Sex-specific alterations in CRF and dopaminergic markers in the lateral septum and mesolimbic system following chronic high-fat diet exposure in rats

Background Obesity is a global health concern closely associated with sedentary lifestyles and the consumption of hypercaloric, hyperpalatable diets. While these factors contribute to excessive food intake and weight gain, the long-term impact of obesogenic diets on neural circuits regulating energy balance remains insufficiently understood. Previous research has identified the lateral septum (LS) as a critical structure involved in stress responses and addiction, with corticotropin-releasing factor (CRF) and dopaminergic signalling playing key roles. However, the influence of chronic high fat diet (HFD) exposure on LS function and its contribution to feeding regulation remains poorly characterized. Methods and Results Male and female Sprague–Dawley rats were fed either a high fat diet (HFD) or standard chow from postnatal day 21–62. Chronic HFD exposure induced anxiolytic-like behavior and increased CRF in the LS of males. In females, HFD elevated dopamine D 1 and D 2 receptor expression, as well as CRF receptor type 2 (CRF 2 ), compared to controls. Moreover, dopamine metabolite levels were elevated in mesolimbic regions in both sexes following HFD exposure. Conclusion These results indicate that the LS undergoes sex-specific molecular and cellular alterations in response to prolonged HFD consumption. The observed alterations in dopamine and CRF signalling suggest that the LS may mediate diet-induced dysregulation of both homeostatic and hedonic aspects of feeding. These findings provide novel insights into the neural mechanisms by which chronic exposure to an obesogenic diet may promote overeating and obesity.