Mast cells function as an alternative modulator of adipogenesis through 15-deoxy-delta-12, 14-prostaglandin J₂

Abstract

Mast cells are one of the major producers of prostaglandins (PGs). The final metabolite of PGs 15-deoxy-delta-12,14-PGJ2(15-deoxy-delta PGJ2) is the endogenous ligand of the peroxisome proliferator-activated receptor (PPAR) γ. PPARγ modulates adipocyte differentiation; therefore, we attempted to investigate whether PGs derived from mast cells influenced on adipogenesis. We found the increase of mast cell numbers in fat tissue of obese mice fed with a high-fat diet allowed us to speculate contributions of mast cells to adipogenesis. Mast cell-mediated induction of adipogenesis was evaluated by using 3T3 L1 cells. Supernatants obtained from mast cells stimulated with calcium ionophore or the high-glucose condition contained 15-deoxy-delta PGJ2and induced adipogenesis of 3T3 L1 cells. Agonistic activity of PGJ2from the supernatants on PPARγ was confirmed by a reporter gene assay. Culture medium collected from calcium ionophore-stimulated bone marrow-derived cultured mast cells (BMCMC) activated PPAR-responsive element in NIH3T3 fibroblasts, and the specific inhibitor of PPARγ canceled the activation. Contribution of mast cells to obesity was evaluated by using mast cell-deficient mice fed with a Western diet. Weight gain of mast cell-deficient mice during high-fat feeding was impaired compared with their littermate wild-type mice; on the other hand, transplantation of bone marrow-derived cultured mast cells to mast cell-deficient mice restored the weight gain by intake of a high-fat diet. In this study, we clearly demonstrated that mast cells produced PGs in response to the high-glucose condition and induced adipocyte differentiation and possibly obesity. This is the first study that provides evidence for a novel role of mast cells in adipogenesis via PPARγ activation.

No Role for Mast Cells in Obesity-Related Metabolic Dysregulation

“…In addition, the obesity-related increase of mast cell numbers is more prominent in gAT (29), thereby suggesting that mast cells might participate in obesity-related AT inflammation and metabolic dysregulation (12). The proposed effects of mast cells in obesity, however, were inferred from experiments in Kit mutant mast cell-deficient mouse strains Kit W/W-v and Kit W-sh/W-sh (12, 13, 18), which displayed significantly lower weight gain and an improved obesity-related metabolic and inflammatory phenotype as compared to control mice. This effect was attributed to the lack of mast cell-derived IFN-γ and IL-6 (12).…”

Different Roles of Mast Cells in Obesity and Diabetes: Lessons from Experimental Animals and Humans

“…Recent studies demonstrated that MC supernatant contains 15-deoxy-delta PGJ 2 that induces pre-adipocyte 3T3-L1 cell adipogenesis (Figure 2). The specific PPARγ antagonist GW9662 blocks this MC activity (Tanaka et al, 2011). Using MC-deficient Kit W/Wv mice, the investigators showed that reduced body weight in Kit W/Wv mice can be reversed by WT bone marrow-derived mast cell (BMMC) transplantation, but not by transplantation of BMMC from hematopoietic PGD synthase (H-PGDS)-deficient mice.…”

“…Using MC-deficient Kit W/Wv mice, the investigators showed that reduced body weight in Kit W/Wv mice can be reversed by WT bone marrow-derived mast cell (BMMC) transplantation, but not by transplantation of BMMC from hematopoietic PGD synthase (H-PGDS)-deficient mice. H-PGDS-deficient BMMC also failed to induce 3T3-L1 differentiation (Tanaka et al, 2011). …”

The impact of mast cells on cardiovascular diseases

“…Likewise, mast cells are shown to co-localize with CD8 þ T cells in mouse WAT (Xu and Shi, 2012) suggesting a role in adipose tissue inflammation. An additional study reported that mast cell deficient Kit W-sh/W-sh mice transplanted with hematopoietic-prostaglandin synthase deficient mast cells are not able to gain weight similarly as mice transplanted with wild-type mast cells, pinpointing the importance of mast cell derived prostaglandins in adipose tissue function (Tanaka et al, 2011). As adipocytes themselves are also an important source of cytokines (Cao, 2014), this adds up to the local inflammatory burden.…”