Increasing fatty acid oxidation remodels the hypothalamic neurometabolome to mitigate stress and inflammation
Modification of hypothalamic fatty acid (FA) metabolism can improve energy homeostasis and prevent hyperphagia and excessive weight gain in diet-induced obesity (DIO) from a diet high in saturated fatty acids. We have shown previously that C75, a stimulator of carnitine palmitoyl transferase-1 (CPT-...
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description | Modification of hypothalamic fatty acid (FA) metabolism can improve energy homeostasis and prevent hyperphagia and excessive weight gain in diet-induced obesity (DIO) from a diet high in saturated fatty acids. We have shown previously that C75, a stimulator of carnitine palmitoyl transferase-1 (CPT-1) and fatty acid oxidation (FAOx), exerts at least some of its hypophagic effects via neuronal mechanisms in the hypothalamus. In the present work, we characterized the effects of C75 and another anorexigenic compound, the glycerol-3-phosphate acyltransferase (GPAT) inhibitor FSG67, on FA metabolism, metabolomics profiles, and metabolic stress responses in cultured hypothalamic neurons and hypothalamic neuronal cell lines during lipid excess with palmitate. Both compounds enhanced palmitate oxidation, increased ATP, and inactivated AMP-activated protein kinase (AMPK) in hypothalamic neurons in vitro. Lipidomics and untargeted metabolomics revealed that enhanced catabolism of FA decreased palmitate availability and prevented the production of fatty acylglycerols, ceramides, and cholesterol esters, lipids that are associated with lipotoxicity-provoked metabolic stress. This improved metabolic signature was accompanied by increased levels of reactive oxygen species (ROS), and yet favorable changes in oxidative stress, overt ER stress, and inflammation. We propose that enhancing FAOx in hypothalamic neurons exposed to excess lipids promotes metabolic remodeling that reduces local inflammatory and cell stress responses. This shift would restore mitochondrial function such that increased FAOx can produce hypothalamic neuronal ATP and lead to decreased food intake and body weight to improve systemic metabolism. |
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We have shown previously that C75, a stimulator of carnitine palmitoyl transferase-1 (CPT-1) and fatty acid oxidation (FAOx), exerts at least some of its hypophagic effects via neuronal mechanisms in the hypothalamus. In the present work, we characterized the effects of C75 and another anorexigenic compound, the glycerol-3-phosphate acyltransferase (GPAT) inhibitor FSG67, on FA metabolism, metabolomics profiles, and metabolic stress responses in cultured hypothalamic neurons and hypothalamic neuronal cell lines during lipid excess with palmitate. Both compounds enhanced palmitate oxidation, increased ATP, and inactivated AMP-activated protein kinase (AMPK) in hypothalamic neurons in vitro. Lipidomics and untargeted metabolomics revealed that enhanced catabolism of FA decreased palmitate availability and prevented the production of fatty acylglycerols, ceramides, and cholesterol esters, lipids that are associated with lipotoxicity-provoked metabolic stress. This improved metabolic signature was accompanied by increased levels of reactive oxygen species (ROS), and yet favorable changes in oxidative stress, overt ER stress, and inflammation. We propose that enhancing FAOx in hypothalamic neurons exposed to excess lipids promotes metabolic remodeling that reduces local inflammatory and cell stress responses. This shift would restore mitochondrial function such that increased FAOx can produce hypothalamic neuronal ATP and lead to decreased food intake and body weight to improve systemic metabolism.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0115642</identifier><identifier>PMID: 25541737</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>4-Butyrolactone - analogs & derivatives ; 4-Butyrolactone - pharmacology ; Acylglycerols ; Acyltransferase ; Adenosine Triphosphate - metabolism ; AMP ; AMP-activated protein kinase ; AMP-Activated Protein Kinases - metabolism ; Animals ; Appetite Depressants - pharmacology ; ATP ; Biology and Life Sciences ; Body weight ; Body weight gain ; Brain ; Brain research ; Carnitine ; Catabolism ; Cell Line ; Cell lines ; Cells, Cultured ; Cellular stress response ; Ceramides ; Ceramides - metabolism ; Cholesterol ; Cholesterol Esters - metabolism ; Cricetinae ; Energy ; Energy balance ; Energy metabolism ; Esters ; Fatty acids ; Food ; Food intake ; Gene expression ; Glycerides - metabolism ; Glycerol ; Glycerol-3-phosphate ; Glycerol-3-Phosphate O-Acyltransferase - antagonists & inhibitors ; Homeostasis ; Humans ; Hyperphagia ; Hypothalamus ; Hypothalamus - cytology ; Hypothalamus - metabolism ; Inflammation ; Inflammation - metabolism ; Insulin resistance ; Kinases ; Lipid metabolism ; Lipids ; Liver diseases ; Medicine ; Medicine and Health Sciences ; Metabolic syndrome ; Metabolism ; Metabolome ; Mice ; Neurology ; Neurons ; Neurons - metabolism ; Neurophysiology ; Neurosciences ; Obesity ; ortho-Aminobenzoates - chemistry ; ortho-Aminobenzoates - pharmacology ; Oxidation ; Oxidation-Reduction ; Oxidation-reduction reactions ; Oxidative stress ; Oxygen ; Palmitates - metabolism ; Palmitic acid ; Phosphates ; Physicians ; Physiological aspects ; Proteins ; Reactive oxygen species ; Reactive Oxygen Species - metabolism ; Recovery of function ; Rodents ; Saturated fatty acids ; Stress, Physiological ; Sulfonamides - chemistry ; Sulfonamides - pharmacology ; Weight control</subject><ispartof>PloS one, 2014-12, Vol.9 (12), p.e115642-e115642</ispartof><rights>COPYRIGHT 2014 Public Library of Science</rights><rights>2014 McFadden et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2014 McFadden et al 2014 McFadden et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c692t-3d8fe1f49ef7dc9f4c277009c95a44045818b74c5dda08b0d42f4f9db10875563</citedby><cites>FETCH-LOGICAL-c692t-3d8fe1f49ef7dc9f4c277009c95a44045818b74c5dda08b0d42f4f9db10875563</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/PMC4277346/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4277346/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,2096,2915,23847,27903,27904,53769,53771,79346,79347</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/25541737$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Makishima, Makoto</contributor><creatorcontrib>McFadden, Joseph W</creatorcontrib><creatorcontrib>Aja, Susan</creatorcontrib><creatorcontrib>Li, Qun</creatorcontrib><creatorcontrib>Bandaru, Veera V R</creatorcontrib><creatorcontrib>Kim, Eun-Kyoung</creatorcontrib><creatorcontrib>Haughey, Norman J</creatorcontrib><creatorcontrib>Kuhajda, Francis P</creatorcontrib><creatorcontrib>Ronnett, Gabriele V</creatorcontrib><title>Increasing fatty acid oxidation remodels the hypothalamic neurometabolome to mitigate stress and inflammation</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>Modification of hypothalamic fatty acid (FA) metabolism can improve energy homeostasis and prevent hyperphagia and excessive weight gain in diet-induced obesity (DIO) from a diet high in saturated fatty acids. We have shown previously that C75, a stimulator of carnitine palmitoyl transferase-1 (CPT-1) and fatty acid oxidation (FAOx), exerts at least some of its hypophagic effects via neuronal mechanisms in the hypothalamus. In the present work, we characterized the effects of C75 and another anorexigenic compound, the glycerol-3-phosphate acyltransferase (GPAT) inhibitor FSG67, on FA metabolism, metabolomics profiles, and metabolic stress responses in cultured hypothalamic neurons and hypothalamic neuronal cell lines during lipid excess with palmitate. Both compounds enhanced palmitate oxidation, increased ATP, and inactivated AMP-activated protein kinase (AMPK) in hypothalamic neurons in vitro. Lipidomics and untargeted metabolomics revealed that enhanced catabolism of FA decreased palmitate availability and prevented the production of fatty acylglycerols, ceramides, and cholesterol esters, lipids that are associated with lipotoxicity-provoked metabolic stress. This improved metabolic signature was accompanied by increased levels of reactive oxygen species (ROS), and yet favorable changes in oxidative stress, overt ER stress, and inflammation. We propose that enhancing FAOx in hypothalamic neurons exposed to excess lipids promotes metabolic remodeling that reduces local inflammatory and cell stress responses. This shift would restore mitochondrial function such that increased FAOx can produce hypothalamic neuronal ATP and lead to decreased food intake and body weight to improve systemic metabolism.</description><subject>4-Butyrolactone - analogs & derivatives</subject><subject>4-Butyrolactone - pharmacology</subject><subject>Acylglycerols</subject><subject>Acyltransferase</subject><subject>Adenosine Triphosphate - metabolism</subject><subject>AMP</subject><subject>AMP-activated protein kinase</subject><subject>AMP-Activated Protein Kinases - metabolism</subject><subject>Animals</subject><subject>Appetite Depressants - pharmacology</subject><subject>ATP</subject><subject>Biology and Life Sciences</subject><subject>Body weight</subject><subject>Body weight gain</subject><subject>Brain</subject><subject>Brain research</subject><subject>Carnitine</subject><subject>Catabolism</subject><subject>Cell Line</subject><subject>Cell lines</subject><subject>Cells, Cultured</subject><subject>Cellular stress response</subject><subject>Ceramides</subject><subject>Ceramides - 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Academic</collection><collection>ProQuest Engineering Collection</collection><collection>ProQuest Biological Science Collection</collection><collection>Agricultural Science Database</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Biological Science Database</collection><collection>Engineering Database</collection><collection>Nursing & Allied Health Premium</collection><collection>Advanced Technologies & Aerospace Database</collection><collection>ProQuest Advanced