We have recently described that animal models of diet-induced metabolic syndrome develop an overactivation of the carotid body (CB) (1). This CB overactivation results in an increase in sympathetic nervous system activity and in a reduction in insulin sensitivity and hypertension (1). These pathological features were prevented by chronic carotid sinus nerve (CSN) resection, meaning that the CB is primordial in controlling peripheral insulin sensitivity and that CB dysfunction is involved in the genesis of these disturbances. In the present work, we have investigated if the high-fat diet alters the chemosensory activity of the CSN in basal conditions and in response to CB classical stimuli- hypoxia and hypercapnia. Two groups of male Wistar rats (12-15 weeks) were used. The control (CTL, n=12) group fed a sham diet and the high-fat (HF, n=9) group fed a 60% lipid-rich diet during 21 days. After this period, insulin sensitivity was evaluated by an insulin tolerance test (ITT) and expressed by KITT. For the recording of CSN activity, CB-CSN was dissected and transferred to a recording chamber superfused with Tyrode bicarbonate equilibrated with normoxia (20%O2+5%CO2). Chemoreceptor activity was identified (spontaneous generation of action potentials at regular intervals) and confirmed by its response to hypoxia (0%O2). Protocols consisted in the perfusion of CB-CSN with solutions equilibrated with hypoxias of 2 intensities (0% or 5%O2+5%CO2) and hypercapnia (20%O2+10%CO2). All animals were killed by an intracardiac overdose of pentobarbital sodium (60 mg/kg i.p.). HF diet significantly decreased insulin sensitivity to 1.54±0.30% glucose/min (p<0.001) (KITT CTL=4.44±0.33%glucose/min). HF diet increased basal CSN frequency of discharge by 124.14% (CTL=1.74±0.38 Hz p<0.05). HF diet did not change the CSN chemosensory response to intense hypoxia as it showed a similar area under of the curve (AUC) for the frequency comparing to controls. However, CSN chemosensory response to moderate hypoxia was higher in the HF than in the control group, as the AUC of the frequency curve increased by 86.19% (p<0.05). Interestingly, the latency of the response to intense and moderate hypoxia was significantly decreased by 42.26% (p<0.05) and by 49.59% (p<0.01), respectively in the HF group suggesting a higher responsiveness to hypoxia. Moreover, in the HF group the time to reach the maximal activity (time to peak) was significantly decreased in response to intense hypoxia (CTL=193.82±10.49 sec vs HF=140.70±19.39 sec, p<0.05), without being altered in moderate hypoxia. HF diet did not alter the responses of CSN to hypercapnia. In conclusion, the HF diet increases the basal frequency of the CSN activity and the response to moderate hypoxia as well as the responsiveness to hypoxia.