Person:

Liu, Conglin

Prior studies demonstrated increased plasma immunoglobulin E (IgE) in diabetic patients, but the direct participation of IgE in diabetes or obesity remains unknown. This study found that plasma IgE levels correlated inversely with body weight, body mass index, and body fat mass among a population of randomly selected obese women. IgE receptor FcεR1-deficient (Fcer1a–/–) mice and diet-induced obesity (DIO) mice demonstrated that FcεR1 deficiency in DIO mice increased food intake, reduced energy expenditure, and increased body weight gain, but improved glucose tolerance and glucose-induced insulin secretion. White adipose tissue (WAT) from Fcer1a–/– mice showed increased expression of phospho-AKT, C/EBPα, PPARγ, Glut4, and Bcl-2, but reduced UCP1 and phospho-JNK expression, tissue macrophage accumulation, and apoptosis, suggesting that IgE reduces adipogenesis and glucose uptake, but induces energy expenditure, adipocyte apoptosis, and WAT inflammation. In 3T3-L1 cells, IgE inhibited the expression of C/EBPα and PPARγ, and preadipocyte adipogenesis, and induced adipocyte apoptosis. IgE reduced 3T3-L1 cell expression of Glut4, phospho-AKT, and glucose uptake, which concurred with improved glucose tolerance in Fcer1a–/– mice. This study established two novel pathways of IgE in reducing body weight gain in DIO mice by suppressing adipogenesis and inducing adipocyte apoptosis, while worsening glucose tolerance by reducing Glut4 expression, glucose uptake, and insulin secretion.

Mast cells (MCs) contribute to the pathogenesis of obesity and diabetes. This study demonstrates that leptin deficiency slants MCs toward anti-inflammatory functions. MCs in the white adipose tissue (WAT) of lean humans and mice express negligible leptin. Adoptive transfer of leptin-deficient MCs expanded ex vivo mitigates diet-induced and pre-established obesity and diabetes in mice. Mechanistic studies show that leptin-deficient MCs polarize macrophages from M1 to M2 functions because of impaired cell signaling and an altered balance between pro-and anti-inflammatory cytokines, but do not affect T cell differentiation. Rampant body weight gain in ob/ob mice, a strain that lacks leptin, associates with reduced MC content in WAT. In ob/ob mice, genetic depletion of MCs exacerbates obesity and diabetes, and repopulation of ex vivo expanded ob/ob MCs ameliorates these diseases.