Metabolism
Myeloid Cell-specific Disruption of Period1 and Period2 Exacerbates Diet-induced Inflammation and Insulin Resistance*

https://doi.org/10.1074/jbc.M113.539601Get rights and content
Under a Creative Commons license
open access

The circadian clockworks gate macrophage inflammatory responses. Given the association between clock dysregulation and metabolic disorders, we conducted experiments to determine the extent to which over-nutrition modulates macrophage clock function and whether macrophage circadian dysregulation is a key factor linking over-nutrition to macrophage proinflammatory activation, adipose tissue inflammation, and systemic insulin resistance. Our results demonstrate that 1) macrophages from high fat diet-fed mice are marked by dysregulation of the molecular clockworks in conjunction with increased proinflammatory activation, 2) global disruption of the clock genes Period1 (Per1) and Per2 recapitulates this amplified macrophage proinflammatory activation, 3) adoptive transfer of Per1/2-disrupted bone marrow cells into wild-type mice potentiates high fat diet-induced adipose and liver tissue inflammation and systemic insulin resistance, and 4) Per1/2-disrupted macrophages similarly exacerbate inflammatory responses and decrease insulin sensitivity in co-cultured adipocytes in vitro. Furthermore, PPARγ levels are decreased in Per1/2-disrupted macrophages and PPARγ2 overexpression ameliorates Per1/2 disruption-associated macrophage proinflammatory activation, suggesting that this transcription factor may link the molecular clockworks to signaling pathways regulating macrophage polarization. Thus, macrophage circadian clock dysregulation is a key process in the physiological cascade by which diet-induced obesity triggers macrophage proinflammatory activation, adipose tissue inflammation, and insulin resistance.

Adipose Tissue
Circadian Clock
Inflammation
Insulin Resistance
Macrophage

Cited by (0)

*

This work was supported, in whole or in part, by National Institutes of Health Grants 1R01DK095828 and 1R01DK095862) (NIDDK; to C. W.). This work was also supported, in whole or in part, by American Diabetes Association Grants 1-10-JF-54 and 1-13-BS-214-BR, American Heart Association Grant 12BGIA9050003 (to C. W.).

5

S.-M. Kim, N. Neuendorff, and, D. J. Earnest, unpublished observations.

1

These authors contributed equally to this work.