Technical Abstract: The effects of hydroxypropyl methylcellulose (HPMC), a highly viscous non-fermentable soluble dietary fiber, were evaluated on adipose tissue inflammation and insulin resistance in diet induced obese (DIO) mice fed a high fat (HF) diet supplemented with either HPMC or insoluble fiber. DIO C57BL/6J mice were fed a HF diet supplemented with 6% HPMC or 6% microcrystalline cellulose (MCC). Gene expression analyses of epididymal adipose tissue by exon microarray and real-time PCR along with glucose and insulin tolerance and intestinal permeability were assessed. HPMC fed mice exhibited significantly reduced body weight gain and adipose tissue weight as well as reduced areas under the curve for 2-hr insulin and glucose responses. HPMC significantly decreased HF diet induced intestinal permeability. Overall, HPMC enhanced insulin sensitivity and glucose metabolism and down-regulated genes related to inflammation and immune response, adipogenesis, and oxidative stress markers. IPA analysis of microarray data identified lipid metabolism, inflammatory disease, and acute phase response pathways as being differentially regulated by HPMC. Conclusions: These results suggest HPMC consumption ameliorates HF diet effects on obesity-induced insulin resistance, adipose tissue inflammatory and immune responses, weight gain, as well as intestinal permeability.