Obesity is a chronic disease of multiple etiologies, dependent on genetic, environmental, metabolic and endocrine factors. An important factor is the energy imbalance between calories consumed and spent. Obesity is a risk factor for metabolic syndrome; both pathologies present mild chronic systemic inflammatory state, with increased cytokines, TNFα and C-reactive protein. Some studies show intestinal modifications derived from a systemic inflammatory state. Until now it has not been determined if a high-fat diet produces histological changes in the small intestine, nor if these are related to the generalized inflammatory state that obesity produces. Our objective is to elucidate whether there is a relationship between obesity produced by high-fat diet intake and the possible histological/morphological alterations in the small intestine. Also, modifications of local inflammation markers IL-1R and TNFαR have been studied. In handling the animals, we followed the European Union Directive for Protection of Vertebrates Used for Experimental and Other Scientific Ends (2010/63/EU). Protocols were approved by the University of Valladolid Institutional Committee for Animal Care and Use (Project Approval Ethical Code: 4505502). Swiss male mice, 3 months old, were used. Mice (n=10) were randomly divided into two groups: Control group (n=5), fed standard diet and experimental group (n=5), fed a high-fat diet, for 5 weeks. At the end of diet period, animals were weighed. After overnight fasting, basal glucose and insulin were determined in plasma; animals were euthanatized with lethal i.p. doses of sodium pentobarbital; segments of small intestine were extracted, fixed in 4% paraformaldehyde in 0.1M PB, and embedded in paraffin. Cuts of tissue 5 μm thick were stained with hematoxylin and eosin. The presence of TNF-αR and IL-1R was identified by fluorescent immunohistochemistry in control and experimental small intestine sections, examined with a fluorescent and white light microscope with coupled camera, the captured images were processed with Metamorph 6.3 software. Mice average weight after 5 weeks of treatment was 32.4g in controls vs 41.4g experimental (p<0.05). Blood glucose was 67.2mg/dL in controls vs 102.8mg/dL experimental (p<0.05); insulinemia was 0.16μg/L in controls vs 0.19μg/L experimental (p = n.s). Height of intestinal villi: 409 ± 18μm vs 312 ± 47μm, (p≤ 0.001); width at medium level: 74 ± 12μm vs 94 ± 25μm, (p= n.s.); distal width: 72 ± 13μm vs 114 ± 27μm, (p<0.05). Values are means ± S.E.M., compared by ANOVA. We found increased goblet and neuroendocrine cells and qualitative increase of fluorescence for both receptors, TNF-α and IL-1, in the intestine of mice with a high-fat diet vs controls. Conclusion: High-fat diet induces obesity and alterions in glucose homeostasis that run with morphological changes and signs of inflammation in the small intestine.