Role of Abscisic Acid in the Whole-Body Regulation of Glucose Uptake and Metabolism

Abstract

Abscisic acid (ABA) is a hormone with a long evolutionary history, dating back to the earliest living organisms, of which modern (ABA-producing) cyanobacteria are likely descendants, which existed long before the separation of the plant and animal kingdoms, with a conserved role as signals regulating cell responses to environmental challenges. In mammals, along with the anti-inflammatory and neuroprotective function of ABA, nanomolar ABA regulates the metabolic response to glucose availability by stimulating glucose uptake in skeletal muscle and adipose tissue via an insulin-independent mechanism and increasing metabolic energy production and also dissipation in brown and white adipocytes. Chronic ABA intake of micrograms per Kg body weight improves blood glucose, lipids, and morphometric parameters (waist circumference and body mass index) in borderline subjects for prediabetes and metabolic syndrome. This review summarizes the most recent in vitro and in vivo data obtained with nanomolar ABA, the involvement of the receptors LANCL1 and LANCL2 in the hormone's action, and the importance of mammals' endowment with two distinct hormones governing the metabolic response to glucose availability. Finally, unresolved issues and future directions for the clinical use of ABA in diabetes are discussed.

Keywords: LANCL1; LANCL2; abscisic acid; diabetes; insulin independent mechanism; metabolic syndrome.

Figure 1

Chemical structure of 2-cis, 4-trans abscisic acid (ABA). ABA (MW 264) has a terpenoid structure and an asymmetric carbon, indicated by the arrow, giving rise to two enantiomers (+)- and (−)-ABA. Most functional activities in plants are attributed to (+)-ABA; in animals, both enantiomers appear to have biological activity [13].

Figure 2

Milestones in the discovery of ABA as an animal hormone. More than 20 years elapsed since the discovery of ABA in plants to its first identification in the mammalian brain as an endogenous molecule. Subsequent studies on the role of ABA as a stress hormone in early Metazoa (marine sponges and hydroids) paved the way toward its identification as an endogenous mammalian hormone (2012) and the identification of its receptors, LANCL1 and LANCL2. In vivo studies on rodents and humans allowed for the filing and granting of patent applications in the EU (2020) and in the US (2021) regarding the use of ABA as a nutraceutical to improve glucose tolerance and metabolism.

Figure 3

ABA-activated signaling pathways and primary functional effects of ABA on cellular metabolism. Deprotonated ABA, the predominant form at neutral pH, crosses the plasma membrane via an anion transporter [74] and binds to its receptors: cytosolic LANCL1 and membrane-anchored LANCL2. Both receptors can activate AMP-dependent kinase (AMPK) and the PGC-1a/sirtuin-1/ERRα axis, which in turn activates transcriptional programs controlling glucose uptake, mitochondrial function, and antioxidant defenses. Downstream of LANCL2, the activation of protein kinase A (PKA) also occurs, leading to phosphorylation and activation of the ADP-ribosyl cyclase CD38, with the production of cyclic ADP-ribose (cADPR) and ADP-ribose, both contributing to the generation of a cytosolic Ca²⁺ wave, via intracellular Ca²⁺ release from ryanodine-sensitive stores (cADPRs) and extracellular Ca²⁺ entry (ADPR).

Figure 4

The ABA-LANCL1/2 receptor system enhances glucose uptake and mitochondrial oxidative function, boosts mitochondrial biogenesis and respiration, and elevates the expression of uncoupling proteins in cardiomyocytes, skeletal myocytes, and beige/brown adipocytes. In addition to these effects, the ABA-LANCL1/2 system also stimulates cell-specific functional features, such as NO generation and ROS-protection mechanisms in cardiomyocytes, the expression of thyroid and beta-adrenergic receptors in brown/beige adipocytes, and physical endurance. The increased heat generation observed in ABA-treated, LANCL1/2-overexpressing cardiomyocytes [124] suggests a possible control of thermogenesis by this hormone/receptor system also on muscle and beige/brown adipocytes.

Figure 5

Non-overlapping functions of ABA and insulin in muscle and adipose tissue. Both ABA and insulin promote glucose transport in muscle and adipose tissues. Insulin increases the conversion of metabolic energy into storage forms such as muscle glycogen, fatty acids, and white adipocyte triglycerides, via the Akt pathway. Activated Akt suppresses AMPK. ABA, on the other hand, stimulates energy production by increasing mitochondrial mass and metabolic and respiratory activity. This in turn leads to increased heat generation, due to the concomitant activation of inner mitochondrial membrane proton leak, which reduces the ΔG for proton pumping and the retrograde electron flux, thus reducing ATP generation and leading to the production of oxidizing radicals [42,44,51].