Macrophage Deletion of SOCS1 Increases Sensitivity to LPS and Palmitic Acid and Results in Systemic Inflammation and Hepatic Insulin Resistance

Abstract

OBJECTIVEMacrophage secretion of proinflammatory cytokines contributes to the pathogenesis of obesity-related insulin resistance. An important regulator of inflammation is the suppressor of cytokine signaling-1 (SOCS1), which inhibits the JAK-STAT and toll-like receptor-4 (TLR4) pathways. Despite the reported role of SOCS1 in inhibiting insulin signaling, it is surprising that a SOCS1 polymorphism that increases SOCS1 promoter activity is associated with enhanced insulin sensitivity despite obesity. In the current study, we investigated the physiological role of myeloid and lymphoid cell SOCS1 in regulating inflammation and insulin sensitivity.RESEARCH DESIGN AND METHODSWe used mice generated by crossing SOCS1 floxed mice with mice expressing Cre recombinase under the control of the LysM-Cre promoter (SOCS1 LysM-Cre). These mice have deletion of SOCS1 in macrophages and lymphocytes. We assessed macrophage inflammation using flow cytometry and serum cytokine levels using Bioplex assays. We then measured insulin sensitivity using glucose tolerance tests and the euglycemic-hyperinsulinemic clamp. Using bone marrow–derived macrophages, we tested the effects of SOCS1 deletion in regulating responses to the TLR4 ligands: lipopolysaccharide (LPS) and palmitic acid.RESULTSSOCS1 LysM-Cre mice had increased macrophage expression of CD11c, enhanced sensitivity to LPS, and palmitic acid and increased serum concentrations of tumor necrosis factor-α, interleukin-6, and monocyte chemoattractant protein. Increased inflammation was associated with impaired glucose tolerance and hyperinsulinemia as a result of reduced hepatic but not skeletal muscle insulin sensitivity.CONCLUSIONSThe expression of SOCS1 in hematopoietic cells protects mice against systemic inflammation and hepatic insulin resistance potentially by inhibiting LPS and palmitate-induced TLR4 signaling in macrophages.

SOCS1 is a negative regulator of metabolic reprogramming during sepsis

“…We have further shown that SOCS1 also inhibits expression of MyD88 and prevents TLR-and IL-1 receptor-mediated NF-κB activation (13). Consistent with these observations, SOCS1-knockout mice show increased production of proinflammatory cytokines, such as TNF-α, IL-12, and IFN-γ, in response to TLR ligands in vitro (14,15) and in vivo (16,17). The precise role of SOCS1 in bacterial sepsis, however, remains undetermined.…”

Hematopoietic AMPK β1 reduces mouse adipose tissue macrophage inflammation and insulin resistance in obesity

“…In contrast, we show that β1 -/-BMT mice develop greater HFD-induced hepatic insulin resistance than WT BMT controls. Since adipose tissue cell size appears to be the primary factor dictating macrophage recruitment and adipose tissue inflammation (55,56) and mice lacking whole-body AMPK β1 do not develop obesity, this may be a likely explanation for the disparity between mice with hematopoietic compared with global deletion of β1.…”

“…WT and β1 -/-bone marrow was isolated from the femur and tibia of 10- to 12-week-old mice as described previously (56). For palmitate treatments, day-8 BMDMs were serum starved 3-4 hours before incubation with the indicated palmitate concentrations at the indicated times, conjugated to 2% (w/v) fatty acid-free and low endotoxin BSA (SigmaAldrich).…”

“…Alexa Fluor 488-labeled antibody specific for AMPK phosphorylated on αT172 (24) was produced using the DyLight 488 Antibody Labeling Kit from Pierce Biotechnology (Rockford). Resident peritoneal cells were harvested from control and ob/ob mice, and F4/80 + CD11b + cells were separated from the remainder of the peritoneal cell population using a FACSAria cell sorter (BD Biosciences) as described previously (56). For assessment of T cell populations, phycoerythrin-CD4 (PE-CD4, 0.8 μg/ml) and Alexa Fluor 700-CD3 (A700-CD3, 0.8 μg/ml) were purchased from eBioscience.…”

Denervation protects limbs from inflammatory arthritis via an impact on the microvasculature

“…We turned to the well-studied K/BxN serum-transfer system, which mimics many of the clinical and immunological features of human inflammatory arthritis (22). The impact of denervation on the response to arthritogenic serum by mice was astonishingly parallel to the effect of central or peripheral denervation on subsequent RA development by humans.…”