Abscisic acid enriched fig extract promotes insulin sensitivity by decreasing systemic inflammation and activating LANCL2 in skeletal muscle

Andrew Leber,Victoria Zoccoli-Rodriguez,Josep Bassaganya-Riera,Nuria Tubau-Juni,Bret Goodpaster,Raquel Hontecillas

doi:10.1038/s41598-020-67300-2

Abstract

Abscisic acid is a phytohormone found in fruits and vegetables and is endogenously produced in mammals. In humans and mice, lanthionine synthetase C-like 2 (LANCL2) has been characterized as the natural receptor for ABA. Herein, we characterize the efficacy of a fig fruit extract of ABA in promoting glycemic control. This ABA-enriched extract, at 0.125 µg ABA/kg body weight, improves glucose tolerance, insulin sensitivity and fasting blood glucose in diet-induced obesity (DIO) and db/db mouse models. In addition to decreasing systemic inflammation and providing glycemic control without increasing insulin, ABA extract modulates the metabolic activity of muscle. ABA increases expression of important glycogen synthase, glucose, fatty acid and mitochondrial metabolism genes and increases direct measures of fatty acid oxidation, glucose oxidation and metabolic flexibility in soleus muscle cells from ABA-treated mice with DIO. Glycolytic and mitochondrial ATP production were increased in ABA-treated human myotubes. Further, ABA synergized with insulin to dramatically increase the rate of glycogen synthesis. The loss of LANCL2 in skeletal muscle abrogated the effect of ABA extract in the DIO model and increased fasting blood glucose levels. This data further supports the clinical development of ABA in the treatment of pre-diabetes, type 2 diabetes and metabolic syndrome.

Highlights

Abscisic acid is a phytohormone found in fruits and vegetables and is endogenously produced in mammals
We discovered that dietary Abscisic acid (ABA) increases insulin sensitivity and suppresses obesity-related inflammation in obese/diabetic db/db mice[12,13]
Mice treated with ABA extract had a greater response to IP insulin resulting in lower blood glucose levels at 15 and 30 in the insulin tolerance test (Fig. 1C) and overall area under the curve (Fig. 1D)

Summary

Introduction

Abscisic acid is a phytohormone found in fruits and vegetables and is endogenously produced in mammals. We characterize the efficacy of a fig fruit extract of ABA in promoting glycemic control This ABA-enriched extract, at 0.125 μg ABA/kg body weight, improves glucose tolerance, insulin sensitivity and fasting blood glucose in diet-induced obesity (DIO) and db/db mouse models. In addition to decreasing systemic inflammation and providing glycemic control without increasing insulin, ABA extract modulates the metabolic activity of muscle. The loss of LANCL2 in skeletal muscle abrogated the effect of ABA extract in the DIO model and increased fasting blood glucose levels. This data further supports the clinical development of ABA in the treatment of pre-diabetes, type 2 diabetes and metabolic syndrome. The ABA/LANCL2 axis has emerged as a new promising target for the treatment of dysfunctional glucose homeostasis and inflammation[15]

Methods

Results

Conclusion