title: High fat induces acute and chronic inflammation in the hypothalamus: effect of high-fat diet, palmitate and TNF-α on appetite-regulating NPY neurons.
abstract: Consumption of dietary fat is one of the key factors leading to obesity. High-fat diet (HFD)-induced obesity is characterized by induction of inflammation in the hypothalamus; however, the temporal regulation of proinflammatory markers and their impact on hypothalamic appetite-regulating neuropeptide Y/agouti-related peptide (NPY/AgRP) neurons remains undefined.
  
  
  
  Mice were injected with an acute lipid infusion for 24 h or fed a HFD over 8-20 weeks. Characterized mouse NPY/AgRP hypothalamic cell lines were used for in vitro experimentation. Immunohistochemistry in brain slices or quantitative real-time PCR in cell lines, was performed to determine changes in the expression of key inflammatory markers and neuropeptides.
  
  
  
  Hypothalamic inflammation, indicated by tumor necrosis factor (TNF)-α expression and astrocytosis in the arcuate nucleus, was evident following acute lipid infusion. HFD for 8 weeks suppressed TNF-α, while significantly increasing heat-shock protein 70 and ciliary neurotrophic factor, both neuroprotective components. HFD for 20 weeks induced TNF-α expression in NPY/AgRP neurons, suggesting a detrimental temporal regulatory mechanism. Using NPY/AgRP hypothalamic cell lines, we found that palmitate provoked a mixed inflammatory response on a panel of inflammatory and endoplasmic reticulum (ER) stress genes, whereas TNF-α significantly upregulated IκBα, nuclear factor (NF)-κB and interleukin-6 mRNA levels. Palmitate and TNF-α exposure predominantly induced NPY mRNA levels. Utilizing an I kappa B kinase β (IKKβ) inhibitor, we demonstrated that these effects potentially occur via the inflammatory IKKβ/NF-κB pathway.
  
  
  
  These findings indicate that acute lipid and chronic HFD feeding in vivo, as well as acute palmitate and TNF-α exposure in vitro, induce markers of inflammation or ER stress in the hypothalamic appetite-stimulating NPY/AgRP neurons over time, which may contribute to a dramatic alteration in NPY/AgRP content or expression. Acute and chronic HFD feeding in vivo temporally regulates arcuate TNF-α expression with reactive astrocytosis, which suggests a time-dependent neurotrophic or neurotoxic role of lipids.
authors: Department of Physiology, University of Toronto, Toronto, Ontario, Canada.
authors: P S
authors: PS
authors: Dalvi
authors: Department of Physiology, University of Toronto, Toronto, Ontario, Canada.
authors: J A
authors: JA
authors: Chalmers
authors: Department of Physiology, University of Toronto, Toronto, Ontario, Canada.
authors: V
authors: V
authors: Luo
authors: Department of Physiology, University of Toronto, Toronto, Ontario, Canada.
authors: D-Yd
authors: DY
authors: Han
authors: Department of Physiology, University of Toronto, Toronto, Ontario, Canada.
authors: L
authors: L
authors: Wellhauser
authors: Department of Physiology, University of Toronto, Toronto, Ontario, Canada.
authors: Y
authors: Y
authors: Liu
authors: Department of Physiology, University of Toronto, Toronto, Ontario, Canada.
authors: D Q
authors: DQ
authors: Tran
authors: Unité de Biologie Fonctionnelle et Adaptative, University of Paris Diderot, Sorbonne Paris Cité, CNRS UMR 8251, Paris, France.
authors: J
authors: J
authors: Castel
authors: Unité de Biologie Fonctionnelle et Adaptative, University of Paris Diderot, Sorbonne Paris Cité, CNRS UMR 8251, Paris, France.
authors: S
authors: S
authors: Luquet
authors: Department of Physiology, University of Toronto, Toronto, Ontario, Canada.|Department of Medicine, University of Toronto, Toronto, Ontario, Canada.|Division of Cellular and Molecular Biology, Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada.
authors: M B
authors: MB
authors: Wheeler
authors: Department of Physiology, University of Toronto, Toronto, Ontario, Canada.|Department of Medicine, University of Toronto, Toronto, Ontario, Canada.|Division of Cellular and Molecular Biology, Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada.|Department of Obstetrics and Gynecology, University of Toronto, Toronto, Ontario, Canada.
authors: D D
authors: DD
authors: Belsham
mesh_terms: D000818:Animals; D001066:Appetite / Q000187:drug effects*; D001111:Arcuate Nucleus of Hypothalamus / Q000473:pathology; D059305:Diet, High-Fat / Q000009:adverse effects*; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D007031:Hypothalamus / Q000187:drug effects / Q000473:pathology*; D007249:Inflammation / Q000139:chemically induced* / Q000473:pathology; D015850:Interleukin-6 / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D009478:Neuropeptide Y / Q000378:metabolism*; D009765:Obesity / Q000473:pathology; D010168:Palmitates / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
chemical_list: D015850:Interleukin-6; D009478:Neuropeptide Y; D010168:Palmitates; D014409:Tumor Necrosis Factor-alpha