Leptin acts in the carotid bodies to increase minute ventilation during wakefulness and sleep and augment the hypoxic ventilatory response

Candela Caballero-Eraso, Mi-Kyung Shin, Huy Pho, Lenise J. Kim, Luis E. Pichard, Zhi Juan Wu, Chenjuan Gu, Slava Berger, Luu Pham, Ho Yee (Bonnie) Yeung, Machiko Shirahata, Alan R Schwartz, Wan-Yee Tang, James Sham, Vsevolod Polotsky

Research output: Contribution to journalArticle

Abstract

Key points: Leptin is a potent respiratory stimulant. A long functional isoform of leptin receptor, LepRb, was detected in the carotid body (CB), a key peripheral hypoxia sensor. However, the effect of leptin on minute ventilation (VE) and the hypoxic ventilatory response (HVR) has not been sufficiently studied. We report that LepRb is present in approximately 74% of the CB glomus cells. Leptin increased carotid sinus nerve activity at baseline and in response to hypoxia in vivo. Subcutaneous infusion of leptin increased VE and HVR in C57BL/6J mice and this effect was abolished by CB denervation. Expression of LepRb in the carotid bodies of LepRb deficient obese db/db mice increased VE during wakefulness and sleep and augmented the HVR. We conclude that leptin acts on LepRb in the CBs to stimulate breathing and HVR, which may protect against sleep disordered breathing in obesity. Abstract: Leptin is a potent respiratory stimulant. The carotid bodies (CB) express the long functional isoform of leptin receptor, LepRb, but the role of leptin in CB has not been fully elucidated. The objectives of the current study were (1) to examine the effect of subcutaneous leptin infusion on minute ventilation (VE) and the hypoxic ventilatory response to 10% O2 (HVR) in C57BL/6J mice before and after CB denervation; (2) to express LepRb in CB of LepRb-deficient obese db/db mice and examine its effects on breathing during sleep and wakefulness and on HVR. We found that leptin enhanced carotid sinus nerve activity at baseline and in response to 10% O2 in vivo. In C57BL/6J mice, leptin increased VE from 1.1 to 1.5 mL/min/g during normoxia (P < 0.01) and from 3.6 to 4.7 mL/min/g during hypoxia (P < 0.001), augmenting HVR from 0.23 to 0.31 mL/min/g/Δ FIO2 (P < 0.001). The effects of leptin on VE and HVR were abolished by CB denervation. In db/db mice, LepRb expression in CB increased VE from 1.1 to 1.3 mL/min/g during normoxia (P < 0.05) and from 2.8 to 3.2 mL/min/g during hypoxia (P < 0.02), increasing HVR. Compared to control db/db mice, LepRb transfected mice showed significantly higher VE throughout non-rapid eye movement (20.1 vs. −27.7 mL/min respectively, P < 0.05) and rapid eye movement sleep (16.5 vs 23.4 mL/min, P < 0.05). We conclude that leptin acts in CB to augment VE and HVR, which may protect against sleep disordered breathing in obesity.

Original languageEnglish (US)
JournalJournal of Physiology
DOIs
StateAccepted/In press - Jan 1 2018

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Carotid Body
Wakefulness
Leptin
Ventilation
Sleep
Denervation
Respiratory System Agents
Inbred C57BL Mouse
Leptin Receptors
Subcutaneous Infusions
Carotid Sinus
Sleep Apnea Syndromes
Protein Isoforms
Respiration
Obesity
REM Sleep
Eye Movements

Keywords

  • Carotid Body
  • Leptin
  • Sleep Apnoea

ASJC Scopus subject areas

  • Physiology

Cite this

Leptin acts in the carotid bodies to increase minute ventilation during wakefulness and sleep and augment the hypoxic ventilatory response. / Caballero-Eraso, Candela; Shin, Mi-Kyung; Pho, Huy; Kim, Lenise J.; Pichard, Luis E.; Wu, Zhi Juan; Gu, Chenjuan; Berger, Slava; Pham, Luu; Yeung, Ho Yee (Bonnie); Shirahata, Machiko; Schwartz, Alan R; Tang, Wan-Yee; Sham, James; Polotsky, Vsevolod.

In: Journal of Physiology, 01.01.2018.

