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Review
, 1793 (7), 1128-43

Regulation of Energy Metabolism Pathways by Estrogens and Estrogenic Chemicals and Potential Implications in Obesity Associated With Increased Exposure to Endocrine Disruptors

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Review

Regulation of Energy Metabolism Pathways by Estrogens and Estrogenic Chemicals and Potential Implications in Obesity Associated With Increased Exposure to Endocrine Disruptors

Jin-Qiang Chen et al. Biochim Biophys Acta.

Abstract

The prevalence of obesity among children, adolescents and adults has been dramatically increasing worldwide during the last several decades. The obesity epidemic has been recognized as one of the major global health problems, because its health hazard is linked to a number of common diseases including breast and prostate cancers. Obesity is caused by combination of genetic and environmental factors. While genetic contribution to obesity has been known to be significant, the genetic factors remain relatively unchanged. Recent studies have highlighted the involvement of environmental "obesogens", i.e. the xenobiotic chemicals that can disrupt the normal development and homeostatic control over adipogenesis and energy balance. Several lines of evidence suggest that increasing exposure to chemicals with endocrine-disrupting activities (endocrine-disrupting chemicals, EDCs) contributes to the increased obesity. The cellular and molecular mechanisms underlying obesogen-associated obesity are just now being appreciated. In this paper, we comprehensively reviewed current knowledge about the role of estrogen receptors alpha and beta (ERalpha and ERbeta) in regulation of energy metabolism pathways, including glucose transport, glycolysis, tricarboxylic acid (TCA) cycle, mitochondrial respiratory chain (MRC), adenosine nucleotide translocator (ANT) and fatty acid beta-oxidation and synthesis, by estrogens; and then examined the disturbance of E(2)/ER-mediated energy metabolism pathways by environmental obesogens; and finally, we discussed the potential implications of disturbance of energy metabolism pathways by obesogens in obesity and pointed out several key aspects of this area that need to be further explored. A better understanding of the cellular and molecular mechanisms underlying obesogen-associated obesity will lead to new approaches for slow down and/or prevention of the increased trend of obesity associated with exposure to obesogens.

Figures

Figure 1
Figure 1. Proposed Models for the Regulation of Energy Metabolism Pathways and Utilization by Estrogens and ERs
There could be two energy flows: constitutive energy flow, indicated by the black arrows; and E2/ER-indcued energy flow, indicated by the bold red arrows
Figure 2
Figure 2. Regulation of Glycolytic Enzymes by E2/ERs
Biochemical reactions of glycolysis and the enzymes that catalyze these reactions are shown. The stimulating effects of E2 on expression and/or activity of the enzymes are indicated by arrows
Figure 3
Figure 3. Regulation of TCA Cycle By Estrogens/ERs
Biochemical reactions of TCA cycle and corresponding enzymes are shown (indicated by red color). Red arrows point to the enzymes whose expression/activity are regulated by E2/ERs.
Figure 4A
Figure 4A. Regulation of MRC Proteins by E2/ERs
MRC complexes I, II, III, IV and V are shown. Genes encoded by nuclear DNA (nDNA) are indicated by green color; genes encoded by mtDNA are indicated by blue color. The number indicates the number of protein subunits. The red, bold arrows indicate the potential effects of E2 on the expression of nDNA- and mtDNA-genes. Potential targets for estrogenic and anti-estrogenic chemicals are marked by the block symptoms. COI, II, III: cytochrome c oxidase subunits I, II and III; cytb: cytocrome b; cyt c:cytochrome c; CoQ: Coenzyme Q; ND 1to ND6: NADH dehydrogenase subunits 1 to 6; mtTFA: mitochondriual transcription factor A; NRF: Nuclear respiratory factor; PGC-1: subunits 6 & 8: ATP synthase subunits 6 & 8.
Figure 4B
Figure 4B. Role of c-myc in the Regulation of MRC Proteins by E2/ERs
The transcription factor, c-myc, is an E2-regulated protein. It is involved in the stimulation of nDNA-encoded MRC gene expression. It also stimulates the expression of mtTFA, a transcription factors involved in mtDNA transcription. C-myc coordinates the expression of both nDNA-encoded and mtDNA-encoded MRC protein synthesis, and thus enhances mitochondrial biogenesis. Red arrows indicate the stimulating effects by E2.
Figure 5
Figure 5. Regulation of ANT by E2/ERs
Bcl-2 is an important component of ANT shuttle. The expression of Bcl-2 and some isoforms of ANT is stimulated by E2. Red arrows indicate the stimulating effects of E2. Mitochondrial H+-ATP synthase is shown in lower panel.
Figure 6
Figure 6. Regulation of fatty acid β-oxidation by E2/ERs
The Biochemical reactions of fatty acid β-oxidation and corresponding enzymes that catalyze these reactions are shown. The enzymes whose expression/activity are stimulated by E2/ERs are indicated by red arrow.

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