Adipocyte Proliferation
Introduction
With the epidemic of obesity on the rise, understanding the proliferation mechanism of adipocytes is extremely important. It is of no surprise in light of metabolic disorders, diabetes and new insights into insulin resistance and cell signaling pathways that there has been a rapid increase in research into the role of adipocytes in the body. The increase in the number of papers published on Pubmed alone shows a large increase in investigation into topics related to adipose cells. With the rapid increase in research, the knowledge of the role and proliforatory mechanism of adipocytes has grown as well but there is still much that remains unknown.
 |
| From- What We Talk About When We Talk About Fat |
Knowledge has improved significantly since the discovery stimulated fat mobilization in the early 1900s, lipogenesis, and the discovery of important genes and such as PPAR (Rosen and Spiegelman 2014). Important signaling molecules involved in fat proliferation like leptin and adiponectin have also been fairly well studied.
Fat Cell Types
Adipocytes have a variety of extracellular markers, and contain characteristic organelles such as a lipid globule and varying amounts of mitochondria, which has much to do with the physical appearance and respective names. The three main classifications of fat cells are brown, beige and white.
White fat is commonly what we think of when fat comes to mind and rightly should, as white fat comprises the vast majority of fat in human adults and most animals. Its primary role seems to be storage and proliferative signaling.
 |
| From- Revisiting the Adipocyte |
White fat is commonly what we think of when fat comes to mind and rightly should, as white fat comprises the vast majority of fat in human adults and most animals. Its primary role seems to be storage and proliferative signaling.
Brown fat is largely present in infants and its primary role seems to be in thermogenesis and heat regulation. The thermo genic ability is primarily due to higher expression levels of uncoupling protein 1 (UCP1), which acts to uncouple respiration to dissipate stored chemical energy in the form of heat (Rosen and Spiegelman 2014). Hydrogen ions are allowed to flow back across the mitochondrial membrane to allow oxidation without ATP synthesis.
Beige fat is generally thought of as bi-functional. They have lower basal levels of UCP1 than brown fat, so in the absence of thermo genic signaling, they are suited for energy storage. Both brown and beige adipocytes are present in much smaller amounts in adults with brown fat basically nonexistent. However, both of these cell types have found to be present to a larger extent in individuals with regular exposure to cold environments (Rosen and Spiegelman 2014).
Where does fat come from?
Fat mass can be attributed, not only to fat cell hypertrophy, but also due to cell proliferation. The development and proliferation of these cells has also been explored fairly indepth. However the proliferation of adipose stem cells that then differentiate into mature adipocytes seems to be the correct mechanism. In other words, future fat cells do not come from mitosis of mature fat cells. In fact, human adipocytes have a turnover of about 8% a year as new cells arise from a progenitor pool (Rigamonti et al. 2011). The 8% obviously applies to a "normal" or non obese individual. Prolonged high fat diet and hormonal signaling can lead to lower overall turnover rate as proliferation increases far beyond the rate of cell death.
An interesting differentiation that is still being explored, is in the transition between white, beige and brown fat. While the functional transition from white to beige fat has been observed upon frequent exposure to cold temperatures, the possible transition from beige to brown has yet to be well documented. However the transition is understandably a focus as a possible therapeutic target for the purpose of up regulating metabolism, proliferation and weight loss.
In general BMP, STAT, and EBP signaling plays a stimulating role in adipocyte progenitor proliferation while WNT signaling has a negative impact. Note that PPARγ, later discussed, plays a role in stimulating differentiation of all types of adipocytes. Since PPARγ is released by growing adipocytes, and also signals cell growth, PPARγ is found to play an increasingly interesting and important role in fat metabolism.
An interesting differentiation that is still being explored, is in the transition between white, beige and brown fat. While the functional transition from white to beige fat has been observed upon frequent exposure to cold temperatures, the possible transition from beige to brown has yet to be well documented. However the transition is understandably a focus as a possible therapeutic target for the purpose of up regulating metabolism, proliferation and weight loss.
