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This study aimed at investigating the alteration of lipid serum profile and histopathological damage in Psammomys obesus fed different high calorie diets. Animals were randomly assigned to four groups. P. obesus of the control group were fed with a Low-Calorie natural Diet, the Chenopodicae plant (0.42 kcal/g). The three other groups were fed high calorie diets rich in carbohydrates and protein or rich in carbohydrates and fat (~3.5 - 4.7 kcal/g). Lipid serum profile was assessed bimonthly during seven-month diets. The recorded energy intake was significantly high in the groups fed high calorie diets compared with the control group. Body weight was significantly increased in animal groups fed high calorie diets. All Psammomys obesus fed high-calorie diets developed dyslipidemia with the distinction of different sub-groups developing or not obesity and diabetes. High calorie diets rich in carbohydrates and fat induced a remarkable increase in lipid serum biomarkers indicating a fast induction of dyslipidemia from the first month of the experiment with a significant increase in transaminase activities after two months revealing pronounced hepatotoxicity and nephrotoxicity which were confirmed by a significant increase in liver and kidney relative weight and adiposity index. Severe histological alterations were recorded in obese, diabetic and dyslipidemic Psammomys obesus with a noticeable hypertrophy of the adipocytes, glomeruli and islets of Langerhans, as well as increased hepatic lipid droplet accumulation, apoptosis, necrosis and inflammation. A significant decrease in the thickness of the whole retinal layer was also observed after seven-months diet.  Animals fed Low-calorie natural diet don’t show any signs of obesity, dyslipidemia or diabetes. The high calorie diets induced rapid and severe changes in body weight, severe metabolic syndrome and histopathological features causing organ structural and functional injuries. Psammomys obesus seems like an excellent model for studying nutritional pathophysiological-metabolic disorders including obesity, diabetes, dyslipidemia and their complications, particularly diabetic retinopathy, comparable to those of human metabolic processes.