Abstract 14674: S100/calgranulins Mediate Inflammation in Brown Adipose Tissue Leading to Impaired Adaptive Thermogenesis and Obesity in hBAC-S100 Transgenic Mice
Serum levels of human S100/calgranulins are associated with increased cardiovascular mortality in diabetes or coronary artery disease. To test whether S100/calgranulins mediate cardio-metabolic diseases, newly generated mice with expression of human DNA containing genes and regulatory elements for S100A8/9 and S100A12 were studied (hBAC-S100 mice). hBAC-S100 mice were crossed with mice lacking RAGE, a signal-transducing receptor for S100/calgranulins.
Results: hBAC-S100 mice developed increased visceral adiposity after 12 months on regular chow diet (25% vs. 12% body fat upon DEXA scanning, p<0.05), or after 8 weeks on high fat diet compared to their wild type (WT) control littermates. Metabolic cage studies prior onset of adiposity demonstrates reduced oxygen consumption and CO2 production in hBAC-S100 mice. hBAC-100 mice have normal body core temperature during 22°C exposure compared to WT (37.16 and 37.05, respectively), but fail to regulate body core temperature at 4°C (37.5 and 38.7, p=0.04). At 22°C, there was no significant difference in brown adipose tissue (BAT) mRNA levels for UCP-1, Ppargc1a, Acsl1 and Acox1. In contrast, physiologic up regulation of those genes in response to cold stress was significantly impaired in BAT of S100/calgranulin transgenic mice (UCP-1: -20%, Ppargc1a: -50%, Acsl1: -40%, Acox: -22%). This impaired response to cold stress was associated with significantly increased mRNA levels for inflammation-regulating genes in hBAC-S100 BAT at 22°C (S100/calgranulin: 8-12 fold, IL-1β: 9-fold, IL-6: 7-fold, MCP-1: 1.7 fold) and down regulation of M2-markers (Arg1: -20%, Clec10a: -15%, Mrc1: -27%). Importantly, hBAC-S100 mice lacking RAGE compared to hBAC-S100 with intact RAGE have normal mRNA levels of inflammation-regulating genes in BAT, normal response to cold exposure (mRNA for UCP-1, Ppargc1a in BAT, and body temperature), and significantly reduced obesity (on chow and HFD) and hyperinsulinemia.
Conclusion: Myeloid-derived human S100/calgranulin promotes M1-skewed inflammation of BAT in a RAGE-dependent manner, and this is associated with disturbed body temperature regulation in response to cold stress, and with the development of adiposity, hyperinsulinemia and impaired glucose tolerance.
Author Disclosures: L. Yan: None. H. Ye: None. B. Chellan: None. P. Ongusaha: None. J. Earley: None. M.A. Hofmann Bowman: None.
- © 2014 by American Heart Association, Inc.