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Transcriptional Regulation of Adipogenesis

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ABSTRACT

Adipocytes are the defining cell type of adipose tissue. Once considered a passive participant in energy storage, adipose tissue is now recognized as a dynamic organ that contributes to several important physiological processes, such as lipid metabolism, systemic energy homeostasis, and whole‐body insulin sensitivity. Therefore, understanding the mechanisms involved in its development and function is of great importance. Adipocyte differentiation is a highly orchestrated process which can vary between different fat depots as well as between the sexes. While hormones, miRNAs, cytoskeletal proteins, and many other effectors can modulate adipocyte development, the best understood regulators of adipogenesis are the transcription factors that inhibit or promote this process. Ectopic expression and knockdown approaches in cultured cells have been widely used to understand the contribution of transcription factors to adipocyte development, providing a basis for more sophisticated in vivo strategies to examine adipogenesis. To date, over two dozen transcription factors have been shown to play important roles in adipocyte development. These transcription factors belong to several families with many different DNA‐binding domains. While peroxisome proliferator‐activated receptor gamma (PPARγ) is undoubtedly the most important transcriptional modulator of adipocyte development in all types of adipose tissue, members of the CCAAT/enhancer‐binding protein, Krüppel‐like transcription factor, signal transducer and activator of transcription, GATA, early B cell factor, and interferon‐regulatory factor families also regulate adipogenesis. The importance of PPARγ activity is underscored by several covalent modifications that modulate its activity and its ability to modulate adipocyte development. This review will primarily focus on the transcriptional control of adipogenesis in white fat cells and on the mechanisms involved in this fine‐tuned developmental process. © 2017 American Physiological Society. Compr Physiol 7:635‐674, 2017.

