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Role of Leptin‐TRPM7 Signaling in Carotid Bodies in the Pathogenesis of Sleep‐Disordered Breathing in Obesity
Author(s) -
Kim Lenise,
Shin MiKyung,
Pho Huy,
Hosamane Nishitha,
AnokyeDanso Frederick,
Ahima Rexford,
Pham Luu,
Polotsky Vsevolod
Publication year - 2021
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2021.35.s1.02610
Subject(s) - leptin , medicine , endocrinology , intermittent hypoxia , ventilation (architecture) , hypoxic ventilatory response , trpm7 , carotid body , obesity , respiratory system , obstructive sleep apnea , receptor , transient receptor potential channel , mechanical engineering , carotid arteries , engineering
Sleep‐disordered breathing (SDB) affects over 50% of obese individuals. Augmented ventilatory response to hypoxia (HVR) leads to respiratory instability and is one of the cardinal traits of SDB in obesity. Peripheral sensing of hypoxia is mainly govern by the carotid bodies (CB). We have shown that leptin, an adipocyte‐produced hormone, acts in the CB to increase ventilation and HVR possibly through the activation of transient receptor potential melastatin 7 (TRPM7) channels. However, the relevance of these findings to diet‐induced obese (DIO) mice has not been demonstrated and the effect of leptin‐TRPM7 signaling in CB on SDB remains unknown. We hypothesized that leptin acts via TRPM7 in the CB to increase the hypoxic chemoreflex leading to SDB in obesity. Methods Male C57BL/6J mice (12 wks‐old, n=17) were fed with high fat diet for 8 weeks. DIO mice were headmounted with EEG/EMG electrodes and underwent a full‐polysomnography in a whole‐body plethysmography chamber. Baseline HVR (10% O 2 +3% CO 2 vs 20.9% O 2 ) was performed while awake. Subsequently mice were transfected with Ad‐mCherry‐U6‐m‐Trpm7‐shRNA (Trpm7 shRNA, n=9) or control shRNA (n=8) in Matrigel @ administered to the CB area bilaterally. Mice recovered for 9‐10 days and HVR/sleep studies were repeated. Another subset of DIO mice (n=5/group) underwent 24‐h metabolic studies. Results Trpm 7 knockdown in the CB significantly decreased minute ventilation during hypoxia and suppressed HVR during wakefulness compared to baseline ( P <0.01) and to control group ( P <0.05). Trpm7 shRNA in the CB increased inspiratory flow, tidal volume and minute ventilation (0.69±0.1 vs 0.81±0.1 mL/min/g) during NREM sleep ( P <0.05) with no significant effects on sleep architecture. Consumed O 2 , produced CO 2 , and respiratory exchange ratio did not change with the Trpm7 knockdown in the CB. Conclusions Trpm7 knockdown in the CB attenuates the hypoxic chemoreflex during wakefulness and improves the obesity‐induced hypoventilation of DIO mice during NREM sleep. Thus, leptin‐TRPM7 signaling in the CB could be a potential therapeutic target for the treatment of obesity‐related SDB.