Purpose: Depression and obesity are closely related diseases sharing common biological mechanisms. PPAR- α and PPAR γ agonists have been hypothesized to improve memory and reduce neuroinflammation. Their exact role in treatment of obesity induced depression has been less understood. The study aims to investigate the potential molecular anti-inflammatory and anti-depressive effects of fenofibrate and/or pioglitazone on obese rats by targeting NEGR1 and BDNF expression. Experimental: Fifty male Swiss rats were equally divided into 5 groups: Group (i): Control group fed with standard rodent chow. Group(ii) High fat diet (HFD) group.Group (iii) Fenofibrate treated group. Group (iv) Pioglitazone treated group. Group (v) Fenofibrate+ pioglitazone treated group. Fenofibrate (18 mg/kg/day) and pioglitazone (3 mg/kg/day) were administered once daily for 4 weeks for rats fed on HFD for 8 weeks. Their effects on obesity-induced depression were evaluated through performing behavioral assessment such as forced swim test (FST) and tail suspension test (TST) , biochemical assessment(lipid profile) and molecular assessment (IL-6, TNF- α , neuronal growth regulator-1(NEGR1) and brain-derived neurotrophic factor (BDNF) expression using RT-PCR. Results: Obese rats manifested severe depressive-like behavior compared to controls, The combined fenofibrate and pioglitazone treatment significantly reduced the body weight, TG , LDL-C levels, downregulated the inflammatory markers and upregulated NEGR1 and BDNF expression compared to pioglitazone treated group. Conclusion: combined fenofibrate and pioglitazone treatment improve depression and obesity in obese rats via the upregulation of brain NEGR1 and BDNF expression holding tight interactions between brain, adipose tissue, and immune system.