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Figure 1. Figure 1. Different shades of adipocytes: white, brown, and beige. White adipocytes comprise the majority of fat cells in mice and men. The primary function of white adipocytes is lipid storage. Brown adipocytes largely function to produce heat. Beige adipocytes have properties similar to both brown and white adipocytes. There is evidence that each type of fat cell comes from a different type of preadipocyte. However, there is also evidence that beige adipocytes result from the transdifferentiation of white adipocytes. Although the characterization of each cell type is well understood, the developmental origins of these different types of cells from preadipocytes and their adipocyte progenitor cells is an emerging area of research.
Figure 2. Figure 2. In vitro studies of adipocyte development. Preadipocytes are cells capable of differentiating into adipocytes with the appropriate hormonal cocktail, which varies for adipogenesis of brown, white, or beige preadipocytes. Examples of preadipocytes include 3T3‐L1 and 3T3‐F442A cells. Nonprecursor cells, fibroblasts and other cell types, do not undergo adipogenesis in the presence of the appropriate hormonal cocktail. Examples of nonprecursor cells include NIH 3T3, Swiss 3T3, and Balb/c fibroblasts. Nonprecursor cells can undergo adipogenesis with ectopic expression of PPARγ or other transcription factors.
Figure 3. Figure 3. Structural motifs of DBD s in transcription factors that regulate adipocyte development. Transcription factors have at least one DBD that mediates their capacity to bind to DNA and regulate transcription. Leucine zipper is a dimerization domain of the bZIP class that contains periodic repetition of leucine residues, which coordinates its ability to bind to DNA; C/EBPs and AP‐1 proteins are examples of leucine zipper proteins. In the zinc‐finger structure, a zinc ion is coordinated by a combination of cysteine and histidine residues. Zinc fingers arise from multiple different folding arrangements (“fold groups”). The classic Cys2His2 zinc finger motif is shown. KLFs, GATAs, and Zfps, as well as all of the nuclear receptors are examples of zinc‐finger proteins. Helix‐loop‐helix is characterized by two α‐helices connected by a loop. SREBP and EBFs are helix‐loop‐helix transcription factors. Helix‐turn‐helix is characterized by two α‐helices joined by a short strand of amino acids and is found in IRFs that regulate adipogenesis. Some adipocyte transcription factors such as KLFs and SREBPs contain more than one structural motif to facilitate DNA binding.
Figure 4. Figure 4. Transcription factors that promote adipogenesis. Many transcription factors are induced during adipocyte differentiation. Some of these, like members of the AP‐1 family, are induced during clonal expansion. Others, like PPARγ, have been shown to promote adipocyte differentiation in vitro and in vivo. The relative timing of the induction of each transcription factor is indicated.
Figure 5. Figure 5. Transcription factors that inhibit adipogenesis. Many specific transcription factors have been shown to inhibit adipocyte development. The expression of most of these transcription factors decreases with adipocyte development. Ectopic expression and knockdown approaches have been used to demonstrate the inhibitory actions of these transcription factors. The relative timing of the action of each transcription factor is indicated.
Figure 6. Figure 6. PPARγ exists in two isoforms, γ1 and γ2. PPARγ proteins are members of the large nuclear hormone receptor superfamily of transcription factors that also includes steroid receptors and TRs. PPARγ1 has 30 fewer amino acids in the N‐terminal region than PPARγ2. The covalent modifications are indicated for both PPARγ proteins. Unlike the other modifications, SUMOylation at lysine 365 in the ligand‐binding domain of PPARγ1 (lysine 395 of PPARγ2) and phosphorylation at serine 243 (serine 273 of PPARγ2) do not appear to play a role in adipocyte development.
Figure 7. Figure 7. Covalent modifications of PPARγ1 and PPARγ2 proteins that modulate PPARγ activity and/or adipocyte development. Serine phosphorylation at residue 112 was the first covalent modification shown to regulate and inhibit PPARγ activity. Since then, several other modifications have been identified. Some of these modifications are closely spaced, such as SUMOylation and phosphorylation. The multiple inhibitory covalent modifications of PPARγ underscore the importance of regulating the activity of this highly adipogenic transcription factor.
Figure 8. Figure 8. Covalent modifications of PPARγ2 that are associated with decreased transcriptional activity and inhibition of adipogenesis. The majority of PPARγ covalent modifications are associated with decreased transcriptional activity and inhibition of adipogenesis. The proposed O‐GlcNAcylation site at threonine84 is based on studies of threonine54 in PPARγ1. All of the other sites shown in this figure have been confirmed by in vitro experiments. To date, only serine112 has been studied in a rigorous manner in vivo.
Figure 9. Figure 9. Covalent modifications of PPARγ proteins that correlate with increased transcriptional activity. Both PPARγ1 and PPARγ2 are highly labile proteins that are targeted to the UPP for degradation. Following ligand binding, there is evidence that ubiquitylation of PPARγ proteins occurs in the ligand‐binding domain when PPARγ is transcriptionally active, and inhibition of proteasome activity is accompanied by increased PPARγ ubiquitylation and sustained transcriptional activity. There is also evidence that PPARγ transcriptional activity is activated by acetylation of lysine293 of PPARγ2 (lysine263 of PPARγ1).
