Oral nitrite restores age-dependent phenotypes in eNOS-null mice
Alterations in the synthesis and bioavailability of NO are central to the pathogenesis of cardiovascular and metabolic disorders. Although endothelial NO synthase-derived (eNOS-derived) NO affects mitochondrial long-chain fatty acid β-oxidation, the pathophysiological significance of this regulation...
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| creator | Tenopoulou, Margarita Doulias, Paschalis-Thomas Nakamoto, Kent Berrios, Kiara Zura, Gabriella Li, Chenxi Faust, Michael Yakovishina, Veronika Evans, Perry Tan, Lu Bennett, Michael J Snyder, Nathaniel W Quinn, 3rd, William J Baur, Joseph A Atochin, Dmitriy N Huang, Paul L Ischiropoulos, Harry |
| description | Alterations in the synthesis and bioavailability of NO are central to the pathogenesis of cardiovascular and metabolic disorders. Although endothelial NO synthase-derived (eNOS-derived) NO affects mitochondrial long-chain fatty acid β-oxidation, the pathophysiological significance of this regulation remains unclear. Accordingly, we determined the contributions of eNOS/NO signaling in the adaptive metabolic responses to fasting and in age-induced metabolic dysfunction. Four-month-old eNOS-/- mice are glucose intolerant and exhibit serum dyslipidemia and decreased capacity to oxidize fatty acids. However, during fasting, eNOS-/- mice redirect acetyl-CoA to ketogenesis to elevate circulating levels of β-hydroxybutyrate similar to wild-type mice. Treatment of 4-month-old eNOS-/- mice with nitrite for 10 days corrected the hypertension and serum hyperlipidemia and normalized the rate of fatty acid oxidation. Fourteen-month-old eNOS-/- mice exhibited metabolic derangements, resulting in reduced utilization of fat to generate energy, lower resting metabolic activity, and diminished physical activity. Seven-month administration of nitrite to eNOS-/- mice reversed the age-dependent metabolic derangements and restored physical activity. While the eNOS/NO signaling is not essential for the metabolic adaptation to fasting, it is critical for regulating systemic metabolic homeostasis in aging. The development of age-dependent metabolic disorder is prevented by low-dose replenishment of bioactive NO. |
| doi_str_mv | 10.1172/jci.insight.122156 |
| format | Article |
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Although endothelial NO synthase-derived (eNOS-derived) NO affects mitochondrial long-chain fatty acid β-oxidation, the pathophysiological significance of this regulation remains unclear. Accordingly, we determined the contributions of eNOS/NO signaling in the adaptive metabolic responses to fasting and in age-induced metabolic dysfunction. Four-month-old eNOS-/- mice are glucose intolerant and exhibit serum dyslipidemia and decreased capacity to oxidize fatty acids. However, during fasting, eNOS-/- mice redirect acetyl-CoA to ketogenesis to elevate circulating levels of β-hydroxybutyrate similar to wild-type mice. Treatment of 4-month-old eNOS-/- mice with nitrite for 10 days corrected the hypertension and serum hyperlipidemia and normalized the rate of fatty acid oxidation. Fourteen-month-old eNOS-/- mice exhibited metabolic derangements, resulting in reduced utilization of fat to generate energy, lower resting metabolic activity, and diminished physical activity. Seven-month administration of nitrite to eNOS-/- mice reversed the age-dependent metabolic derangements and restored physical activity. While the eNOS/NO signaling is not essential for the metabolic adaptation to fasting, it is critical for regulating systemic metabolic homeostasis in aging. The development of age-dependent metabolic disorder is prevented by low-dose replenishment of bioactive NO.