Role of Inositols and Inositol Phosphates in Energy Metabolism

Abstract

Recently, inositols, especially myo-inositol and inositol hexakisphosphate, also known as phytic acid or IP6, with their biological activities received much attention for their role in multiple health beneficial effects. Although their roles in cancer treatment and prevention have been extensively reported, interestingly, they may also have distinctive properties in energy metabolism and metabolic disorders. We review inositols and inositol phosphate metabolism in mammalian cells to establish their biological activities and highlight their potential roles in energy metabolism. These molecules are known to decrease insulin resistance, increase insulin sensitivity, and have diverse properties with importance from cell signaling to metabolism. Evidence showed that inositol phosphates might enhance the browning of white adipocytes and directly improve insulin sensitivity through adipocytes. In addition, inositol pyrophosphates containing high-energy phosphate bonds are considered in increasing cellular energetics. Despite all recent advances, many aspects of the bioactivity of inositol phosphates are still not clear, especially their effects on insulin resistance and alteration of metabolism, so more research is needed.

Keywords: IP6; energy metabolism; inositol phosphates; insulin resistance; myo-inositol.

Figure 1

Structures of the 9 stereoisomers of inositol, which exist under 9 stereoisomeric forms through epimerization of its hydroxyl groups. Myo-Inositol (framed) is the most common isomer in plants and animal cells.

Figure 2

The inositol polyphosphates pathway in human cells. The figure shows metabolism cascade of inositol phosphate molecules from the well-known Ins (1,4,5) P3 formation via phospholipase C to higher inositol phosphates, including pyrophosphates (5PP-IP5 or IP7 and I,5PP-IP4 or IP8). In contrast, inositol triphosphates Ins (1,3,4) P3 and Ins (1,4,5) P3 can be broken down into lower inositol phosphates and eventually myoIns. DIPP1: Diphosphoinositol polyphosphate phosphohydrolase 1; IMPase 1: Inositol monophosphatase 1; INPP4AT1: Type I inositol 3,4-bisphosphate 4-phosphatase; INPP4AT2: Type II inositol 3,4-bisphosphate 4-phosphatase; IP3K A: Inositol-trisphosphate 3-kinase A; IP6K1: Inositol hexakisphosphate kinase 1; IPMK: Inositol polyphosphate multikinase; IPPase: Inositol polyphosphate 1-phosphatase; IPPK: Inositol-pentakisphosphate 2-kinase; IPS1: Inositol-3-phosphate synthase 1; ITPK1: Inositol-tetrakisphosphate 1-kinase; MIPPase1: Multiple inositol polyphosphate phosphatase; PPIP5K: Inositol hexakisphosphate and diphosphoinositol-pentakisphosphate kinase 5; PtdIns (4,5) P2: Phosphatidylinositol 4,5-bisphosphate 5-phosphatase A [18].

Figure 3

The structure of IP6 and the turtle analogy. Panel (A) shows chair conformation of myo-inositol hexakisphosphate (IP6) with the unique configuration of phosphate groups in positions 1, 2 and 3 (axial-equatorial-axial). Panel (B) shows Agranoff’s turtle analogy.

Figure 4

The basic pathway of inositol polyphosphates involved in energy metabolism. The figure shows an oversimplified pathway from PIP2 to pyrophosphates, with IP6 having a central role and position.

Figure 5

The diagram shows the effects of myoIns, d-chiro-inositol, and IP6 on insulin metabolism, glucose metabolism, and other metabolic profiles (A) and the effects of IP6K1 disruption in metabolic target tissues including adipose tissues, liver, and skeletal muscle (B).