Technologies & Aerospace Collection</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Environmental Science Database</collection><collection>Materials Science Collection</collection><collection>Publicly Available Content Database</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>Engineering Collection</collection><collection>Environmental Science Collection</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>PloS one</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>McFadden, Joseph W</au><au>Aja, Susan</au><au>Li, Qun</au><au>Bandaru, Veera V R</au><au>Kim, Eun-Kyoung</au><au>Haughey, Norman J</au><au>Kuhajda, Francis P</au><au>Ronnett, Gabriele V</au><au>Makishima, Makoto</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Increasing fatty acid oxidation remodels the hypothalamic neurometabolome to mitigate stress and inflammation</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2014-12-26</date><risdate>2014</risdate><volume>9</volume><issue>12</issue><spage>e115642</spage><epage>e115642</epage><pages>e115642-e115642</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>Modification of hypothalamic fatty acid (FA) metabolism can improve energy homeostasis and prevent hyperphagia and excessive weight gain in diet-induced obesity (DIO) from a diet high in saturated fatty acids. We have shown previously that C75, a stimulator of carnitine palmitoyl transferase-1 (CPT-1) and fatty acid oxidation (FAOx), exerts at least some of its hypophagic effects via neuronal mechanisms in the hypothalamus. In the present work, we characterized the effects of C75 and another anorexigenic compound, the glycerol-3-phosphate acyltransferase (GPAT) inhibitor FSG67, on FA metabolism, metabolomics profiles, and metabolic stress responses in cultured hypothalamic neurons and hypothalamic neuronal cell lines during lipid excess with palmitate. Both compounds enhanced palmitate oxidation, increased ATP, and inactivated AMP-activated protein kinase (AMPK) in hypothalamic neurons in vitro. Lipidomics and untargeted metabolomics revealed that enhanced catabolism of FA decreased palmitate availability and prevented the production of fatty acylglycerols, ceramides, and cholesterol esters, lipids that are associated with lipotoxicity-provoked metabolic stress. This improved metabolic signature was accompanied by increased levels of reactive oxygen species (ROS), and yet favorable changes in oxidative stress, overt ER stress, and inflammation. We propose that enhancing FAOx in hypothalamic neurons exposed to excess lipids promotes metabolic remodeling that reduces local inflammatory and cell stress responses. This shift would restore mitochondrial function such that increased FAOx can produce hypothalamic neuronal ATP and lead to decreased food intake and body weight to improve systemic metabolism.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>25541737</pmid><doi>10.1371/journal.pone.0115642</doi><oa>free_for_read</oa></addata></record> |
fulltext | fulltext |
identifier | ISSN: 1932-6203 |
ispartof | PloS one, 2014-12, Vol.9 (12), p.e115642-e115642 |
issn | 1932-6203 1932-6203 |
language | eng |
recordid | cdi_plos_journals_1640559887 |
source | MEDLINE; DOAJ Directory of Open Access Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central; Free Full-Text Journals in Chemistry; Public Library of Science (PLoS) |
subjects | 4-Butyrolactone - analogs & derivatives 4-Butyrolactone - pharmacology Acylglycerols Acyltransferase Adenosine Triphosphate - metabolism AMP AMP-activated protein kinase AMP-Activated Protein Kinases - metabolism Animals Appetite Depressants - pharmacology ATP Biology and Life Sciences Body weight Body weight gain Brain Brain research Carnitine Catabolism Cell Line Cell lines Cells, Cultured Cellular stress response Ceramides Ceramides - metabolism Cholesterol Cholesterol Esters - metabolism Cricetinae Energy Energy balance Energy metabolism Esters Fatty acids Food Food intake Gene expression Glycerides - metabolism Glycerol Glycerol-3-phosphate Glycerol-3-Phosphate O-Acyltransferase - antagonists & inhibitors Homeostasis Humans Hyperphagia Hypothalamus Hypothalamus - cytology Hypothalamus - metabolism Inflammation Inflammation - metabolism Insulin resistance Kinases Lipid metabolism Lipids Liver diseases Medicine Medicine and Health Sciences Metabolic syndrome Metabolism Metabolome Mice Neurology Neurons Neurons - metabolism Neurophysiology Neurosciences Obesity ortho-Aminobenzoates - chemistry ortho-Aminobenzoates - pharmacology Oxidation Oxidation-Reduction Oxidation-reduction reactions Oxidative stress Oxygen Palmitates - metabolism Palmitic acid Phosphates Physicians Physiological aspects Proteins Reactive oxygen species Reactive Oxygen Species - metabolism Recovery of function Rodents Saturated fatty acids Stress, Physiological Sulfonamides - chemistry Sulfonamides - pharmacology Weight control |
title | Increasing fatty acid oxidation remodels the hypothalamic neurometabolome to mitigate stress and inflammation |
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