In general BMP, STAT, and EBP signaling plays a stimulating role in adipocyte progenitor proliferation while WNT signaling has a negative impact. Note that PPARγ, later discussed, plays a role in stimulating differentiation of all types of adipocytes. Since PPARγ is released by growing adipocytes, and also signals cell growth, PPARγ is found to play an increasingly interesting and important role in fat metabolism.
Understanding adipocyte development provides key insights into proliferative mechanisms. All fat cells originally arise from mesenchymal stem cells during development. However the extent that fat cells continue to arise from mesenchymal cells in the bone before migrating to tissues during early stages of differentiation is unclear, however, preadipocytes or adipose stem cells are found perivascularly in adulthood . White and beige adipocytes are both generated from adipoblasts, and preadipocytes prior to differentiating into white adipocytes (Jiang Y. et al. 2012). The process involving the conversion of white to beige fat cells is not explicitly known but seems to be determined largely by environmental factors.
Brown adipocytes have a distinct lineage, arising instead from myogenic stem cells. These cells also give rise to skeletal muscle with remarkably different properties. However, the lineage of brown fat may have something to do with the increased mitochondrial content, like that of muscle, needed for thermogenesis.
Traditionaly, activation of the canonical Wnt and hedgehog pathways are thought to discourage adipogenesis while encouraging osteogenesis but the pathway is still somewhat disputed, likely due to the extent of crosstalk. IGF and Insulin are known to be major promoters of adipogenesis (Rosen and Spiegelman 2014). While the majority of growth factors influencing differentiation are common following nutritional surplus, the nuclear receptor proliferator-activated receptor-γ (PPARγ) serves as a master regulator and is both required and sufficient for adipocyte proliferation and differentiation. (Jiang Y. et al. 2012).
 |
| From- Snapshot: Adipocyte Life Cycle |
In Living Organisms
Adipocyte proliferation begins with adipose stem cells. Adipose stem cells located perivascularly and must replicate often to keep up with the maturation and turnover rate of adipocytes. In the body, positive and negative regulation of, adipocyte stem cells is regulated by a large number of signaling molecules as previously discussed. Those of which involved in the stem cell progression through the cell cycle include cyclin D1, Rb, p21 and others (Jiang Y. et al. 2012). Various circulating hormonal signals such as growth and thyroid hormone also understandably play a global role in regulation. Angiogenic factors such as vascular endothelial growth factor (VEGF) as well as hepatocyte growth factor (HGF) also play a role in promoting stem cell proliferation (Jiang Y. et al. 2012). While the stem cells multiply near blood vessels, mural cells migrate into tissue where they further mature and are filled with lipid droplets that include those taken from dead fat cells. Macrophages are thought to play an important role in adipocyte recycling and turnover related to replacement of older fat cells. After reaching maturity, adipocytes undergo hypertrophy in response to nutrient excess (Jiang et al. 2012). Again, the master regulator of both proliferation and differentiation in the case of adipocytes is thought to be PPARγ.
Role of PPARγ in Proliferation
PPARs are a family of genes that control expression of gene networks involved in lipid metabolism, adipogenesis and inflammation. They function by binding with a ligand or other regulatory element as a heterodimer with retinoid X receptor (RXR) and altering transcription through a change in conformation(Ahmadian et al. 2013).
There are three known PPARs that arise from alternative splicing. PPARα is an activator of fatty acid oxidation and is expressed in brown fat, the heart and liver (Ahmadian et al. 2013).. PPARδ/β is actualy ubiquitously expressed and acts to promote fatty acid metabolism in skeletal muscle, heart and liver (Ahmadian et al. 2013). PPARγ1 is expressed in a variety of tissues while PPARγ2 is primarily in adipose tissue, to the greatest extent in white fat, but has also been found to be present in other tissues after prolonged high fat diet. PPARγ is also present in monocytes and macrophages. All members of the PPAR family have a conserved DNA binding domain, but differ in lipid binding domains and activation domains (Ahmadian et al. 2013).
