title: Saturated lipids decrease mitofusin 2 leading to endoplasmic reticulum stress activation and insulin resistance in hypothalamic cells.
abstract: Endoplasmic reticulum (ER) and mitochondria dysfunction contribute to insulin resistance generation during obesity and diabetes. ER and mitochondria interact through Mitofusin 2 (MTF2), which anchors in the outer mitochondrial and ER membranes regulating energy metabolism. Ablation of MTF2 leads to ER stress activation and insulin resistance. Here we determine whether lipotoxic insult induced by saturated lipids decreases MTF2 expression leading to ER stress response in hypothalamus and its effects on insulin sensitivity using in vitro and in vivo models. We found that lipotoxic stimulation induced by palmitic acid, but not the monounsaturated palmitoleic acid, decreases MTF2 protein levels in hypothalamic mHypoA-CLU192 cells. Also, palmitic acid incubation activates ER stress response evidenced by increase in the protein levels of GRP78/BIP marker at later stage than MTF2 downregulation. Additionally, we found that MTF2 alterations induced by palmitic, but not palmitoleic, stimulation exacerbate insulin resistance in hypothalamic cells. Insulin resistance induced by palmitic acid is prevented by pre-incubation of the anti-inflammatory and the ER stress release reagents, sodium salicylate and 4 phenylbutirate, respectively. Finally, we demonstrated that lipotoxic insult induced by high fat feeding to mice decreases MTF2 proteins levels in arcuate nucleus of hypothalamus. Our data indicate that saturated lipids modulate MTF2 expression in hypothalamus coordinating the ER stress response and the susceptibility to insulin resistance.
authors.affiliation: Departamento de Bioquímica, Universidad Autónoma de Nuevo León, Monterrey, Mexico; Neuroscience Unit, Centro de Investigación y Desarrollo en Ciencias de la Salud, Universidad Autonoma de Nuevo Leon, Monterrey, Mexico.
authors.forename: Brenda
authors.initials: B
authors.lastname: Diaz
authors.affiliation: Departamento de Bioquímica, Universidad Autónoma de Nuevo León, Monterrey, Mexico; Gene Therapy Unit, Centro de Investigación y Desarrollo en Ciencias de la Salud, Universidad Autonoma de Nuevo Leon, Monterrey, Mexico.
authors.forename: Lizeth
authors.initials: L
authors.lastname: Fuentes-Mera
authors.affiliation: Departamento Fisiología de la Nutrición, Instituto Nacional de Ciencias Medicas y Nutrición, Mexico.
authors.forename: Armando
authors.initials: A
authors.lastname: Tovar
authors.affiliation: Instituto de Fisiología Celular, Universidad Nacional Autónoma de México, Mexico.
authors.forename: Teresa
authors.initials: T
authors.lastname: Montiel
authors.affiliation: Instituto de Fisiología Celular, Universidad Nacional Autónoma de México, Mexico.
authors.forename: Lourdes
authors.initials: L
authors.lastname: Massieu
authors.affiliation: Departamento de Bioquímica, Universidad Autónoma de Nuevo León, Monterrey, Mexico.
authors.forename: Herminia Guadalupe
authors.initials: HG
authors.lastname: Martínez-Rodríguez
authors.affiliation: Departamento de Bioquímica, Universidad Autónoma de Nuevo León, Monterrey, Mexico; Neuroscience Unit, Centro de Investigación y Desarrollo en Ciencias de la Salud, Universidad Autonoma de Nuevo Leon, Monterrey, Mexico. Electronic address: acm590@hotmail.com.
authors.forename: Alberto
authors.initials: A
authors.lastname: Camacho
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001835:Body Weight / Q000187:drug effects / Q000502:physiology; D059305:Diet, High-Fat; D004305:Dose-Response Relationship, Drug; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D007031:Hypothalamus / Q000166:cytology*; D007333:Insulin Resistance / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D051058:Oncogene Protein v-akt / Q000378:metabolism; D019308:Palmitic Acid / Q000494:pharmacology*; D063151:Polycomb Repressive Complex 2 / Q000235:genetics / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D013997:Time Factors
chemical_list: D000091342:Endoplasmic Reticulum Chaperone BiP; D004791:Enzyme Inhibitors; C000717248:Hspa5 protein, mouse; C568886:Mtf2 protein, mouse; D017382:Reactive Oxygen Species; D019308:Palmitic Acid; D063151:Polycomb Repressive Complex 2; D051058:Oncogene Protein v-akt
keywords: Endoplasmic reticulum stress; Hypothalamus; Insulin resistance; Mitofusin 2