Genetic deletion of mast cell serotonin synthesis prevents the development of obesity and insulin resistance

Julian M Yabut,Bo Wang,Waliul I Khan,Gregory R Steinberg,Wesley Wong,Elizabeth D Crane,Julie M Leroux,Eric M Desjardins,Eric J Chan,Emily A Day,Katherine M Morrison,Justin D Crane

doi:10.1038/s41467-019-14080-7

Abstract

Obesity is linked with insulin resistance and is characterized by excessive accumulation of adipose tissue due to chronic energy imbalance. Increasing thermogenic brown and beige adipose tissue futile cycling may be an important strategy to increase energy expenditure in obesity, however, brown adipose tissue metabolic activity is lower with obesity. Herein, we report that the exposure of mice to thermoneutrality promotes the infiltration of white adipose tissue with mast cells that are highly enriched with tryptophan hydroxylase 1 (Tph1), the rate limiting enzyme regulating peripheral serotonin synthesis. Engraftment of mast cell-deficient mice with Tph1−/− mast cells or selective mast cell deletion of Tph1 enhances uncoupling protein 1 (Ucp1) expression in white adipose tissue and protects mice from developing obesity and insulin resistance. These data suggest that therapies aimed at inhibiting mast cell Tph1 may represent a therapeutic approach for the treatment of obesity and type 2 diabetes.

Highlights

Obesity is linked with insulin resistance and is characterized by excessive accumulation of adipose tissue due to chronic energy imbalance
To delineate the potential role of Tph[1] and peripheral serotonin for inhibiting adipose tissue thermogenesis and the primary cell type(s) that might be mediating this effect, we first conducted experiments in mice housed at thermoneutrality (TN; 29 °C); a condition known to dramatically reduce adipose tissue thermogenesis compared to housing mice at room temperature (RT; 22 °C)[19,20]
We subsequently examined Tph[1] expression and found that it was unchanged in Brown adipose tissue (BAT), but was significantly elevated in inguinal white adipose tissue (WAT) and gonadal WAT (Fig. 1b)

Summary

Introduction

Obesity is linked with insulin resistance and is characterized by excessive accumulation of adipose tissue due to chronic energy imbalance. In mice fed a high-fat diet, genetic removal of Tph[1] in mast cells from two distinct mouse models elevates basal metabolic rate, increases WAT Ucp[1] and protects mice from obesity, insulin resistance and fatty liver disease compared to relevant controls. These data establish a role for mast cells in regulating adipose tissue thermogenesis and suggest that the therapeutic targeting of mast cell Tph[1] may be a future strategy for the treatment of obesity and related metabolic disorders including insulin resistance and NAFLD

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Results

Conclusion