While the activated PPARγ functions as a promoter of adipocyte proliferation, it is also important to note PPARγ's vital importance as an inhibitor of gene expression unless activated. Unactivated, or in certain modified isoforms, the hormone receptor can play an anti-mitotic role within the cell.
Post Transcriptional Modification of the Master Regulator
As the global effects of PPARγ are discussed more in depth in the next section, it is important to realize that simply activating or inhibiting PPARγ for therapeutic purposes to reduce adipocyte proliferation is generally not an option. More research is needed into the mechanisms and possible partial inhibition or modulation as a treatment for metabolic disease.
Cellular Effects Resulting in Proliferative Signaling
PPARγ has been shown to activate gene expression following exposure to various fatty acids, very few specific endogenous ligands have been identified. However after activation following the initial introduction of a high fat diet, thiazolidinediones (TZDs), or other endogenous ligands, genes are expressed that result in increased glucose utilization, via increased Glut4, CAP and IRS in addition to increased fatty acid metabolism marked by an increase in LPL ACS, and PEPCK (Ahmadian et al. 2013). TZD's or high fat diet also stimulates maturation in preadipocytes by via STAT's and EBP discussed previously.
Activation of PPARγ also triggers the up regulation of the secreated signaling molecules adiponectin and resisting among others. In general adiponectin seemingly acts throughout the body to increase insulin sensitivity, while resistin is thought to do the opposite (Ahmadian et al. 2013). In the case of metabolic disorders resulting from obesity, the increased number of adipocytes are able to secrete a larger volume of signaling molecules that can result in more adipocyte proliferation when received by stem cells, as well as problems with glucose uptake into cells.
Activation of PPARγ also triggers the up regulation of the secreated signaling molecules adiponectin and resisting among others. In general adiponectin seemingly acts throughout the body to increase insulin sensitivity, while resistin is thought to do the opposite (Ahmadian et al. 2013). In the case of metabolic disorders resulting from obesity, the increased number of adipocytes are able to secrete a larger volume of signaling molecules that can result in more adipocyte proliferation when received by stem cells, as well as problems with glucose uptake into cells.
 |
| From- PPARγ Signaling and Metabolism |
Systemic Effects
The effects of PPARγ activation has a large impact throughout the body as a result of signaling by fat cells. An increase in adiponectin is thought to increase adipocyte proliferation, glucose uptake by cells, decrease glucogenesis in the liver while increasing expression activity of PPARγ (Rosen and Spiegelmen 2014).
While TZD's previously mentioned are considered as a treatment for diabetes, as downstream affects of PPARγ increase insultin sensitivity and glucose uptake in tissues, the activation of such a large regulator as PPARγ has much greater global effects throughout the body that must be considered. The resulting up regulation of TNF-α has stimulating effects on phagocytic cells that can either aid immunity or result in inflammation (Ahmadian et al. 2013). Up regulation of FGF's have also been shown to increase osteoclastogenesis, possibly leading to decreased bone density over time (Ahmadian et al. 2013). Sensitization to glucose also results in lipid storage in a variety of tissues including the liver and heart which can cause problems over time.
While TZD's previously mentioned are considered as a treatment for diabetes, as downstream affects of PPARγ increase insultin sensitivity and glucose uptake in tissues, the activation of such a large regulator as PPARγ has much greater global effects throughout the body that must be considered. The resulting up regulation of TNF-α has stimulating effects on phagocytic cells that can either aid immunity or result in inflammation (Ahmadian et al. 2013). Up regulation of FGF's have also been shown to increase osteoclastogenesis, possibly leading to decreased bone density over time (Ahmadian et al. 2013). Sensitization to glucose also results in lipid storage in a variety of tissues including the liver and heart which can cause problems over time.