Figure 10. Figure 10. The role of C/EBP proteins in adipogenesis. Both C/EBPβ and C/EBPδ are induced early during adipogenesis. C/EBPβ is highly responsive to induction by MIX, a component of the hormonal induction cocktail that increases cAMP signaling. C/EBPδ is activated by DEX, a synthetic GC that promotes adipogenesis. These C/EBP proteins increase the expression of both PPARγ and C/EBPα. Both PPARγ and C/EBPα can regulate the expression of one another. In addition, C/EBPβ is responsible for Wnt/β‐catenin inhibition and regulation of MCE, a process in which growth‐arrested preadipocytes re‐enter the cell cycle before they differentiate into adipocytes.
Figure 11. Figure 11. Wnt/β‐Catenin signaling pathway and inhibition of adipocyte development. Wnt agonists such as Wnt6/10a/10b, NELL1, and Grem2 bind to Frizzled receptors and LRP coreceptors and act through the intracellular protein Dvl, blocking the activity of GSK3β (glycogen synthase kinase‐3) and promoting cytosolic accumulation of β‐catenin, which then translocates to the nucleus and binds to the promoter region of the adipogenic genes PPARγ and C/EBPα, repressing their transcription and, consequently, adipogenesis. WISP2, when secreted, can activate the canonical Wnt pathway and attenuate PPARγ activation; it can also act in the cytosol, where it interacts with ZFP423, preventing it from translocating to the nucleus and activating PPARγ expression.
Figure 12. Figure 12. Wnt/β‐Catenin signaling pathway and activation of adipocyte development. Wnt antagonists such as DKK1, sFRP1/4, XBP1, TREM2, and NRX bind to Frizzled receptors and LRP coreceptors, inactivating the cytosolic protein Dvl. GSK3β is then active and phosphorylates β‐catenin which is thereby targeted for ubiquitylation and subsequent degradation by the UPP. In addition, when BMP4 is present, ZFP423 dissociates from WISP2 and can then translocate to the nucleus and interact with the PPARγ promoter to enhance its expression and promote adipocyte differentiation.
Figure 13. Figure 13. TGF‐β and BMPs act via Smads to regulate adipogenesis. BMP2 and 4 bind to their serine/threonine kinase receptors I and recruit type II receptors, which then transphosphorylate the type I receptors. The activated heterotetrameric complexes phosphorylate R‐Smads (1/5/8), which associate with co‐Smad (Smad4). The Smad complex associates with Shn‐2, translocates to the nucleus, and binds with C/EBPα to induce PPARγ expression. Conversely, PPARγ expression can be inhibited by Tob2, which prevents the Smad complex from translocating into the nucleus and can also block C/EBPα from binding to the PPARγ promoter in the nucleus. Additionally, TGF‐β binds to its serine/threonine kinase receptors II that recruit and transphosphorylate type I receptors. Activated heterotetrameric complexes phosphorylate R‐Smads (2/3), which associate with co‐Smad (Smad4). The Smad complexes then translocate to the nucleus and inhibit PPARγ expression.
Figure 14. Figure 14. Homology of nuclear receptors that modulate adipocyte development. Steroid hormone receptors are transcription factors that bind to DNA and regulate the transcriptional activity of many genes. All of these proteins, like PPARγ, are part of the nuclear receptor superfamily and share the same domains types. The A/B domain located in the N‐terminal part of the protein possesses a ligand‐independent transactivation function (AF‐1). DNA binding occurs at the C domain, the most conserved part of steroid receptors, as well as at the D domain located immediately downstream. The E domain is where the ligand binds, and it can also contribute to receptor dimerization. Some receptors such as ER also have an F domain.
Figure 15. Figure 15. The effect of steroid hormones on adipogenesis. (A) Sex Steroids. Estrogen (E) and the primary androgen, testosterone, enter preadipocytes by diffusing through the plasma membrane. Testosterone is converted to DHT, which has a high affinity for the AR. Estrogen binds to its receptor (ER), forming a homodimer, which translocates to the nucleus and binds EREs in a number of genes. Similarly, DHT bound to AR forms a homodimer that binds AREs in a variety of genes. The majority of the evidence suggests that ER and AR inhibit adipogenesis. (B) Adrenal steroids. Cortisol, the primary GC, and aldosterone, the primary mineralocorticoid (MC), diffuse through the plasma membrane. GC/GR homodimers translocate to the nucleus where they modulate the expression of many genes that have glucocorticoid response elements (GREs). Lipin 1 and KLF15 are GC/GR target genes that are induced during adipogenesis. It is well known that both GR and mineralocorticoid receptor (MR) are expressed in preadipocytes. However, recent studies demonstrate that the levels of GR are several hundred fold higher than MR, and loss of MR does not impact adipogenesis, suggesting that actions of MC on adipogenesis are mediated by GR.
Figure 16. Figure 16. Homology of ER and ERRs. Some of the members of nuclear receptor superfamily are considered “orphans” since no ligands have been discovered. Three of these orphan receptors are named ERRs because they have 68% homology with ER in the DBD (domain C). Since these receptors have only 36% homology in the ligand‐binding domain (domain E), they cannot bind estrogen, but they can bind to the same DNA response elements as estrogen receptors. Notably, the majority of studies demonstrate that ER and ERR have opposite effects on adipogenesis.
Figure 17. Figure 17. The activation of TRs promotes adipogenesis. Although TRs have similarities to steroid hormones, there are a couple of key differences in the pathway. First, thyroid hormone does not diffuse through the plasma membrane, but requires a transport protein such as monocarboxylate transporter 8 (MCT8). Another difference is that un‐liganded TRs bind to DNA at thyroid response elements (TRE) and repress transcription. When thyroid hormone, T3, is present, it is transported through the membrane, travels through the cytosol to the nucleus where it binds its receptor (TR) and activates gene expression. Like PPARγ, TRs dimerize with RXRα and its associated ligand, retinoic acid (RA). In preadipocytes, TRs promote differentiation, particularly to beige and brown adipocytes.


