REGULATION OF FEEDING BEHAVIOUR BY THE MEDIAL SEPTUM IS IMPAIRED IN OBESITY

Food-related sensory cues strongly influence feeding behaviour, yet the neural mechanisms underlying these effects and how they are altered in obesity remain poorly understood. The medial septum contains a population of glutamatergic neurons (MSVGLUT2) that we previously identified as being selectively activated by food odours and suppressing feeding when stimulated prior to the dark phase. Notably, this effect is absent in diet-induced obese mice, prompting us to determine how obesity remodels the septal circuitry and the impact this has on the regulation of feeding.
To assess the responsiveness of MS^VGLUT2 neurons we used in vivo fibre photometry calcium recording and found that MS^VGLUT2 neurons in obese mice were rapidly and robustly activated by food odours, comparable to responses observed in lean controls. Despite intact odour-evoked activation, the chemogenetic activation of MS^VGLUT2 neurons prior to the dark phase reduced food intake exclusively in lean mice while obese mice showed no change in feeding behaviour following the same manipulation, suggesting that the regulatory function of this neuronal population is disrupted in obesity. To further explore this functional impairment, we performed proteomic profiling of the septal region and found that prolonged high-fat feeding altered the protein landscape revealing molecular changes that may disrupt MS^VGLUT2 neuronal signalling.
Together, these findings demonstrate that prolonged obesity preserves sensory responsiveness but fundamentally alters septal circuitry, impairing the ability of MS^VGLUT2 neurons to translate food-related sensory cues into appropriate feeding behaviour.