Regulation of Thermogenic Adipocyte Differentiation and Adaptive Thermogenesis Through Histone Acetylation

Abstract

Over the past decade, the increasing prevalence of obesity and its associated metabolic disorders constitutes one of the most concerning healthcare issues for countries worldwide. In an effort to curb the increased mortality and morbidity derived from the obesity epidemic, various therapeutic strategies have been developed by researchers. In the recent years, advances in the field of adipocyte biology have revealed that the thermogenic adipose tissue holds great potential in ameliorating metabolic disorders. Additionally, epigenetic research has shed light on the effects of histone acetylation on adipogenesis and thermogenesis, thereby establishing the essential roles which histone acetyltransferases (HATs) and histone deacetylases (HDACs) play in metabolism and systemic energy homeostasis. In regard to the therapeutic potential of thermogenic adipocytes for the treatment of metabolic diseases, herein, we describe the current state of knowledge of the regulation of thermogenic adipocyte differentiation and adaptive thermogenesis through histone acetylation. Furthermore, we highlight how different HATs and HDACs maintain the epigenetic transcriptional network to mediate the pathogenesis of various metabolic comorbidities. Finally, we provide insights into recent advances of the potential therapeutic applications and development of HAT and HDAC inhibitors to alleviate these pathological conditions.

Keywords: adaptive thermogenesis; epigenetics; gene expression; histone acetylation; histone acetyltransferase inhibitors; histone deacetylase inhibitors; histone deacetylation; thermogenic adipocyte differentiation.

Figure 1

The different types of adipocytes, and HATs/HDACs that regulate brown adipogenesis and adaptive thermogenesis. (A) The three main types of adipocytes: white, brown, and beige adipocytes. White adipocytes are involved in energy storage, while brown adipocytes are involved in adaptive thermogenesis during which heat is produced. Brown adipocytes also consist of a high mitochondrial content and UCP1 expression. Beige adipocytes are derived from white adipocyte precursor cells and similar to brown adipocytes, they can undergo adaptive thermogenesis upon stimulation, through a process known as browning. (B) Histone acetylation and deacetylation are mediated by HATs and HDACs, respectively. Examples of HATs/HDACs and their inhibitors that are involved in regulating thermogenic adipocyte differentiation, adaptive thermogenesis, and the pathogenesis of metabolic disorders.

Figure 2

Co-crystal structures of human PCAF–CoA (PDB code: 1CM0) and GCN5–Ac-CoA (PDB code: 1Z4R) HAT domains. PCAF–CoA is shown in purple, while GCN5–Ac-CoA is shown in gray. (A) Structure of PCAF–CoA comprising a central core composed of a β-sheet flanked by a parallel α-helix on one side, as well as α and β segments surrounding it. CoA is shown as green sticks. (B) Magnified view of the CoA molecule in a bent conformation. (C) Interaction between PCAF residues and CoA at the catalytic site. Hydrogen bonds are shown as blue dashed lines. (D) Superimposition of PCAF–CoA and GCN5–Ac-CoA overall structures. CoA and Ac-CoA are shown as sticks in the same color as their corresponding HAT proteins. (E) Superimposition of PCAF–CoA and GCN5–Ac-CoA residues at the catalytic site. CoA and Ac-CoA have been removed for clarity. All structural figures were produced using PyMOL (The PyMOL Molecular Graphics System, Version 2.3.2 Schrödinger, LLC) (69).

Figure 3

HATs that are involved in brown adipocyte differentiation/adipogenesis and adaptive thermogenesis, as well as compounds (HATis) that have been demonstrated to inhibit them. (A) GCN5/PCAF and CBP/p300 mediate brown adipocyte differentiation/adipogenesis by inducing the expression of PPARγ-target, BAT-selective, thermogenic and adipogenic genes through PRDM16 and MLL3/MLL4, respectively, as well as PPARγ. (B) TIF2, SRC-1 and p/CIP mediate adaptive thermogenesis by inducing the expression of BAT-specific PPARγ-target genes. SRC-1 and p/CIP have also been shown to interact with each other to regulate the expression of these genes.

Figure 4

Crystal structure of p300 catalytic domain in complex with CoA, containing PEG1 and PEG2 (PDB code: 4PZR). p300 is shown in pink, CoA is shown as green sticks, and the PEG moieties are shown as cyan sticks. (A) Overall structure of p300–CoA catalytic domain comprising a central β-sheet and α-helices around it. (B) Surface of the catalytic site and the region surrounding it. The shallow, negatively charged groove composed of Ser1396, Tyr1397, Thr1357, and Asp1625 is colored in purple.

Figure 5

Structural features of human HDACs. (A) Zinc- and NAD⁺-dependent classes HDACs: Catalytic domains of zinc-dependent HDAC2–SAHA (PDB code: 4LXZ) comprising an arginase fold colored in orange, and NAD⁺-dependent SIRT2 (PDB code: 1J8F) comprising a Rossmann fold colored in red. (B) Class IIa HDACs: HDAC4–TFMK inhibitor (PDB code: 2VQJ) and HDAC7–TSA (PDB code: 3C10) structures comprising a catalytic zinc-binding domain and an additional structural zinc-binding domain. The structural zinc ions are coordinated by histidine and cysteine residues shown as sticks.

Figure 6

Structural features of the class IIb HDAC, HDAC6 ZnF-UBD. (A) Overall structure of the ZnF-UBD of HDAC6 (PDB code: 3C5K). (B) Surface representation of inhibitor-bound human HDAC6 ZnF-UBD (PDB code: 5WBN). The electrostatic potential map shows the inhibitor-bound primary binding pocket, and the opening of a secondary cavity that can be potentially targeted to increase inhibitor selectivity. Basic, acidic and hydrophobic regions are shown in blue, red, and white, respectively. The inhibitor is shown as green sticks.

Figure 7

HDACs that are involved in adaptive thermogenesis and browning, as well as compounds (HDACis) that have been demonstrated to inhibit them. (A) HDAC1/2/3/6/11 and SIRT1/3 mediate adaptive thermogenesis by inducing the expression of BAT-specific, thermogenic, lipid β-oxidation, and transcription regulation-related genes. (B) HDAC3 and SIRT1 mediate browning of white adipocytes by inducing the expression of oxidative metabolic genes and classical BAT markers.