Deficiency of Stat1 in CD11c+ Cells Alters Adipose Tissue Inflammation and Improves Metabolic Dysfunctions in Mice Fed High-Fat Diet

Abstract

<a>CD11c<sup>+</sup> macrophages/dendritic cells (MDCs) are increased and display classically activated M1-like phenotype in obese adipose tissue (AT) and may contribute to AT inflammation and insulin resistance. Stat1 is a key transcription factor for MDC polarization into M1-like phenotype. Here, we examined the role of Stat1 in obesity-induced AT MDC polarization and inflammation and insulin resistance using mice with specific knockout of Stat1 in MDCs (cKO). Stat1 was upregulated and phosphorylated, indicating activation, early and persistently in AT and AT MDCs of wild-type mice fed high-fat diet (HFD). Compared to littermate controls, cKO mice fed HFD (16 weeks) had reductions in MDC (mainly CD11c<sup>+</sup> macrophage) M1-like polarization and interferon-</a>g–expressing T helper type 1 (Th1) cells, but increases in interleukin-5–expressing Th2 cells and eosinophils in perigonadal and inguinal AT, and enhanced inguinal AT browning, with increased energy expenditure. cKO mice compared with controls also had significant reductions in triglyceride content in the liver and skeletal muscle and exhibited improved insulin sensitivity and glucose tolerance. Taken together, our results demonstrated that Stat1 in MDCs plays an important role in obesity-induced MDC M1-like polarization and AT inflammation and contributes to insulin resistance and metabolic dysfunctions in obese mice.

Loss of Lkb1 disturbs adipose tissue dendritic cells and protects mice from obesity under high-fat feeding condition

“…CD11c + myeloid cells are active members in obese adipose tissue [16,17,34]. To investigate the role of Lkb1 in adipose tissue CD11c + cells, we thus generated Lkb1 conditional knockout CD11c Cre Lkb1 f/f mice and established a diet-induced obesity (DIO) model.…”

“…Mounting evidences have elaborated adipose immune status is closely associated with obesity and threatening metabolism disorders [1,8,35]. CD11c + myeloid cells are involved in overnutrition associated immune-metabolic disorders [14,16,17,36], therefore, understanding of the underlying molecular basis becomes essential in developing intervention strategies for these threatens. Previous studies have revealed the critical role of the nutrient sensor Lkb1 in controlling the function of splenic and lymphoid CD11c + dendritic cells [28,29,37,38].…”

“…Among these immune populations, CD11c + cells are considered a therapeutic target for obesity-associated metabolic disorders because ablation of this population could alleviate the obese-induced insulin sensitivity [12][13][14][15][16]. Fat CD11c + cells are composed of adipose tissue macrophages (ATM) and dendritic cells (ATDC), which could be clearly distinguished with CD64 and CD11c in CD45 + cells [14,17]. There is another well-recognized gating strategy as "CD45 + MHCⅡ + CD11c hi " to identify ATDC [13].…”