Insulin resistance and white adipose tissue inflammation are uncoupled in energetically challenged Fsp27-deficient mice

Abstract

Fsp27 is a lipid droplet-associated protein almost exclusively expressed in adipocytes where it facilitates unilocular lipid droplet formation. In mice, Fsp27 deficiency is associated with increased basal lipolysis, ‘browning’ of white fat and a healthy metabolic profile, whereas a patient with congenital CIDEC deficiency manifested an adverse lipodystrophic phenotype. Here we reconcile these data by showing that exposing Fsp27-null mice to a substantial energetic stress by crossing them with ob/ob mice or BATless mice, or feeding them a high-fat diet, results in hepatic steatosis and insulin resistance. We also observe a striking reduction in adipose inflammation and increase in adiponectin levels in all three models. This appears to reflect reduced activation of the inflammasome and less adipocyte death. These findings highlight the importance of Fsp27 in facilitating optimal energy storage in adipocytes and represent a rare example where adipose inflammation and hepatic insulin resistance are disassociated.

Lipopolysaccharide-binding protein is a negative regulator of adipose tissue browning in mice and humans

“…However, a discrepancy between circulating concentrations of innate immune system proteins in obese patients and the metabolic phenotype of the corresponding knockout mice has also been reported for lipocalin-2 [34,35] and IL-6 [4,36]. Other mouse models with loss of function of proinflammatory factors leading to impaired inflammation, such as the dominant-negative Tnfa transgenic mouse [37] and Fsp27-deficient mice [38], show reduced inflammation in adipose tissue associated with weight loss, but also insulin resistance. In fact, mice lacking LPS-binding capacity due to Cd14 knockout show reduced proinflammatory responses to LPS, but with significantly impaired glucose tolerance [39].…”

Differential Roles of Cell Death-inducing DNA Fragmentation Factor-α-like Effector (CIDE) Proteins in Promoting Lipid Droplet Fusion and Growth in Subpopulations of Hepatocytes

“…, ob/ob mice were maintained as described previously (33)(34)(35). All mice used were on a C57BL/6J background.…”

“…Mouse primary hepatocytes were isolated as described previously (35). The isolated hepatocytes were seeded at a density of 10 6 cells per dish in glass bottom microwell dishes (P35G-1.5-14-C, MatTek Corp.) in DMEM (Invitrogen) containing 10% FBS (Invitrogen).…”

“…The proteins were subjected to Western blot analysis with the desired antibodies. The antibodies against Cidea, Cideb, and Cidec were used as described previously (35). Antibodies against ␤-actin (Sigma, A5441, 1:2000), FLAG (Sigma, F1804, 1:1000), HA (Santa Cruz Biotechnology, sc-7392, 1:1000), and Plin2 (Fitzgerald Industries, 20R-Ap002, 1:8000) were used for Western blot analysis.…”

“…Antibodies and Western Blot Analysis-Methods for LD isolation, tissue homogenization, immunoprecipitation, two-step co-immunoprecipitation, and Western blot sample preparation were previously described (30,35). The proteins were subjected to Western blot analysis with the desired antibodies.…”