</description><identifier>ISSN: 2379-3708</identifier><identifier>EISSN: 2379-3708</identifier><identifier>DOI: 10.1172/jci.insight.122156</identifier><identifier>PMID: 30135317</identifier><language>eng</language><publisher>United States: American Society for Clinical Investigation</publisher><subject>Administration, Oral ; Aging - drug effects ; Aging - metabolism ; Animals ; Disease Models, Animal ; Drug Evaluation, Preclinical ; Fasting - metabolism ; Homeostasis - drug effects ; Humans ; Hyperlipidemias - drug therapy ; Hyperlipidemias - genetics ; Hyperlipidemias - metabolism ; Hypertension - drug therapy ; Hypertension - genetics ; Hypertension - metabolism ; Male ; Mice ; Mice, Knockout ; Nitric Oxide - metabolism ; Nitric Oxide Synthase Type III - deficiency ; Nitric Oxide Synthase Type III - genetics ; Signal Transduction - drug effects ; Sodium Nitrite - administration & dosage ; Time Factors ; Treatment Outcome</subject><ispartof>JCI insight, 2018-08, Vol.3 (16)</ispartof><rights>Copyright © 2018, American Society for Clinical Investigation 2018 American Society for Clinical Investigation</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c369t-49a360975b1a1a4af59a8fcbc3a1e379c1c698bb91ce83d4e268c7d25cd4fe1f3</citedby><cites>FETCH-LOGICAL-c369t-49a360975b1a1a4af59a8fcbc3a1e379c1c698bb91ce83d4e268c7d25cd4fe1f3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC6141175/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC6141175/$$EHTML$$P50$$Gpubmedcentral$$H</linktohtml><link.rule.ids>230,314,723,776,780,881,27901,27902,53766,53768</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/30135317$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Tenopoulou, Margarita</creatorcontrib><creatorcontrib>Doulias, Paschalis-Thomas</creatorcontrib><creatorcontrib>Nakamoto, Kent</creatorcontrib><creatorcontrib>Berrios, Kiara</creatorcontrib><creatorcontrib>Zura, Gabriella</creatorcontrib><creatorcontrib>Li, Chenxi</creatorcontrib><creatorcontrib>Faust, Michael</creatorcontrib><creatorcontrib>Yakovishina, Veronika</creatorcontrib><creatorcontrib>Evans, Perry</creatorcontrib><creatorcontrib>Tan, Lu</creatorcontrib><creatorcontrib>Bennett, Michael J</creatorcontrib><creatorcontrib>Snyder, Nathaniel W</creatorcontrib><creatorcontrib>Quinn, 3rd, William J</creatorcontrib><creatorcontrib>Baur, Joseph A</creatorcontrib><creatorcontrib>Atochin, Dmitriy N</creatorcontrib><creatorcontrib>Huang, Paul L</creatorcontrib><creatorcontrib>Ischiropoulos, Harry</creatorcontrib><title>Oral nitrite restores age-dependent phenotypes in eNOS-null mice</title><title>JCI insight</title><addtitle>JCI Insight</addtitle><description>Alterations in the synthesis and bioavailability of NO are central to the pathogenesis of cardiovascular and metabolic disorders. Although endothelial NO synthase-derived (eNOS-derived) NO affects mitochondrial long-chain fatty acid β-oxidation, the pathophysiological significance of this regulation remains unclear. Accordingly, we determined the contributions of eNOS/NO signaling in the adaptive metabolic responses to fasting and in age-induced metabolic dysfunction. Four-month-old eNOS-/- mice are glucose intolerant and exhibit serum dyslipidemia and decreased capacity to oxidize fatty acids. However, during fasting, eNOS-/- mice redirect acetyl-CoA to ketogenesis to elevate circulating levels of β-hydroxybutyrate similar to wild-type mice. Treatment of 4-month-old eNOS-/- mice with nitrite for 10 days corrected the hypertension and serum hyperlipidemia and normalized the rate of fatty acid oxidation. Fourteen-month-old eNOS-/- mice exhibited metabolic derangements, resulting in reduced utilization of fat to generate energy, lower resting metabolic activity, and diminished physical activity. Seven-month administration of nitrite to eNOS-/- mice reversed the age-dependent metabolic derangements and restored physical activity. While the eNOS/NO signaling is not essential for the metabolic adaptation to fasting, it is critical for regulating systemic metabolic homeostasis in aging. The development of age-dependent metabolic disorder is prevented by low-dose replenishment of bioactive NO.</description><subject>Administration, Oral</subject><subject>Aging - drug effects</subject><subject>Aging - metabolism</subject><subject>Animals</subject><subject>Disease Models, Animal</subject><subject>Drug Evaluation, Preclinical</subject><subject>Fasting - metabolism</subject><subject>Homeostasis - drug effects</subject><subject>Humans</subject><subject>Hyperlipidemias - drug therapy</subject><subject>Hyperlipidemias - genetics</subject><subject>Hyperlipidemias - metabolism</subject><subject>Hypertension - drug therapy</subject><subject>Hypertension - genetics</subject><subject>Hypertension - metabolism</subject><subject>Male</subject><subject>Mice</subject><subject>Mice, Knockout</subject><subject>Nitric Oxide - metabolism</subject><subject>Nitric Oxide Synthase Type III - deficiency</subject><subject>Nitric Oxide Synthase Type III - genetics</subject><subject>Signal Transduction - drug effects</subject><subject>Sodium Nitrite - administration & dosage</subject><subject>Time Factors</subject><subject>Treatment Outcome</subject><issn>2379-3708</issn><issn>2379-3708</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2018</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpVkN1KAzEQhYMoVmpfwAvZF9iaSTb7cyNK8Q-KvVCvQzY726Zss0uSCn17I62l3swMHM6Zw0fIDdApQMHu1tpMjfVmuQpTYAxEfkauGC-qlBe0PD-5R2Ti_ZpSCkXGqCgvyYhT4IJDcUUeFk51iTXBmYCJQx_6OBK1xLTBAW2DNiTDCm0fdkMUjE3wffGR2m3XJRuj8ZpctKrzODnsMfl6fvqcvabzxcvb7HGeap5XIc0qxXNaFaIGBSpTrahU2epacwUYm2rQeVXWdQUaS95kyPJSFw0TuslahJaPyf0-d9jWG2x07BWby8GZjXI72Ssj_yvWrOSy_5Y5ZBGYiAFsH6Bd773D9ugFKn-RyohUHpDKPdJouj39erT8AeQ_Odt3KA</recordid><startdate>20180823</startdate><enddate>20180823</enddate><creator>Tenopoulou, Margarita</creator><creator>Doulias, Paschalis-Thomas</creator><creator>Nakamoto, Kent</creator><creator>Berrios, Kiara</creator><creator>Zura, Gabriella</creator><creator>Li, Chenxi</creator><creator>Faust, Michael</creator><creator>Yakovishina, Veronika</creator><creator>Evans, Perry</creator><creator>Tan, Lu</creator><creator>Bennett, Michael J</creator><creator>Snyder, Nathaniel W</creator><creator>Quinn, 3rd, William J</creator><creator>Baur, Joseph A</creator><creator>Atochin, Dmitriy N</creator><creator>Huang, Paul L</creator><creator>Ischiropoulos, Harry</creator><general>American Society for Clinical Investigation</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>5PM</scope></search><sort><creationdate>20180823</creationdate><title>Oral nitrite restores age-dependent phenotypes in eNOS-null mice</title><author>Tenopoulou, Margarita ; 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Although endothelial NO synthase-derived (eNOS-derived) NO affects mitochondrial long-chain fatty acid β-oxidation, the pathophysiological significance of this regulation remains unclear. Accordingly, we determined the contributions of eNOS/NO signaling in the adaptive metabolic responses to fasting and in age-induced metabolic dysfunction. Four-month-old eNOS-/- mice are glucose intolerant and exhibit serum dyslipidemia and decreased capacity to oxidize fatty acids. However, during fasting, eNOS-/- mice redirect acetyl-CoA to ketogenesis to elevate circulating levels of β-hydroxybutyrate similar to wild-type mice. Treatment of 4-month-old eNOS-/- mice with nitrite for 10 days corrected the hypertension and serum hyperlipidemia and normalized the rate of fatty acid oxidation. Fourteen-month-old eNOS-/- mice exhibited metabolic derangements, resulting in reduced utilization of fat to generate energy, lower resting metabolic activity, and diminished physical activity. Seven-month administration of nitrite to eNOS-/- mice reversed the age-dependent metabolic derangements and restored physical activity. While the eNOS/NO signaling is not essential for the metabolic adaptation to fasting, it is critical for regulating systemic metabolic homeostasis in aging. The development of age-dependent metabolic disorder is prevented by low-dose replenishment of bioactive NO.</abstract><cop>United States</cop><pub>American Society for Clinical Investigation</pub><pmid>30135317</pmid><doi>10.1172/jci.insight.122156</doi><oa>free_for_read</oa></addata></record> |
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| subjects | Administration, Oral Aging - drug effects Aging - metabolism Animals Disease Models, Animal Drug Evaluation, Preclinical Fasting - metabolism Homeostasis - drug effects Humans Hyperlipidemias - drug therapy Hyperlipidemias - genetics Hyperlipidemias - metabolism Hypertension - drug therapy Hypertension - genetics Hypertension - metabolism Male Mice Mice, Knockout Nitric Oxide - metabolism Nitric Oxide Synthase Type III - deficiency Nitric Oxide Synthase Type III - genetics Signal Transduction - drug effects Sodium Nitrite - administration & dosage Time Factors Treatment Outcome |
| title | Oral nitrite restores age-dependent phenotypes in eNOS-null mice |
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