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Energy homeostasis is regulated by the hypothalamus but fails when animals are fed a high-fat diet (HFD), and leptin insensitivity and obesity develops. To elucidate the possible mechanisms underlying these effects, a microarray-based transcriptomics approach was used to identify novel genes regulated by HFD and leptin in the mouse hypothalamus.
Mouse global array data identified
as a novel gene highly upregulated by both a HFD and leptin challenge. In situ hybridisation showed
expression upregulation by HFD and leptin in all major hypothalamic nuclei in agreement with transcriptomic gene expression data. Immunohistochemistry and studies in the hypothalamic clonal neuronal cell line, mHypoE-N42 (N42), confirmed that alpha 1-antichymotrypsin (α
AC), the protein encoded by
, is localised to neurons and revealed that it is secreted into the media.
expression in N42 neurons is upregulated by palmitic acid and by leptin, together with
and
, and all three genes are downregulated by the anti-inflammatory monounsaturated fat, oleic acid. Additionally, palmitate upregulation of
in N42 neurons is blocked by the NFκB inhibitor, BAY11, and the upregulation of
expression in the hypothalamus by HFD is blunted in IL-1 receptor 1 knockout (
) mice.
These data demonstrate that
expression is implicated in nutritionally mediated hypothalamic inflammation.