ScopeSensory neurons expressing the sodium channel Nav1.8 contain a repertoire of receptors for nutrient, hormonal, and inflammatory ligands. However, their function in key regulators of energy homeostasis control is not well understood and is completely unexplored in females.Methods and resultsMice lacking neurons expressing the sodium channel Nav1.8 were generated using an ablation strategy based on cre recombinase‐mediated expression of diphtheria toxin fragment A (DTA) (Nav1.8‐cre/DTA mice) to investigate whether these neurons modulate body weight, food intake, gut hormone secretion, gastrointestinal transit, and glucose tolerance in response to nutrient challenges in a sex‐dependent manner. Male Nav1.8‐cre/DTA mice show resistance to gain weight in response to high‐fat high‐sugar diet (HFHSD), whereas females lacking Nav1.8+ neurons have improved oral glucose tolerance accompanied by higher insulin levels and attenuated glucagon secretion after an oral glucose load. Female Nav1.8‐cre/DTA mice also show higher fasting and postprandial glucagon like peptide‐1 (GLP‐1) levels with an increased number of GLP‐1‐positive cells. Finally, ablation of Nav1.8‐expressing neurons accelerates the gastrointestinal transit in female mice under HFHSD.ConclusionThis data demonstrates sex‐dependent differences in the Nav1.8‐mediated regulation of energy metabolism, and provides new insights that may help in the design of sex‐specific neuromodulation therapies for metabolic disorders induced by diets rich in fats and simple sugars.