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High fat induces acute and chronic inflammation in the hypothalamus: effect of high-fat diet, palmitate and TNF-α on appetite-regulating NPY neurons.
Int J Obes (Lond). 2017 01; 41(1):149-158.IJ

Abstract

BACKGROUND

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.

METHODS

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.

RESULTS

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.

CONCLUSIONS

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.

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Publisher Full Text (DOI)

Authors+Show Affiliations

Department of Physiology, University of Toronto, Toronto, Ontario, Canada.

Department of Physiology, University of Toronto, Toronto, Ontario, Canada.

Department of Physiology, University of Toronto, Toronto, Ontario, Canada.

Department of Physiology, University of Toronto, Toronto, Ontario, Canada.

Department of Physiology, University of Toronto, Toronto, Ontario, Canada.

Department of Physiology, University of Toronto, Toronto, Ontario, Canada.

Department of Physiology, University of Toronto, Toronto, Ontario, Canada.

Unité de Biologie Fonctionnelle et Adaptative, University of Paris Diderot, Sorbonne Paris Cité, CNRS UMR 8251, Paris, France.

Unité de Biologie Fonctionnelle et Adaptative, University of Paris Diderot, Sorbonne Paris Cité, CNRS UMR 8251, Paris, France.

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 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.

MeSH

AnimalsAppetiteArcuate Nucleus of HypothalamusDiet, High-FatDisease Models, AnimalGene Expression RegulationHypothalamusInflammationInterleukin-6MaleMiceMice, Inbred C57BLNeuronsNeuropeptide YObesityPalmitatesTumor Necrosis Factor-alpha

Pub Type(s)

Journal Article

Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

27773938

Citation

Dalvi, P S., et al. "High Fat Induces Acute and Chronic Inflammation in the Hypothalamus: Effect of High-fat Diet, Palmitate and TNF-α On Appetite-regulating NPY Neurons." International Journal of Obesity (2005), vol. 41, no. 1, 2017, pp. 149-158.

Dalvi PS, Chalmers JA, Luo V, et al. High fat induces acute and chronic inflammation in the hypothalamus: effect of high-fat diet, palmitate and TNF-α on appetite-regulating NPY neurons. Int J Obes (Lond). 2017;41(1):149-158.

Dalvi, P. S., Chalmers, J. A., Luo, V., Han, D. Y., Wellhauser, L., Liu, Y., Tran, D. Q., Castel, J., Luquet, S., Wheeler, M. B., & Belsham, D. D. (2017). High fat induces acute and chronic inflammation in the hypothalamus: effect of high-fat diet, palmitate and TNF-α on appetite-regulating NPY neurons. International Journal of Obesity (2005), 41(1), 149-158. https://doi.org/10.1038/ijo.2016.183

Dalvi PS, et al. High Fat Induces Acute and Chronic Inflammation in the Hypothalamus: Effect of High-fat Diet, Palmitate and TNF-α On Appetite-regulating NPY Neurons. Int J Obes (Lond). 2017;41(1):149-158. PubMed PMID: 27773938.

* Article titles in AMA citation format should be in sentence-case

TY - JOUR T1 - High fat induces acute and chronic inflammation in the hypothalamus: effect of high-fat diet, palmitate and TNF-α on appetite-regulating NPY neurons. AU - Dalvi,P S, AU - Chalmers,J A, AU - Luo,V, AU - Han,D-Yd, AU - Wellhauser,L, AU - Liu,Y, AU - Tran,D Q, AU - Castel,J, AU - Luquet,S, AU - Wheeler,M B, AU - Belsham,D D, Y1 - 2016/10/24/ PY - 2016/05/24/received PY - 2016/08/18/revised PY - 2016/09/18/accepted PY - 2016/10/25/pubmed PY - 2018/2/17/medline PY - 2016/10/25/entrez SP - 149 EP - 158 JF - International journal of obesity (2005) JO - Int J Obes (Lond) VL - 41 IS - 1 N2 - BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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. SN - 1476-5497 UR - https://www.unboundmedicine.com/medline/citation/27773938/High_fat_induces_acute_and_chronic_inflammation_in_the_hypothalamus:_effect_of_high_fat_diet_palmitate_and_TNF_α_on_appetite_regulating_NPY_neurons_ DB - PRIME DP - Unbound Medicine ER -