Abstract
The fundamental importance of the hypothalamus in the regulation of autonomic and cardiovascular functions is well established. However, the molecular processes involved are not well understood. Here, we show that the mammalian (or mechanistic) target of rapamycin (mTOR) signaling in the hypothalamus is tied to the activity of the sympathetic nervous system and to cardiovascular function. Modulation of mTOR complex 1 (mTORC1) signaling caused dramatic changes in sympathetic traffic, blood flow, and arterial pressure. Our data also demonstrate the importance of hypothalamic mTORC1 signaling in transducing the sympathetic and cardiovascular actions of leptin. Moreover, we show that the PI3K pathway links the leptin receptor to mTORC1 signaling and that changes in its activity impact sympathetic traffic and arterial pressure. These findings establish mTORC1 activity in the hypothalamus as a key determinant of sympathetic and cardiovascular regulation and suggest that dysregulated hypothalamic mTORC1 activity may influence the development of cardiovascular diseases.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Arterial Pressure / drug effects
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Class I Phosphatidylinositol 3-Kinases / antagonists & inhibitors
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Class I Phosphatidylinositol 3-Kinases / genetics
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Class I Phosphatidylinositol 3-Kinases / metabolism
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Hypothalamus / metabolism*
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Leptin / metabolism*
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Leucine / pharmacology
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Mechanistic Target of Rapamycin Complex 1
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Mice
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Mice, Inbred C57BL
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Multiprotein Complexes
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Phosphatidylinositol 3-Kinases / metabolism
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Phosphoinositide-3 Kinase Inhibitors
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Phosphorylation
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Proteins / antagonists & inhibitors
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Proteins / metabolism*
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RNA Interference
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RNA, Small Interfering / metabolism
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Rats
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Rats, Sprague-Dawley
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Receptors, Leptin / metabolism
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Ribosomal Protein S6 Kinases, 70-kDa / metabolism
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Signal Transduction / drug effects
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Sirolimus / pharmacology
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Sympathetic Nervous System / drug effects
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Sympathetic Nervous System / metabolism
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TOR Serine-Threonine Kinases
Substances
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Leptin
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Multiprotein Complexes
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Phosphoinositide-3 Kinase Inhibitors
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Proteins
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RNA, Small Interfering
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Receptors, Leptin
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Class I Phosphatidylinositol 3-Kinases
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p110delta protein, rat
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Mechanistic Target of Rapamycin Complex 1
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Ribosomal Protein S6 Kinases, 70-kDa
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TOR Serine-Threonine Kinases
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Leucine
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Sirolimus