Figure 1. Different shades of adipocytes: white, brown, and beige. White adipocytes comprise the majority of fat cells in mice and men. The primary function of white adipocytes is lipid storage. Brown adipocytes largely function to produce heat. Beige adipocytes have properties similar to both brown and white adipocytes. There is evidence that each type of fat cell comes from a different type of preadipocyte. However, there is also evidence that beige adipocytes result from the transdifferentiation of white adipocytes. Although the characterization of each cell type is well understood, the developmental origins of these different types of cells from preadipocytes and their adipocyte progenitor cells is an emerging area of research.


Figure 2. In vitro studies of adipocyte development. Preadipocytes are cells capable of differentiating into adipocytes with the appropriate hormonal cocktail, which varies for adipogenesis of brown, white, or beige preadipocytes. Examples of preadipocytes include 3T3‐L1 and 3T3‐F442A cells. Nonprecursor cells, fibroblasts and other cell types, do not undergo adipogenesis in the presence of the appropriate hormonal cocktail. Examples of nonprecursor cells include NIH 3T3, Swiss 3T3, and Balb/c fibroblasts. Nonprecursor cells can undergo adipogenesis with ectopic expression of PPARγ or other transcription factors.


Figure 3. Structural motifs of DBD s in transcription factors that regulate adipocyte development. Transcription factors have at least one DBD that mediates their capacity to bind to DNA and regulate transcription. Leucine zipper is a dimerization domain of the bZIP class that contains periodic repetition of leucine residues, which coordinates its ability to bind to DNA; C/EBPs and AP‐1 proteins are examples of leucine zipper proteins. In the zinc‐finger structure, a zinc ion is coordinated by a combination of cysteine and histidine residues. Zinc fingers arise from multiple different folding arrangements (“fold groups”). The classic Cys2His2 zinc finger motif is shown. KLFs, GATAs, and Zfps, as well as all of the nuclear receptors are examples of zinc‐finger proteins. Helix‐loop‐helix is characterized by two α‐helices connected by a loop. SREBP and EBFs are helix‐loop‐helix transcription factors. Helix‐turn‐helix is characterized by two α‐helices joined by a short strand of amino acids and is found in IRFs that regulate adipogenesis. Some adipocyte transcription factors such as KLFs and SREBPs contain more than one structural motif to facilitate DNA binding.


Figure 4. Transcription factors that promote adipogenesis. Many transcription factors are induced during adipocyte differentiation. Some of these, like members of the AP‐1 family, are induced during clonal expansion. Others, like PPARγ, have been shown to promote adipocyte differentiation in vitro and in vivo. The relative timing of the induction of each transcription factor is indicated.


Figure 5. Transcription factors that inhibit adipogenesis. Many specific transcription factors have been shown to inhibit adipocyte development. The expression of most of these transcription factors decreases with adipocyte development. Ectopic expression and knockdown approaches have been used to demonstrate the inhibitory actions of these transcription factors. The relative timing of the action of each transcription factor is indicated.


