Diet-induced obesity in mice increases carotid body chemosensitivity via the leptin-TRPM7 pathway

Authors

Arijit Roy, Department of Anesthesiology & Critical Care Medicine, The George Washington University, Washington, DC, USA.
Mi-Kyung Shin, Department of Anesthesiology & Critical Care Medicine, The George Washington University, Washington, DC, USA.
Dashdulam Davaanyam, Department of Anesthesiology & Critical Care Medicine, The George Washington University, Washington, DC, USA.
Noah Williams, Department of Anesthesiology & Critical Care Medicine, The George Washington University, Washington, DC, USA.
Sean M. Lee, Department of Surgery, Office of Clinical Research, The George Washington University, Washington, DC, USA.
Wan-Yee Tang, Department of Environmental and Occupational Health, University of Pittsburgh Graduate School of Public Health, Pittsburgh, Pennsylvania, USA.
Vsevolod Y. Polotsky, Department of Anesthesiology & Critical Care Medicine, The George Washington University, Washington, DC, USA.

Document Type

Journal Article

Publication Date

9-1-2025

Journal

The Journal of physiology

Volume

603

Issue

17

DOI

10.1113/JP288722

Keywords

Trpm7; carotid body; hypertension; leptin; obesity

Abstract

Diet-induced obesity (DIO) is associated with increased circulating level of the hormone leptin. We have previously shown that leptin augments hypoxic ventilatory response in mice, and the response is abolished by carotid body (CB) denervation, and that leptin induces hypertension in DIO acting on transient receptor potential melastatin 7 (Trpm7) channels in CB. However CB chemosensory responses in DIO have not been sufficiently elucidated. The aim of this study was to examine the effects of DIO and leptin on carotid sinus nerve (CSN) activity and the role of Trpm7 at normoxic and hypoxic conditions. We measured afferent CSN activity using a novel ex vivo perfused CB preparation in four groups of mice on the C57BL/6J background: lean wild type, DIO wildtype, Trpm7-DIO transfected with adenoviral vectors harbouring Cre-recombinase and green fluorescent protein (Ad-Cre-GFP) or control GFP (Ad-GFP). Leptin augmented CSN responses to normoxic (PO = 100 Torr) and hypoxic (PO = 60 Torr) conditions. Compared to lean male mice, in DIO mice (a) CSN response to hypoxia was 50% greater, (b) leptin had a greater impact on CSN activity at normoxic and hypoxic conditions. Leptin-induced CSN activities were attenuated by Trpm7 antagonist FTY720 and by Trpm7 knockdown in CB. There was no significant difference between CB chemosensitivity response to leptin in male and female mice. We conclude that CB chemosensitivity is increased in DIO compared to lean mice, and CB Trpm7 channel could be a therapeutic target for obesity-related hypertension. KEY POINTS: We have developed a novel ex vivo perfused murine carotid body (CB) preparation to evaluate carotid sinus nerve (CSN) activity using physiologically relevant levels of PO at normoxic and hypoxic conditions. Diet-induced obesity (DIO) increases baseline (normoxic) CSN activity, independent of leptin. DIO augments CB hypoxic chemoreflex gain via leptin. The effect of leptin on CB hypoxic chemoreflex is completely abolished by a Trpm7 blocker FTY720 and prevented by Trpm7 knockdown in CB. FTY720 does not have any effect on CSN activity in the absence of leptin. Taken together our new findings provide direct evidence that obesity increases CB chemoreflex via the leptin-Trpm7 pathway.

APA Citation

Roy, Arijit; Shin, Mi-Kyung; Davaanyam, Dashdulam; Williams, Noah; Lee, Sean M.; Tang, Wan-Yee; and Polotsky, Vsevolod Y., "Diet-induced obesity in mice increases carotid body chemosensitivity via the leptin-TRPM7 pathway" (2025). GW Authored Works. Paper 7696.
https://hsrc.himmelfarb.gwu.edu/gwhpubs/7696

Department

School of Medicine and Health Sciences Student Works