The Structure Basis of Phytochemicals as Metabolic Signals for Combating Obesity

Abstract

The consumption of phytochemicals, bioactive compounds in fruits and vegetables, has been demonstrated to ameliorate obesity and related metabolic symptoms by regulating specific metabolic pathways. This review summarizes the progress made in our understanding of the potential of phytochemicals as metabolic signals: we discuss herein selected molecular mechanisms which are involved in the occurrence of obesity that may be regulated by phytochemicals. The focus of our review highlights the regulation of transcription factors toll like receptor 4 (TLR4), nuclear factor (erythroid-derived 2)-like 2 (Nrf2), the peroxisome proliferator-activated receptors (PPARs), fat mass and obesity-associated protein (FTO) and regulation of microRNAs (miRNA). In this review, the effect of phytochemicals on signaling pathways involved in obesity were discussed on the basis of their chemical structure, suggesting molecular mechanisms for how phytochemicals may impact these signaling pathways. For example, compounds with an isothiocyanate group or an α, β-unsaturated carbonyl group may interact with the TLR4 signaling pathway. Regarding Nrf2, we examine compounds possessing an α, β-unsaturated carbonyl group which binds covalently with the cysteine thiols of Keap1. Additionally, phytochemical activation of PPARs, FTO and miRNAs were summarized. This information may be of value to better understand how specific phytochemicals interact with specific signaling pathways and help guide the development of new drugs to combat obesity and related metabolic diseases.

Keywords: metabolic signals; obesity; phytochemicals; structure; transcription factors.

Figure 1

Potential TLR4 signaling pathway induced by phytochemicals.

Figure 2

Reaction of thiol groups in the TLR4 signaling pathway with the α,β-unsaturated carbonyl group of phytochemicals.

Figure 3

An overview of phytochemical-derived agonists and the biological function of PPARs. (A) Agonists of PPARγ. (B) Agonists of PPARα. (C) Agonists of PPARβ.

Figure 4

Summary of Keap1 protein structure and binding to phytochemicals. (A) Domain structures of Keap1 protein. Seven cysteine residues (Cys151, Cys257, Cys273, Cys288, Cys297, Cys434, and Cys613) are responsible for covalent binding with phytochemicals to activate Nrf2. (B) Phytochemicals with α, β-unsaturated carbonyl groups having highly potent binding with cysteine residues of Keap1 through covalent modification. (C) Non-covalent binding cavity and residues of Kelch domain of Keap1 with phytochemicals. The reactive unsaturated carbonyl group of phytochemicals and potential non-covalent binding residues of Kelch domain of Keap1 are highlighted using red font.

Figure 5

Summary of molecular mechanism of FTO-induced obesity, FTO protein structure and its binding with rhein. (A) Mechanism of FTO-induced obesity through regulating food intake, thermogenesis and adipogenesis. (B) Domain structures of FTO protein. Seven amino acid residues (Arg96, His231, Asp233, His307, Arg316, Arg322, and Ile370) are responsible for FTO activity. (C) Binding cavity and residues of FTO protein with rhein. The potential binding residues of FTO are highlighted using red font.