Research output: Contribution to journalArticle

Caballero-Eraso, Candela ; Shin, Mi-Kyung ; Pho, Huy ; Kim, Lenise J. ; Pichard, Luis E. ; Wu, Zhi Juan ; Gu, Chenjuan ; Berger, Slava ; Pham, Luu ; Yeung, Ho Yee (Bonnie) ; Shirahata, Machiko ; Schwartz, Alan R ; Tang, Wan-Yee ; Sham, James ; Polotsky, Vsevolod. / Leptin acts in the carotid bodies to increase minute ventilation during wakefulness and sleep and augment the hypoxic ventilatory response. In: Journal of Physiology. 2018.
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abstract = "Key points: Leptin is a potent respiratory stimulant. A long functional isoform of leptin receptor, LepRb, was detected in the carotid body (CB), a key peripheral hypoxia sensor. However, the effect of leptin on minute ventilation (VE) and the hypoxic ventilatory response (HVR) has not been sufficiently studied. We report that LepRb is present in approximately 74{\%} of the CB glomus cells. Leptin increased carotid sinus nerve activity at baseline and in response to hypoxia in vivo. Subcutaneous infusion of leptin increased VE and HVR in C57BL/6J mice and this effect was abolished by CB denervation. Expression of LepRb in the carotid bodies of LepRb deficient obese db/db mice increased VE during wakefulness and sleep and augmented the HVR. We conclude that leptin acts on LepRb in the CBs to stimulate breathing and HVR, which may protect against sleep disordered breathing in obesity. Abstract: Leptin is a potent respiratory stimulant. The carotid bodies (CB) express the long functional isoform of leptin receptor, LepRb, but the role of leptin in CB has not been fully elucidated. The objectives of the current study were (1) to examine the effect of subcutaneous leptin infusion on minute ventilation (VE) and the hypoxic ventilatory response to 10{\%} O2 (HVR) in C57BL/6J mice before and after CB denervation; (2) to express LepRb in CB of LepRb-deficient obese db/db mice and examine its effects on breathing during sleep and wakefulness and on HVR. We found that leptin enhanced carotid sinus nerve activity at baseline and in response to 10{\%} O2 in vivo. In C57BL/6J mice, leptin increased VE from 1.1 to 1.5 mL/min/g during normoxia (P < 0.01) and from 3.6 to 4.7 mL/min/g during hypoxia (P < 0.001), augmenting HVR from 0.23 to 0.31 mL/min/g/Δ FIO2 (P < 0.001). The effects of leptin on VE and HVR were abolished by CB denervation. In db/db mice, LepRb expression in CB increased VE from 1.1 to 1.3 mL/min/g during normoxia (P < 0.05) and from 2.8 to 3.2 mL/min/g during hypoxia (P < 0.02), increasing HVR. Compared to control db/db mice, LepRb transfected mice showed significantly higher VE throughout non-rapid eye movement (20.1 vs. −27.7 mL/min respectively, P < 0.05) and rapid eye movement sleep (16.5 vs 23.4 mL/min, P < 0.05). We conclude that leptin acts in CB to augment VE and HVR, which may protect against sleep disordered breathing in obesity.",
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T1 - Leptin acts in the carotid bodies to increase minute ventilation during wakefulness and sleep and augment the hypoxic ventilatory response

AU - Caballero-Eraso, Candela

AU - Shin, Mi-Kyung

AU - Pho, Huy

AU - Kim, Lenise J.

AU - Pichard, Luis E.

AU - Wu, Zhi Juan

AU - Gu, Chenjuan

AU - Berger, Slava

AU - Pham, Luu

AU - Yeung, Ho Yee (Bonnie)

