Obesity is associated with a high risk of type-2 diabetes predisposing patients to diabetic nephropathy (DN), the leading cause of end-stage renal failure worldwide. Glomerular injury is a prominent pathological feature of DN. Sestrin 2 (Sesn2) is a stress-induced protein, but its role in DN has not been investigated. Therefore, we have determined the impact of Sesn2 deletion in a mouse model of obesity-induced nephropathy. We examined the effects of Sesn2-deficiency in a long-term (22 weeks) mouse model of high fat diet (HFD)-induced obesity. The severity of renal pathology in wild type (Sesn2+/+) mice (fed HFD or chow diets) was compared to that in Sesn2-deficient mice (Sesn2-/-) fed HFD or chow diets (n = 3 to 4 mice per group). All animal work was carried out under approved protocol by the Institutional Animal Care and Use Committee (IACUC) of the University of Texas health science center (San Antonio) and followed the principles of laboratory animal care (NIH). Data showed that Sesn2 ablation exacerbated HFD-induced glomerular fibrotic injury as evidenced by mesangial matrix hypertrophy (Sesn2+/+: chow 182.4±29 vs 321.7±37.5 HFD, p<0.001; Sesn2-/-: chow 270±24.8 vs 343.2±65 HFD) and accumulation of both fibronectin (Sesn2+/+: chow 7.37±0.89 vs 11.83±0.89 HFD, p<0.05; Sesn2-/-: chow 12.44±2.72 vs 13.18±0.81 HFD), and collagen IV (Sesn2+/+: chow 2.98±0.63 vs 7.35±0.74 HFD, p<0.01; Sesn2-/-: chow 6.26±1.47 vs 6.51±0.76 HFD). Western blot analysis revealed that Sesn2-/- mice fed HFD or chow diets exhibited an upregulation of protein expression of key lipogenic enzymes, fatty acid translocase CD36 (an indicator of lipid uptake) (Sesn2+/+: chow 0.1±0.01 vs 0.4±0.05 HFD, p<0.01; Sesn2-/-: chow 0.45±0.08 vs 0.92±0.09 HFD, p<0.01), fatty acid synthase (Sesn2+/+: chow 0.15±0.02 vs 0.55±0.02 HFD, p<0.01; Sesn2-/-: chow 0.56±0.07 vs 1.1±0.05 HFD, p<0.01) and ATP citrate lyase (ACLY) (Sesn2+/+: chow 0.11±0.01 vs 0.36±0.1 HFD, p<0.01; Sesn2-/-: chow 0.53±0.06 vs 1.32±0.14 HFD, p<0.01). Sesn2-deficiency in obese mice resulted in podocyte loss as indicated by reduced expression of synaptopodin (Sesn2+/+: chow 2.98±0.63 vs 7.35±0.74 HFD, p<0.01; Sesn2-/-: chow 6.26±1.47 vs 6.51±0.76 HFD). Interestingly, glomerular lesions similar to those observed in HFD-fed wild-type mice were detected in Sesn2-/- mice fed a chow diet, indicating that the basal deletion of Sesn2 is deleterious by itself. We provide the first evidence that Sesn2 is renoprotective in obesity-induced nephropathy by diminishing lipid accumulation and blocking excessive lipid uptake and de novo lipid synthesis. Understanding the protective of Sesn2 should yield novel therapeutic interventions to effectively preserve glomerular function in obesity and diabetes.