title: Arachidonic acid impairs hypothalamic leptin signaling and hepatic energy homeostasis in mice.
abstract: Epidemiological evidence suggests that the consumption of a diet high in n-6 polyunsaturated fatty acids (PUFA) is associated with the development of leptin resistance and obesity. We aim to examine the central effect of n-6 PUFA, arachidonic acid (ARA) on leptin sensitivity and leptin-regulated hepatic glucose and lipid metabolism. We found that intracerebroventricular injection of ARA (25 nmol/day) for 2.5 days reversed the effect of central leptin on hypothalamic JAK2, pSTAT3, pAkt, and pFOXO1 protein levels, which was concomitant with a pro-inflammatory response in the hypothalamus. ARA also attenuated the effect of central leptin on hepatic glucose and lipid metabolism by reversing the mRNA expression of the genes involved in gluconeogenesis (G6Pase, PEPCK), glucose transportation (GLUT2), lipogenesis (FAS, SCD1), and cholesterol synthesis (HMG-CoA reductase). These results indicate that an increased exposure to central n-6 PUFA induces central cellular leptin resistance with concomitant defective JAK2-STAT3 and PI3K-Akt signaling.
authors.affiliation: School of Medicine, Illawarra Health and Medical Research Institute, University of Wollongong, NSW 2522, Australia.
authors.forename: Licai
authors.initials: L
authors.lastname: Cheng
authors.affiliation: School of Medicine, Illawarra Health and Medical Research Institute, University of Wollongong, NSW 2522, Australia; Schizophrenia Research Institute (SRI), 405 Liverpool St, Sydney, NSW 2010, Australia. Electronic address: yinghua@uow.edu.au.
authors.forename: Yinghua
authors.initials: Y
authors.lastname: Yu
authors.affiliation: School of Medicine, Illawarra Health and Medical Research Institute, University of Wollongong, NSW 2522, Australia; Schizophrenia Research Institute (SRI), 405 Liverpool St, Sydney, NSW 2010, Australia.
authors.forename: Qingsheng
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: School of Medicine, Illawarra Health and Medical Research Institute, University of Wollongong, NSW 2522, Australia; ANSTO Life Sciences, Australian Nuclear Science and Technology Organisation (ANSTO), Lucas Heights, NSW 2234, Australia.
authors.forename: Alexander
authors.initials: A
authors.lastname: Szabo
authors.affiliation: School of Medicine, Illawarra Health and Medical Research Institute, University of Wollongong, NSW 2522, Australia.
authors.forename: Hongqin
authors.initials: H
authors.lastname: Wang
authors.affiliation: School of Medicine, Illawarra Health and Medical Research Institute, University of Wollongong, NSW 2522, Australia; Schizophrenia Research Institute (SRI), 405 Liverpool St, Sydney, NSW 2010, Australia. Electronic address: xhuang@uow.edu.au.
authors.forename: Xu-Feng
authors.initials: XF
authors.lastname: Huang
mesh_terms: D000818:Animals; D016718:Arachidonic Acid / Q000494:pharmacology*; D002149:Energy Intake; D004734:Energy Metabolism; D005947:Glucose / Q000378:metabolism; D006706:Homeostasis; D007031:Hypothalamus / Q000276:immunology / Q000378:metabolism; D020738:Leptin / Q000502:physiology*; D050356:Lipid Metabolism; D008099:Liver / Q000378:metabolism*; D008297:Male; D008810:Mice, Inbred C57BL; D010286:Paraventricular Hypothalamic Nucleus / Q000276:immunology / Q000378:metabolism*; D015398:Signal Transduction; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
chemical_list: D020738:Leptin; D016718:Arachidonic Acid; D014446:Tyrosine 3-Monooxygenase; D005947:Glucose
keywords: Arachidonic acid; Glucose metabolism; Hypothalamus; Inflammation; Leptin resistance; Lipid metabolism