AU - Shirahata, Machiko

AU - Schwartz, Alan R

AU - Tang, Wan-Yee

AU - Sham, James

AU - Polotsky, Vsevolod

PY - 2018/1/1

Y1 - 2018/1/1

N2 - Key points: Leptin is a potent respiratory stimulant. A long functional isoform of leptin receptor, LepRb, was detected in the carotid body (CB), a key peripheral hypoxia sensor. However, the effect of leptin on minute ventilation (VE) and the hypoxic ventilatory response (HVR) has not been sufficiently studied. We report that LepRb is present in approximately 74% of the CB glomus cells. Leptin increased carotid sinus nerve activity at baseline and in response to hypoxia in vivo. Subcutaneous infusion of leptin increased VE and HVR in C57BL/6J mice and this effect was abolished by CB denervation. Expression of LepRb in the carotid bodies of LepRb deficient obese db/db mice increased VE during wakefulness and sleep and augmented the HVR. We conclude that leptin acts on LepRb in the CBs to stimulate breathing and HVR, which may protect against sleep disordered breathing in obesity. Abstract: Leptin is a potent respiratory stimulant. The carotid bodies (CB) express the long functional isoform of leptin receptor, LepRb, but the role of leptin in CB has not been fully elucidated. The objectives of the current study were (1) to examine the effect of subcutaneous leptin infusion on minute ventilation (VE) and the hypoxic ventilatory response to 10% O2 (HVR) in C57BL/6J mice before and after CB denervation; (2) to express LepRb in CB of LepRb-deficient obese db/db mice and examine its effects on breathing during sleep and wakefulness and on HVR. We found that leptin enhanced carotid sinus nerve activity at baseline and in response to 10% O2 in vivo. In C57BL/6J mice, leptin increased VE from 1.1 to 1.5 mL/min/g during normoxia (P < 0.01) and from 3.6 to 4.7 mL/min/g during hypoxia (P < 0.001), augmenting HVR from 0.23 to 0.31 mL/min/g/Δ FIO2 (P < 0.001). The effects of leptin on VE and HVR were abolished by CB denervation. In db/db mice, LepRb expression in CB increased VE from 1.1 to 1.3 mL/min/g during normoxia (P < 0.05) and from 2.8 to 3.2 mL/min/g during hypoxia (P < 0.02), increasing HVR. Compared to control db/db mice, LepRb transfected mice showed significantly higher VE throughout non-rapid eye movement (20.1 vs. −27.7 mL/min respectively, P < 0.05) and rapid eye movement sleep (16.5 vs 23.4 mL/min, P < 0.05). We conclude that leptin acts in CB to augment VE and HVR, which may protect against sleep disordered breathing in obesity.

AB - Key points: Leptin is a potent respiratory stimulant. A long functional isoform of leptin receptor, LepRb, was detected in the carotid body (CB), a key peripheral hypoxia sensor. However, the effect of leptin on minute ventilation (VE) and the hypoxic ventilatory response (HVR) has not been sufficiently studied. We report that LepRb is present in approximately 74% of the CB glomus cells. Leptin increased carotid sinus nerve activity at baseline and in response to hypoxia in vivo. Subcutaneous infusion of leptin increased VE and HVR in C57BL/6J mice and this effect was abolished by CB denervation. Expression of LepRb in the carotid bodies of LepRb deficient obese db/db mice increased VE during wakefulness and sleep and augmented the HVR. We conclude that leptin acts on LepRb in the CBs to stimulate breathing and HVR, which may protect against sleep disordered breathing in obesity. Abstract: Leptin is a potent respiratory stimulant. The carotid bodies (CB) express the long functional isoform of leptin receptor, LepRb, but the role of leptin in CB has not been fully elucidated. The objectives of the current study were (1) to examine the effect of subcutaneous leptin infusion on minute ventilation (VE) and the hypoxic ventilatory response to 10% O2 (HVR) in C57BL/6J mice before and after CB denervation; (2) to express LepRb in CB of LepRb-deficient obese db/db mice and examine its effects on breathing during sleep and wakefulness and on HVR. We found that leptin enhanced carotid sinus nerve activity at baseline and in response to 10% O2 in vivo. In C57BL/6J mice, leptin increased VE from 1.1 to 1.5 mL/min/g during normoxia (P < 0.01) and from 3.6 to 4.7 mL/min/g during hypoxia (P < 0.001), augmenting HVR from 0.23 to 0.31 mL/min/g/Δ FIO2 (P < 0.001). The effects of leptin on VE and HVR were abolished by CB denervation. In db/db mice, LepRb expression in CB increased VE from 1.1 to 1.3 mL/min/g during normoxia (P < 0.05) and from 2.8 to 3.2 mL/min/g during hypoxia (P < 0.02), increasing HVR. Compared to control db/db mice, LepRb transfected mice showed significantly higher VE throughout non-rapid eye movement (20.1 vs. −27.7 mL/min respectively, P < 0.05) and rapid eye movement sleep (16.5 vs 23.4 mL/min, P < 0.05). We conclude that leptin acts in CB to augment VE and HVR, which may protect against sleep disordered breathing in obesity.

KW - Carotid Body

KW - Leptin

KW - Sleep Apnoea

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