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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Veröffentlicht in:PloS one 2014-12, Vol.9 (12), p.e115642-e115642
Hauptverfasser: McFadden, Joseph W, Aja, Susan, Li, Qun, Bandaru, Veera V R, Kim, Eun-Kyoung, Haughey, Norman J, Kuhajda, Francis P, Ronnett, Gabriele V
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container_title PloS one
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creator McFadden, Joseph W
Aja, Susan
Li, Qun
Bandaru, Veera V R
Kim, Eun-Kyoung
Haughey, Norman J
Kuhajda, Francis P
Ronnett, Gabriele V
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.
doi_str_mv 10.1371/journal.pone.0115642
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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. 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Medical Complete (Alumni)</collection><collection>Materials Science Database</collection><collection>Nursing &amp; Allied Health Database (Alumni Edition)</collection><collection>Meteorological &amp; Geoastrophysical Abstracts - Academic</collection><collection>ProQuest Engineering Collection</collection><collection>ProQuest Biological Science Collection</collection><collection>Agricultural Science Database</collection><collection>Health &amp; 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 &amp; Allied Health Premium</collection><collection>Advanced Technologies &amp; Aerospace Database</collection><collection>ProQuest Advanced Technologies &amp; 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>
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identifier ISSN: 1932-6203
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issn 1932-6203
1932-6203
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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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