Background: Intermittent hypoxia (IH) sensitizes the carotid body (CB), a peripheral chemoreceptor located at the carotid bifurcation and plays a vital role in detecting blood oxygen levels and modulating sympathetic nerve activity, which results in an increase in baseline carotid sinus nerve activity (CSN), hypoxic chemoreflex and systemic hypertension. We have previously shown that IH increases plasma leptin levels and that leptin increases CSN activity in obesity by upregulating CB TRPM7. Our unpublished data has shown that IH upregulates both leptin receptor Leprb and Trpm7 gene expression in the CB oxygen sensing type I glomus cells. Hypothesis: IH increases baseline CSN activity and the CB hypoxic chemoreflex and the effects of IH will be augmented by leptin and attenuated by Trpm7 knockout in CB type I glomus cells. Methods: Trpm7 flox (control, N =12) and Trpm7 flox x ThCre (N=12), which have Trpm7 KO in all tyrosine hydroxylase positive cells, including CB type I glomus cells, mice were exposed to 5 days of IH to simulate sleep apnea like cycles (% of O 2 dropping from 21% to 6%O 2 with rapid return to 21% 60 times/hr, N = 6 per strain) or room air (RA, N = 6 per strain). Mice were rapidly sacrificed under 2% isoflurane analgesia, and CB bifurcations were surgically isolated from the IH/RA exposed animals for ex vivo recordings of CSN activityat normoxic (PO 2 =100 Torr) and hypoxic (PO 2 = 60 Torr) conditions, in the absence or presence of leptin (50 nm) and a TRPM7 inhibitor FTY720 (3 mM) in the perfusate. Two-way repeated-measures ANOVA was performed to analyze the effects of condition (RA vs IH), drug (leptin and leptin + FTY720), and their interaction (condition x drug) on basal CSN activity and hypoxia-evoked chemosensitivity Δ(Hx − Nx). Results: (A) In Trpm7 flox control mice, both IH and leptin produced highly significant effects on CSN activity. CSN activity was markedly greater after IH exposure compared to RA (P < 0.001). Leptin significantly increased CSN activity under both RA and IH (P < 0.001), but the effect was much stronger under IH (interaction; P < 0.001). Co-application of FTY720 (3 mM) attenuated the leptin-induced excitation. For ΔCSN activity (Hx − Nx), similar trends were observed: IH (P = 0.009), leptin (P < 0.001), and their interaction (P = 0.012) were all significant and FTY720 abolishing the effect of leptin. (B) In Trpm7 flox x ThCre mice, no significant effect of IH and leptin were detected for basal CSN activity. For the hypoxic chemoreflex ΔCSN activity (Hx − Nx), the effect of IH remained significant (P = 0.007), but leptin and FTY720 produced no significant modulation, in contrast to the strong leptin effect seen in Trpm7 flox controls. Summary & Conclusion: IH augments baseline CSN activity via the leptin-Trpm7 pathway. IH augments the CB hypoxic chemoreflex in the absence of leptin, but leptin amplifies the CB hypoxic chemoreflex, and the effect of leptin was abolished by Trpm7 knockout, which suggests that leptin acts via the Trpm7-dependent mechanism. Targeting the leptin–Trpm7 signaling axis could offer a novel therapeutic approach to alleviate CB–driven sympathetic excitation in metabolic and sleep-related cardiovascular disorders. Supported by NIH Grant # R01 HL133100. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.
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