No Role for Mast Cells in Obesity-Related Metabolic Dysregulation

Abstract

Obesity-related adipose tissue (AT) inflammation that promotes metabolic dysregulation is associated with increased AT mast cell numbers. Mast cells are potent inducers of inflammatory responses and could potentially contribute to obesity-induced AT inflammation and metabolic dysregulation. Conflicting findings were reported on obesity-related metabolic dysfunction in mast cell-deficient mice, thus creating a controversy that has not been resolved to date. Whereas traditional Kit hypomorphic mast cell-deficient strains featured reduced diet-induced obesity and diabetes, a Kit-independent model of mast cell deficiency, Cpa3Cre/+ mice, displayed no alterations in obesity and insulin sensitivity. Herein, we analyzed diet-induced obesity in Mcpt5-Cre R-DTA mice, in which the lack of mast cells is caused by a principle different from mast cell deficiency in Cpa3Cre/+ mice or Kit mutations. We observed no difference between mast cell-deficient and -proficient mice in diet-induced obesity with regards to weight gain, glucose tolerance, insulin resistance, metabolic parameters, hepatic steatosis, and AT or liver inflammation. We conclude that mast cells play no essential role in obesity and related pathologies.

Crosstalk Between Mast Cells and Adipocytes in Physiologic and Pathologic Conditions

“…No difference in terms of accumulation of M1-macrophages, or upregulation of inflammatory cytokines including IL-1β, IL-6, IL-10, and TNF, was reported. Furthermore, MC deficiency had no marked differences in obesity and obesity-related dysregulation [79]. Although MC numbers increase upon exposure to high-fat diet, the weight of evidence, taking into account the different genetic models used, indicates that the absence of these cells does not protect from obesity and IR.…”

Inflammatory Signaling and Brown Fat Activity

“…Several alternative (c-kit-independent) genetic models of mast cell depletion have found that there is essentially no effect of mast cells in obesity and related pathologies. That is because diet-induced obese mice with either deficiency or proficiency of mast cells exhibits similar profiles of weight gain, glucose tolerance, insulin sensitivity, metabolic parameters, and AT or liver inflammation (93,94). Further research is needed to fully understand the role of mast cells in brown and beige adipocytes especially in humans.…”

Mast cells drive IgE-mediated disease but might be bystanders in many other inflammatory and neoplastic conditions

“…25 The list of seemingly MC-dependent immune and disease processes inferred from observations in KIT mutant strains that did not reproduce in KIT-independent models has grown long. 48,[51][52][53]55,57,58,[64][65][66][67][68][69][70] These discrepancies must reflect a fundamental problem inherent to either one or the other type of model. Overwhelming evidence has accumulated indicating that KIT mutants have important problems as models of MC deficiency, even in cases in which the original experiments in the KIT mutant strains had been controlled by reconstitution with in vitro-differentiated MCs.…”

“…181,193 However, when obesity was induced in 2 different KIT-independent MC deficiency mouse models, absence of MCs was without detectable effect on metabolic regulation. 65,68 Moreover, using genetic dissociation of MC deficiency from KIT deficiency, Gutierrez et al 55,68 demonstrated that hypomorphic KIT expression in hematopoietic cells other than MCs had important effects on immune regulation that were responsible for the protection of KIT mutant mice from obesity and type II diabetes. Collectively, the available evidence from mouse models points to a bystander role of MCs in type II diabetes.…”