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Tumour necrosis factor α induces neuroinflammation and insulin resistance in immortalised hypothalamic neurones through independent pathways
Author(s) -
Clemenzi Matthew N.,
Wellhauser Leigh,
Aljghami Makram E.,
Belsham Denise D.
Publication year - 2019
Publication title -
journal of neuroendocrinology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.062
H-Index - 116
eISSN - 1365-2826
pISSN - 0953-8194
DOI - 10.1111/jne.12678
Subject(s) - endocrinology , medicine , insulin resistance , tumor necrosis factor alpha , biology , neuroinflammation , insulin , inflammation , proinflammatory cytokine
The links between obesity, inflammation and insulin resistance, which are all key characteristics of type 2 diabetes mellitus, are yet to be delineated in the brain. One of the key neuroinflammatory proteins detected in the hypothalamus with over‐nutrition is tumour necrosis factor ( TNF) α. Using immortalised embryonic rat and mouse hypothalamic cell lines ( rH ypoE‐7 and mH ypoE‐46) that express orexigenic neuropeptide Y and agouti‐related peptide, we investigated changes in insulin signalling and inflammatory gene marker mRNA expression after TNF α exposure. A quantitative polymerase chain reaction array of 84 inflammatory markers (cytokines, chemokines and receptors) demonstrated an increase in the expression of multiple genes encoding inflammatory markers upon exposure to 100 ng mL ‐1 TNF α for 4 hours. Furthermore, neurones pre‐exposed to TNF α (50 ng mL ‐1 ) for 6 or 16 hours exhibited a significant reduction in phosphorylated A kt compared to control after insulin treatment, indicating the attenuation of insulin signalling. mRNA expression of insulin signalling‐related genes was also decreased with exposure to TNF α. TNF α significantly increased mRNA expression of I κ B α, Tnfrsf1a and IL 6 at 4 and 24 hours, activating a pro‐inflammatory state. An inhibitor study using an inhibitor of nuclear factor kappa B kinase subunit β ( IKK ‐β) inhibitor, PS 1145, demonstrated that TNF α‐induced neuroinflammatory marker expression occurs through the IKK ‐β/ nuclear factor‐kappa B pathway, whereas oleate, a monounsaturated fatty acid, had no effect on inflammatory markers. To test the efficacy of anti‐inflammatory treatment to reverse insulin resistance, neurones were treated with TNF α and PS 1145, which did not significantly restore the TNF α‐induced changes in cellular insulin sensitivity, indicating that an alternative pathway may be involved. In conclusion, exposure to the inflammatory cytokine TNF α causes cellular insulin resistance and inflammation marker expression in the rH ypoE‐7 and mH ypoE‐46 neurones, consistent with effects seen with TNF α in peripheral tissues. It also mimics insulin‐ and palmitate‐induced insulin resistance in hypothalamic neurones. The present study provides further evidence that altered central energy metabolism may be caused by obesity‐induced cytokine expression.