Figure 6. PPARγ exists in two isoforms, γ1 and γ2. PPARγ proteins are members of the large nuclear hormone receptor superfamily of transcription factors that also includes steroid receptors and TRs. PPARγ1 has 30 fewer amino acids in the N‐terminal region than PPARγ2. The covalent modifications are indicated for both PPARγ proteins. Unlike the other modifications, SUMOylation at lysine 365 in the ligand‐binding domain of PPARγ1 (lysine 395 of PPARγ2) and phosphorylation at serine 243 (serine 273 of PPARγ2) do not appear to play a role in adipocyte development.


Figure 7. Covalent modifications of PPARγ1 and PPARγ2 proteins that modulate PPARγ activity and/or adipocyte development. Serine phosphorylation at residue 112 was the first covalent modification shown to regulate and inhibit PPARγ activity. Since then, several other modifications have been identified. Some of these modifications are closely spaced, such as SUMOylation and phosphorylation. The multiple inhibitory covalent modifications of PPARγ underscore the importance of regulating the activity of this highly adipogenic transcription factor.


Figure 8. Covalent modifications of PPARγ2 that are associated with decreased transcriptional activity and inhibition of adipogenesis. The majority of PPARγ covalent modifications are associated with decreased transcriptional activity and inhibition of adipogenesis. The proposed O‐GlcNAcylation site at threonine84 is based on studies of threonine54 in PPARγ1. All of the other sites shown in this figure have been confirmed by in vitro experiments. To date, only serine112 has been studied in a rigorous manner in vivo.


Figure 9. Covalent modifications of PPARγ proteins that correlate with increased transcriptional activity. Both PPARγ1 and PPARγ2 are highly labile proteins that are targeted to the UPP for degradation. Following ligand binding, there is evidence that ubiquitylation of PPARγ proteins occurs in the ligand‐binding domain when PPARγ is transcriptionally active, and inhibition of proteasome activity is accompanied by increased PPARγ ubiquitylation and sustained transcriptional activity. There is also evidence that PPARγ transcriptional activity is activated by acetylation of lysine293 of PPARγ2 (lysine263 of PPARγ1).


Figure 10. The role of C/EBP proteins in adipogenesis. Both C/EBPβ and C/EBPδ are induced early during adipogenesis. C/EBPβ is highly responsive to induction by MIX, a component of the hormonal induction cocktail that increases cAMP signaling. C/EBPδ is activated by DEX, a synthetic GC that promotes adipogenesis. These C/EBP proteins increase the expression of both PPARγ and C/EBPα. Both PPARγ and C/EBPα can regulate the expression of one another. In addition, C/EBPβ is responsible for Wnt/β‐catenin inhibition and regulation of MCE, a process in which growth‐arrested preadipocytes re‐enter the cell cycle before they differentiate into adipocytes.


Figure 11. Wnt/β‐Catenin signaling pathway and inhibition of adipocyte development. Wnt agonists such as Wnt6/10a/10b, NELL1, and Grem2 bind to Frizzled receptors and LRP coreceptors and act through the intracellular protein Dvl, blocking the activity of GSK3β (glycogen synthase kinase‐3) and promoting cytosolic accumulation of β‐catenin, which then translocates to the nucleus and binds to the promoter region of the adipogenic genes PPARγ and C/EBPα, repressing their transcription and, consequently, adipogenesis. WISP2, when secreted, can activate the canonical Wnt pathway and attenuate PPARγ activation; it can also act in the cytosol, where it interacts with ZFP423, preventing it from translocating to the nucleus and activating PPARγ expression.


Figure 12. Wnt/β‐Catenin signaling pathway and activation of adipocyte development. Wnt antagonists such as DKK1, sFRP1/4, XBP1, TREM2, and NRX bind to Frizzled receptors and LRP coreceptors, inactivating the cytosolic protein Dvl. GSK3β is then active and phosphorylates β‐catenin which is thereby targeted for ubiquitylation and subsequent degradation by the UPP. In addition, when BMP4 is present, ZFP423 dissociates from WISP2 and can then translocate to the nucleus and interact with the PPARγ promoter to enhance its expression and promote adipocyte differentiation.


