Background and aims: Caffeine, a non-selective adenosine receptor antagonist, is one of the psychotropic substances most consumed in the world (1). Chronic caffeine intake improves weight gain (2,3), insulin sensitivity and glucose tolerance in animals (3,4) and humans (5) contributing to reduced risk of type 2 diabetes. Knowing that caffeine positively impacts metabolism, and that angiogenesis contributes to its improvement, we investigated if the beneficial effects of chronic caffeine intake on diet-induced insulin resistant animals involve improvements in lipid metabolism and angiogenic mechanisms in the adipose tissue. Materials and Methods: Male Wistar rats aged 8-12 weeks were submitted to 3 and 19 weeks of high-fat diet (HF, 60% of lipids) or to control diet. In the last 2 and 6 weeks, respectively, groups were divided, and half submitted to caffeine treatment (1g/L) in drinking water. At the end of diet period insulin-sensitive tissues were collected. Proteins related to lipid metabolism: ATP citrate lyase (ACL) and hormone-sensitive lipase (HSL); to angiogenesis: platelet endothelial cell adhesion molecule (CD31) and vascular endothelial growth factor (VEGF); and to insulin signaling pathways: protein Kinase B (Akt) and insulin receptor (IR) were evaluated. Hematoxylin-eosin staining was performed to evaluate adipocyte perimeter and immunohistochemistry for CD31 and VEGF expression analysis. Laboratory care followed the European Union Directive 2010/63/EU and was approved by NOVA Medical School Ethics Committee. Data was analysed using graphpad prism software using t-test student and ONE or TWO-Way ANOVA with Turkey’s multiple comparison test. p-values<0.05 were considered significantly different. Results: 3 weeks of HF diet increased weight gain (182.3%, p<0.0001), visceral fat (49.7%, p<0.05), adipocytes perimeter (35.9%, p<0.05) and HSL expression (51.99%, p<0.05); and decreased ACL (33%, p=0.06) in comparison to control group. 19 weeks of HF diet increased weight gain (191.3%, p<0.05), visceral fat (40.6%, p<0.01) and adipocytes perimeter (66.1%, p<0.0001); and decreased the expression of HSL (18.91%, p<0.05) in comparison to control group. Caffeine treatment, in 3 and 19 weeks of HF diet respectively, decreased weight gain (80.8%, p<0.01 and 66.4%, p<0.05), visceral fat (62.8%, p<0.05 and 58.3%, p<0.001) and adipocytes perimeter in the 19 weeks group (56.4%, p<0.0001). Also, caffeine treatment tendentially decrease the expression of ACL (18.2%, p=0.67) in 3 weeks of HF diet without alterations for 19 weeks and HSL expression (18.29%, p=0.61) in 3 weeks of HF diet and increased (28.9%, p=0.42) for the 19 weeks of HF diet. Insulin signaling pathway markers were not altered by HF diet or caffeine treatment in both groups. 3 weeks of HF diet tendentially decreased CD31 expression (55.83%, p<0.05) and VEGF expression (35.30%, p=0.52), and caffeine treatment increased CD31 (53.23%, p<0.05) and VEGF (68.07%, p=0.79) expression. The 19 weeks diet group showed a tendency to decrease CD31 expression (56.77%, p=0.13) effects not altered by caffeine treatment. Conclusion: Caffeine administration in HF diet animals impacts weight gain, fat accumulation and adipose tissue signaling pathways, due to the contribution of increased lipolysis and angiogenesis markers. These results open new doors for a caffeine-based therapeutic approach for metabolic diseases related with adipose tissue dysfunction.