High fat induces acute and chronic inflammation in the hypothalamus: effect of high-fat diet, palmitate and TNF-alpha on appetite-regulating NPY neurons

Ps Dalvi (1) , Ja Chalmers (2) , V Luo (2) , Dyd Han (2) , L Wellhauser (2) , Y Liu (2) , Dq Tran (2) , J Castel (3) , S Luquet (3) , Mb Wheeler (2) , Dd Belsham (2)

1 University of Bradford
2 University of Toronto
3 BFA (UMR_8251 / U1133) - Unité de Biologie Fonctionnelle et Adaptative

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)-alpha expression and astrocytosis in the arcuate nucleus, was evident following acute lipid infusion. HFD for 8 weeks suppressed TNF-alpha, while significantly increasing heat-shock protein 70 and ciliary neurotrophic factor, both neuroprotective components. HFD for 20 weeks induced TNF-a 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-a significantly upregulated I kappa Ba, nuclear factor (NF)-kappa B and interleukin-6 mRNA levels. Palmitate and TNF-a exposure predominantly induced NPY mRNA levels. Utilizing an I kappa B kinase beta (I kappa kappa beta) inhibitor, we demonstrated that these effects potentially occur via the inflammatory I kappa kappa beta/NF-kappa B pathway. CONCLUSIONS: These findings indicate that acute lipid and chronic HFD feeding in vivo, as well as acute palmitate and TNF-alpha 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-alpha expression with reactive astrocytosis, which suggests a time-dependent neurotrophic or neurotoxic role of lipids.

Mots clés: ENDOPLASMIC-RETICULUM STRESS; NECROSIS-FACTOR-ALPHA; INSULIN-RESISTANCE; KAPPA-B; INDUCED OBESE; LEPTIN; RECEPTOR; MICE; ACTIVATION; EXPRESSION

Domaines: Sciences du Vivant [q-bio]

Ps Dalvi, Ja Chalmers, V Luo, Dyd Han, L Wellhauser, et al.. High fat induces acute and chronic inflammation in the hypothalamus: effect of high-fat diet, palmitate and TNF-alpha on appetite-regulating NPY neurons. International Journal of Obesity, 2017, 41 (1), pp.149-158. ⟨10.1038/ijo.2016.183⟩. ⟨hal-03108269⟩