIR vs. chow), evidence of AT inflammation only became apparent after 16 weeks.  Despite marked hepatic lipid accumulation and insulin resistance, we were unable to detect any significant increase in inflammatory markers in liver throughout the HFF time course. In contrast to inflammation, defects in lipid metabolism were noted in adipose (increased ceramide and sphingomyelin) and liver (increased di- and triacylglycerol) at the time points when these tissues developed insulin resistance. In conclusion, insulin resistance develops early in response to HFF and is associated with defects in lipid metabolism. Our findings demonstrate that insulin resistance develops independent of changes in inflammation, indicating that inflammation is not a causative factor in the development of insulin resistance in high fat fed mice.