Early central cardiovagal dysfunction after high fat diet in a murine model

Misty M. Strain; Liliana Espinoza; Stephanie Fedorchak; Erica L. Littlejohn; Mary Ann Andrade; Glenn M. Toney; Carie R. Boychuk

doi:10.1038/s41598-023-32492-w

Early central cardiovagal dysfunction after high fat diet in a murine model

Misty M. Strain, Liliana Espinoza, Stephanie Fedorchak, Erica L. Littlejohn, Mary Ann Andrade, Glenn M. Toney, Carie R. Boychuk

Behavioral Science

Research output: Contribution to journal › Article › peer-review

Abstract

High fat diet (HFD) promotes cardiovascular disease and blunted cardiac vagal regulation. Temporal onset of loss of cardiac vagal control and its underlying mechanism are presently unclear. We tested our hypothesis that reduced central vagal regulation occurs early after HFD and contributes to poor cardiac regulation using cardiovascular testing paired with pharmacology in mice, molecular biology, and a novel bi-transgenic mouse line. Results show HFD, compared to normal fat diet (NFD), significantly blunted cardio/pulmonary chemoreflex bradycardic responses after 15 days, extending as far as tested (> 30 days). HFD produced resting tachycardia by day 3, reflected significant loss of parasympathetic tone. No differences in bradycardic responses to graded electrical stimulation of the distal cut end of the cervical vagus indicated diet-induced differences in vagal activity were centrally mediated. In nucleus ambiguus (NA), surface expression of δ-subunit containing type A gamma-aminobutyric acid receptors (GABA_A(δ)R) increased at day 15 of HFD. Novel mice lacking δ-subunit expression in vagal motor neurons (ChAT-δ^null) failed to exhibit blunted reflex bradycardia or resting tachycardia after two weeks of HFD. Thus, reduced parasympathetic output contributes to early HFD-induced HR dysregulation, likely through increased GABA_A(δ)Rs. Results underscore need for research on mechanisms of early onset increases in GABA_A(δ)R expression and parasympathetic dysfunction after HFD.

Original language	English
Article number	6550
Journal	Scientific Reports
Volume	13
Issue number	1
DOIs	https://doi.org/10.1038/s41598-023-32492-w
State	Published - Dec 2023

Bibliographical note

Funding Information:
This research was supported by NIH R01 HL157366 to CRB, American Heart Association 20PRE35180105 to LE, and NIH T32 HL007446 for MMS. We would like to thank Raehum Paik, B.S. and Selika Garza, B.S. at The Mouse Genome Engineering and Transgenic Facility at UT Health San Antonio for their help characterizing and managing our transgenic mouse line. qRT-PCR sequencing was performed by Bioanalytic and Single-cell core (BASiC) at UT Health San Antonio.

Funding Information:
This research was supported by NIH R01 HL157366 to CRB, American Heart Association 20PRE35180105 to LE, and NIH T32 HL007446 for MMS. We would like to thank Raehum Paik, B.S. and Selika Garza, B.S. at The Mouse Genome Engineering and Transgenic Facility at UT Health San Antonio for their help characterizing and managing our transgenic mouse line. qRT-PCR sequencing was performed by Bioanalytic and Single-cell core (BASiC) at UT Health San Antonio.

Publisher Copyright:
© 2023, The Author(s).

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Cite this

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title = "Early central cardiovagal dysfunction after high fat diet in a murine model",

abstract = "High fat diet (HFD) promotes cardiovascular disease and blunted cardiac vagal regulation. Temporal onset of loss of cardiac vagal control and its underlying mechanism are presently unclear. We tested our hypothesis that reduced central vagal regulation occurs early after HFD and contributes to poor cardiac regulation using cardiovascular testing paired with pharmacology in mice, molecular biology, and a novel bi-transgenic mouse line. Results show HFD, compared to normal fat diet (NFD), significantly blunted cardio/pulmonary chemoreflex bradycardic responses after 15 days, extending as far as tested (> 30 days). HFD produced resting tachycardia by day 3, reflected significant loss of parasympathetic tone. No differences in bradycardic responses to graded electrical stimulation of the distal cut end of the cervical vagus indicated diet-induced differences in vagal activity were centrally mediated. In nucleus ambiguus (NA), surface expression of δ-subunit containing type A gamma-aminobutyric acid receptors (GABAA(δ)R) increased at day 15 of HFD. Novel mice lacking δ-subunit expression in vagal motor neurons (ChAT-δnull) failed to exhibit blunted reflex bradycardia or resting tachycardia after two weeks of HFD. Thus, reduced parasympathetic output contributes to early HFD-induced HR dysregulation, likely through increased GABAA(δ)Rs. Results underscore need for research on mechanisms of early onset increases in GABAA(δ)R expression and parasympathetic dysfunction after HFD.",

author = "Strain, {Misty M.} and Liliana Espinoza and Stephanie Fedorchak and Littlejohn, {Erica L.} and Andrade, {Mary Ann} and Toney, {Glenn M.} and Boychuk, {Carie R.}",

note = "Funding Information: This research was supported by NIH R01 HL157366 to CRB, American Heart Association 20PRE35180105 to LE, and NIH T32 HL007446 for MMS. We would like to thank Raehum Paik, B.S. and Selika Garza, B.S. at The Mouse Genome Engineering and Transgenic Facility at UT Health San Antonio for their help characterizing and managing our transgenic mouse line. qRT-PCR sequencing was performed by Bioanalytic and Single-cell core (BASiC) at UT Health San Antonio. Funding Information: This research was supported by NIH R01 HL157366 to CRB, American Heart Association 20PRE35180105 to LE, and NIH T32 HL007446 for MMS. We would like to thank Raehum Paik, B.S. and Selika Garza, B.S. at The Mouse Genome Engineering and Transgenic Facility at UT Health San Antonio for their help characterizing and managing our transgenic mouse line. qRT-PCR sequencing was performed by Bioanalytic and Single-cell core (BASiC) at UT Health San Antonio. Publisher Copyright: {\textcopyright} 2023, The Author(s).",

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AU - Andrade, Mary Ann

AU - Toney, Glenn M.

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N1 - Funding Information: This research was supported by NIH R01 HL157366 to CRB, American Heart Association 20PRE35180105 to LE, and NIH T32 HL007446 for MMS. We would like to thank Raehum Paik, B.S. and Selika Garza, B.S. at The Mouse Genome Engineering and Transgenic Facility at UT Health San Antonio for their help characterizing and managing our transgenic mouse line. qRT-PCR sequencing was performed by Bioanalytic and Single-cell core (BASiC) at UT Health San Antonio. Funding Information: This research was supported by NIH R01 HL157366 to CRB, American Heart Association 20PRE35180105 to LE, and NIH T32 HL007446 for MMS. We would like to thank Raehum Paik, B.S. and Selika Garza, B.S. at The Mouse Genome Engineering and Transgenic Facility at UT Health San Antonio for their help characterizing and managing our transgenic mouse line. qRT-PCR sequencing was performed by Bioanalytic and Single-cell core (BASiC) at UT Health San Antonio. Publisher Copyright: © 2023, The Author(s).

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Early central cardiovagal dysfunction after high fat diet in a murine model

Abstract

Bibliographical note

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