Diet-induced obesity in mice increases carotid body chemosensitivity via the leptin-TRPM7 pathway: implications for obesity-induced hypertension

Obesity is associated with increased circulating level of the hormone leptin. Previously we have shown in mice that, leptin induces hypertension acting on transient receptor potential melastatin 7 (Trpm7) channels in the carotid body (CB), a multi-modal peripheral chemoreceptor that controls breathing and drives sympathetic tone. Further, leptin augments hypoxic ventilatory response in mice, and the response is abolished by CB denervation. This suggests a potential increase in CB chemosensitivity. However, no comparative study of CB chemosensory responses has been conducted in lean and obese mice to support this notion. To address this, we measured afferent carotid sinus nerve (CSN) activity, using a novel ex vivo perfused mouse (male/female) CB preparation from four groups of mice with C57BL/6J background : (i) lean (male b.w. 35 ± 0.5 gm and female b.w.24±1.8 gm), (ii) obese (DIO) (male b.w. 53 ± 1.5gm), (iii) Trpm7 flox -DIO + Ad-Cre-GFP (male b.w. 42± 1.2gm and (iv) Trpm7 flox -DIO + Ad-GFP (male b.w. 41± 1.4 gm). We found that in obese male mice, compared to lean male mice; (a) CB CSN baseline activity and response to hypoxia (PO 2 =60 Torr) were 50% greater, (b) in presence of leptin (50nM), CB CSN responses to normoxia (PO 2 =100Torr) and hypoxia were 50% and 150% greater respectively. Leptin-induced increase in CB CSN responses were reduced by Trpm7 antagonist FTY720 (3µM) in both lean and obese animals. There was no significant difference between CB chemosensitivity response to leptin in lean male and female mice.Trpm7 knockdown in CB did not affect hypoxic chemoreflex, but abolished responses to leptin and FTY720. Immuno-quantification of Trpm7 receptors indicated overall upregulation of CB Trpm7 receptor in obese compared to lean mice. We conclude that, increased sensitization of CB in obese mice leads to increase in CB chemosensitivity compared to lean mice and functional inhibition of CB Trpm7 receptors could be a therapeutic target for obesity related hypertension. Grant support: NIH R01 HL1331000. This abstract was presented at the American Physiology Summit 2025 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.