Figure 13. TGF‐β and BMPs act via Smads to regulate adipogenesis. BMP2 and 4 bind to their serine/threonine kinase receptors I and recruit type II receptors, which then transphosphorylate the type I receptors. The activated heterotetrameric complexes phosphorylate R‐Smads (1/5/8), which associate with co‐Smad (Smad4). The Smad complex associates with Shn‐2, translocates to the nucleus, and binds with C/EBPα to induce PPARγ expression. Conversely, PPARγ expression can be inhibited by Tob2, which prevents the Smad complex from translocating into the nucleus and can also block C/EBPα from binding to the PPARγ promoter in the nucleus. Additionally, TGF‐β binds to its serine/threonine kinase receptors II that recruit and transphosphorylate type I receptors. Activated heterotetrameric complexes phosphorylate R‐Smads (2/3), which associate with co‐Smad (Smad4). The Smad complexes then translocate to the nucleus and inhibit PPARγ expression.


Figure 14. Homology of nuclear receptors that modulate adipocyte development. Steroid hormone receptors are transcription factors that bind to DNA and regulate the transcriptional activity of many genes. All of these proteins, like PPARγ, are part of the nuclear receptor superfamily and share the same domains types. The A/B domain located in the N‐terminal part of the protein possesses a ligand‐independent transactivation function (AF‐1). DNA binding occurs at the C domain, the most conserved part of steroid receptors, as well as at the D domain located immediately downstream. The E domain is where the ligand binds, and it can also contribute to receptor dimerization. Some receptors such as ER also have an F domain.


Figure 15. The effect of steroid hormones on adipogenesis. (A) Sex Steroids. Estrogen (E) and the primary androgen, testosterone, enter preadipocytes by diffusing through the plasma membrane. Testosterone is converted to DHT, which has a high affinity for the AR. Estrogen binds to its receptor (ER), forming a homodimer, which translocates to the nucleus and binds EREs in a number of genes. Similarly, DHT bound to AR forms a homodimer that binds AREs in a variety of genes. The majority of the evidence suggests that ER and AR inhibit adipogenesis. (B) Adrenal steroids. Cortisol, the primary GC, and aldosterone, the primary mineralocorticoid (MC), diffuse through the plasma membrane. GC/GR homodimers translocate to the nucleus where they modulate the expression of many genes that have glucocorticoid response elements (GREs). Lipin 1 and KLF15 are GC/GR target genes that are induced during adipogenesis. It is well known that both GR and mineralocorticoid receptor (MR) are expressed in preadipocytes. However, recent studies demonstrate that the levels of GR are several hundred fold higher than MR, and loss of MR does not impact adipogenesis, suggesting that actions of MC on adipogenesis are mediated by GR.


Figure 16. Homology of ER and ERRs. Some of the members of nuclear receptor superfamily are considered “orphans” since no ligands have been discovered. Three of these orphan receptors are named ERRs because they have 68% homology with ER in the DBD (domain C). Since these receptors have only 36% homology in the ligand‐binding domain (domain E), they cannot bind estrogen, but they can bind to the same DNA response elements as estrogen receptors. Notably, the majority of studies demonstrate that ER and ERR have opposite effects on adipogenesis.


Figure 17. The activation of TRs promotes adipogenesis. Although TRs have similarities to steroid hormones, there are a couple of key differences in the pathway. First, thyroid hormone does not diffuse through the plasma membrane, but requires a transport protein such as monocarboxylate transporter 8 (MCT8). Another difference is that un‐liganded TRs bind to DNA at thyroid response elements (TRE) and repress transcription. When thyroid hormone, T3, is present, it is transported through the membrane, travels through the cytosol to the nucleus where it binds its receptor (TR) and activates gene expression. Like PPARγ, TRs dimerize with RXRα and its associated ligand, retinoic acid (RA). In preadipocytes, TRs promote differentiation, particularly to beige and brown adipocytes.
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Paula Mota de Sá, Allison J. Richard, Hardy Hang, Jacqueline M. Stephens. Transcriptional Regulation of Adipogenesis. Compr Physiol 2017, 7: 635-674. doi: 10.1002/cphy.c160022