Abscisic Acid: A Conserved Hormone in Plants and Humans and a Promising Aid to Combat Prediabetes and the Metabolic Syndrome

Abstract

Abscisic acid (ABA) is a hormone with a very long evolutionary history, dating back to the earliest living organisms, of which modern (ABA-producing) cyanobacteria are likely the descendants, well before separation of the plant and animal kingdoms, with a conserved role as a signal regulating cell responses to environmental challenges. In mammals, nanomolar ABA controls the metabolic response to glucose availability by stimulating glucose uptake in skeletal muscle and adipose tissue with an insulin-independent mechanism and increasing energy expenditure in the brown and white adipose tissues. Activation by ABA of AMP-dependent kinase (AMPK), in contrast to the insulin-induced activation of AMPK-inhibiting Akt, is responsible for stimulation of GLUT4-mediated muscle glucose uptake, and for the browning effect on white adipocytes. Intake of micrograms per Kg body weight of ABA improves glucose tolerance in both normal and in borderline subjects and chronic intake of such a dose of ABA improves blood glucose, lipids and morphometric parameters (waist circumference and body mass index) in borderline subjects for prediabetes and the metabolic syndrome. This review summarizes the most recent results obtained in vivo with microgram amounts of ABA, the role of the receptor LANCL2 in the hormone's action and the significance of the endowment by mammals of two different hormones controlling the metabolic response to glucose availability. Finally, open issues in need of further investigation and perspectives for the clinical use of nutraceutical ABA are discussed.

Keywords: AMP-activated protein kinase; abscisic acid; adipocyte browning; food supplement; insulin resistance; metabolic syndrome; prediabetes; type 2 diabetes mellitus.

Figure 1

Structure of ABA. 2-cis, 4-trans-Abscisic acid has an asymmetric carbon atom (arrow) generating two enantiomers S-(+)-ABA and R-(-)-ABA. (+)-ABA is the naturally-occurring form in plants, although (-)-ABA is active in some vegetal functional assays [2].

Figure 2

The active ingredient of the food supplement is the ABA-containing vegetal extract. Six volunteers introduced a standardized carbohydrate-rich breakfast, one without any supplement (control), one with one tablet of the formulated food supplement (Food suppl) and another taking only the amount of vegetal extract (ABAMET^®) present in one tablet of the food supplement. The three experiments were performed one week apart. The food supplement or ABAMET^® were taken before the meal [20] Mean ± SD values of the incremental AUC of glycemia in the time frames 0–60 and 0–120 min are shown. p values by paired, two-tailed t-test of the comparison between each bar with the respective control bar are shown.

Figure 3

Non-overlapping roles of ABA and insulin in the regulation of energy metabolism. Insulin, via the kinase Akt, stimulates glucose uptake in skeletal muscle and white adipose tissue (WAT), triglyceride synthesis in adipocytes, preadipocyte differentiation into WAT and increased hepatic triglyceride synthesis and lipoprotein export into the blood. Nanomolar ABA, via the AMP-dependent protein kinase (AMPK), stimulates muscle glucose uptake similarly to insulin, but the effect on adipose tissue is different. ABA does not induce preadipocytes differentiation; instead, it stimulates the expression of browning genes in the WAT and increases glucose uptake and mitochondrial uncoupling in brown adipose tissue (BAT). The effect of insulin and of ABA on body weight (BW) is opposite, with insulin inducing an increase and ABA instead favoring a decrease. The relative plasma concentrations of these hormones is likely to affect BW homeostasis and energy metabolism. Via Akt, insulin inhibits AMPK and the metabolic responses to low cell energy levels.

Figure 4

LANCL2^−/− mice have a reduced glucose tolerance, but respond to ABA. Eight-hour fasted, male LANCL2^−/− (KO) and wild-type (WT) mice (6/group) were subjected to OGTT (2 g glucose/Kg body weight) without or with ABA (1 µg/Kg body weight). Glycemia was measured before gavage (time zero) and at 30, 60 and 120 min thereafter. The incremental AUC of glycemia was calculated in the time frames 0–60 and 0–120 min by the trapezoidal rule on values relative to time zero. p values by two-tailed unpaired t-test (KO vs. WT) or by two-tailed paired t-test (KO + ABA vs. KO). The genetic ablation of LANCL2 in KO mice was confirmed by genotyping. Absence of LANCL2 protein expression in skeletal muscle, liver, WAT and BAT of KO mice was confirmed by Western blot (not shown), (Magnone M., unpublished results).