Epigenetic Regulation of Adipogenesis in Development of Metabolic Syndrome

Abstract

Obesity is one of the biggest public health concerns identified by an increase in adipose tissue mass as a result of adipocyte hypertrophy and hyperplasia. Pertaining to the importance of adipose tissue in various biological processes, any alteration in its function results in impaired metabolic health. In this review, we discuss how adipose tissue maintains the metabolic health through secretion of various adipokines and inflammatory mediators and how its dysfunction leads to the development of severe metabolic disorders and influences cancer progression. Impairment in the adipocyte function occurs due to individuals' genetics and/or environmental factor(s) that largely affect the epigenetic profile leading to altered gene expression and onset of obesity in adults. Moreover, several crucial aspects of adipose biology, including the regulation of different transcription factors, are controlled by epigenetic events. Therefore, understanding the intricacies of adipogenesis is crucial for recognizing its relevance in underlying disease conditions and identifying the therapeutic interventions for obesity and metabolic syndrome.

Keywords: adipogenesis; insulin resistance; metabolic syndrome; obesity; transgenerational inheritance.

FIGURE 1

Adipocytes have remarkable plastic properties. In usual scenario adipose tissue consists of white, brown and occasional beige adipocytes. The main function of white adipocytes is to store lipids to meet the metabolic requirements of the body while brown adipocytes are required for thermogenesis. Beige adipocytes have the ability to switch between energy storage and expenditure. However, during certain conditions like cold exposure or strenuous exercise, white adipocytes trans-differentiates to beige or brown adipocytes while during the state of positive energy when there is lack of lipid storage, brown/beige adipocytes can be converted back to white adipocytes to increase the energy stores. During pregnancy and lactation, subcutaneous white adipocytes of the breast tissue convert to pink adipocytes which are basically the milk secreting glands formed by lipid-rich elements and brown adipocytes trans-differentiate to myoepithelial cells of mammary glands. All these conversions are reversible, i.e., post-lactation, pink adipocytes convert back to white and brown adipocytes.

FIGURE 2

Cell signaling events triggered by altered adipokine production during obesity. Expansion of adipose tissue in obese condition leads to altered adipokine production. High concentration of leptin and resistin results in the activation of different signaling pathways within the cell (Akt/GSK3, MTA/Wnt1, Src/FAK, ERK/JNK, JAK/STAT, PI3K, and MAPK). These signaling pathways ultimately lead to cancer cell invasion and metastasis. On the other hand, high adiponectin concentration leads to MAPK inhibition and AMPK inactivation which is responsible for its pro-apototic and anti-tumoral activities.

FIGURE 3

Immune cell distribution in lean and obese state. In lean adipose tissue with normal metabolic function, M2 macrophages are uniformly distributed throughout the tissue. The lean AT milieu also consists of CD4+ T cells and Treg cells having anti-inflammatory properties. Adiponectin to leptin ratio is high which contributes to the insulin responsive state of the adipocytes. In obese state, macrophages switch to M1 type which forms a crown like structure (CLS) around the adipocytes. Adipocyte hypertrophy results in the rupture of adipocytes and releases FFAs. In addition to M1 macrophages, obese state is also associated with an increase in CD8⁺ T cells, dendritic cells and IgG antibody producing B cells responsible for pathogenic state of AT. Obesity is also associated with abnormal adipokine profile, i.e., increased release pro-inflammatory adipokines. Aberrant secretion of adipokines (leptin, IL-6, adipsin, RBP-4, and IL-1β), chemokines (CCL2 and CXCL1) and macrophage factors (TNF-α) causes metabolic dysfunction and insulin resistance.

FIGURE 4

Cascade of transcription factors in adipocyte differentiation. Many transcription factors act as positive regulators that express at different stages of adipocyte differentiation (pre-adipocytes to mature adipocytes). The differentiation process initiates upon induction of cells with adipogenic cocktail which helps in activation of certain transcription factors like CREBP, KLF4, 5, and 9, and CEBPβ/δ. CEBPβ and CEBPδ triggers the second wave of adipogenesis by activating PPARγ, CEBPα and SREBP. The PPAR proteins dimerizes with retinoic X receptor (RXR) for interaction with target promoters containing PPAR-response elements. PPARγ and CEBPα are the key proteins that targets the essential genes required for adipogenesis. To regulate the process of adipogenesis, some transcription factors like KLF2 and GATA2/3 act as negative regulators and inhibits the expression of CEBPα and PPARγ by direct or indirect repression of the transcription cascade.

FIGURE 5

Epigenetic modification of genes involved in adipogenesis. Methylation of gene promoters, that are necessary for adipogenesis, results in inactivation of the genes leading to reduced adipogenesis, whereas acetylation of promoter region brings about active adipocyte differentiation. Histone modification through HATs or HMTs that are recruited at the gene promoter by CEBPβ results in either activation or repression of the genes that are essential for adipogenesis. Chromatin remodeling complexes, such as SWI/SNF, tends to change the chromatin structure, thereby making the DNA either accessible or inaccessible for the transcription of adipogenesis specific genes to happen. Non-coding RNAs also govern the transcription of master regulators of adipogenesis by activating (miR-143, RP11-142A22.4) or repressing (miR-27, ADNCR) the transcription of key genes required for adipogenesis. Uncontrolled expression of genes involved in adipogenesis could ultimately lead to metabolic disorders.

FIGURE 6

Interaction between environment/genetic factors and epigenetic changes in establishment of obesity and obesity-associated metabolic disorders. Environmental factors like exposure to drugs/toxic chemicals, lack of physical activity, sedentary lifestyle, poor and unhealthy diet, stress/anxiety, smoking/alcohol abuse along with genetic makeup of an organism can have direct influence on epigenetic marks and result in increased adiposity. The changes in epigenetic landscape through various histone modifications, changes in chromatin accessibility and DNA methylation results in obesity and other metabolic disorders like diabetes, hypertension, lipodystrophy, cardiovascular diseases, NAFLD, cancer, etc.