 |
| From- PPARγ Signaling and Metabolism |
Taking a global approach with regards to PPARγ as a therapeutic target for decreasing fat proliferation rates and metabolic disorders is extremely important, and simple inhibition or activation is clearly impossible without the possibility of a wide range of symptoms. While simple inhibition is no good, PPARγ is still a vital regulatory protein that has modular therapeutic potential. However, many of the signaling cascades previously discussed, both in adipocyte proliferation influenced by PPARγ and resulting recreation of signaling molecules, are clearly unbalanced in many cases of obesity. Prolonged activation of PPARγ by high fat diet or ligand signaling can have an almost cascading effect in which more proliferating adipocytes can result in greater activation signaling. Increased activation and subsequent signaling is likely the cause of detrimental global effects that are seen above (Ahmadian et al. 2013). Many tissues understandably become less responsive to insulin signaling when there is increased glucose in the bloodstream as well as increased insulin secreted by the pancreas. There is still much to be learned about the role of PPARγ in regards to its modification and modulated action as a result of largely unknown signaling ligands.
What Are We Learning?
Epigenetics
Schmidt et al. in 2012 looked at data related to the relative binding location of PPARγ in relation to nearby histone tags in mice as well as humans. They found that in both mice and humans, PPARγ binds 85-95% of the time to regions containing one or more of a handful of histone modificaitons associated with open chromatin. Not only that but that the level of acetylation associated with binding sites changed in relation to the state of the cell. Preadipocytes had higher levels of acetylation during adipogenesis.
Shi et al. in 2014 looked at the effect of a specific pork miRNA, as they are not only similar biologicly, but a major source of food. Certain miRNA have been shown to be present in the bloodstream after ingestion.
Transfected miRNA-199a-5p agomir, a mimicking synthetic oligonucleotide, found in subcutaneous pork fat was found to decrease levels of cav-1 mRNA , a gene involved fat filling during adipogenesis. Transfection was also remarkably shown to decrease levels of PPARγ and other regulators of adipogenesis. Interestingly, the same miRNA overexpressed in human mesenchymal cells led to an aproximatley 70% decrease in P2, a fatty acid binding protein considered to be a cell marker of adipogenic cells. There are also several other miRNA that have being found to play important roles in adipogenesis. The combination of miRNA from foods may play an important role in metabolism.
Transfected miRNA-199a-5p agomir, a mimicking synthetic oligonucleotide, found in subcutaneous pork fat was found to decrease levels of cav-1 mRNA , a gene involved fat filling during adipogenesis. Transfection was also remarkably shown to decrease levels of PPARγ and other regulators of adipogenesis. Interestingly, the same miRNA overexpressed in human mesenchymal cells led to an aproximatley 70% decrease in P2, a fatty acid binding protein considered to be a cell marker of adipogenic cells. There are also several other miRNA that have being found to play important roles in adipogenesis. The combination of miRNA from foods may play an important role in metabolism.
Immunity
Poloni et al. in 2015 exposed t-lymphocytes to cultures of mature human adipocytes to study possible proliforatory effects.
Upon incubation for 4 days of cultures containing just lymphocytes, lymphocytes with phytohemagglutnin (PHA)- a T-cell stimulator, and lymphocytes with mature adipocytes, there was a significant increase in lymphocyte proliferation of all types measured when incubated with adipocytes. The media in which the mature adipocytes were grown was also analyzed to reveal higher amounts of proinflamatory cytokines compared to anti-inflammatory ones detected. They also found that when distributed throughout a culture containing adipocytes., after only a few hours all of the lymphocytes were arranged close to mature adipocytes rather than evenly distributed throughout the media suggesting that adipocytes also secrete chemo-attractant factors. Potential impact of adipocytes on immunity and even autoimmune disorders is brought to light, as well as the inflammatory potential associated with obesity.
Upon incubation for 4 days of cultures containing just lymphocytes, lymphocytes with phytohemagglutnin (PHA)- a T-cell stimulator, and lymphocytes with mature adipocytes, there was a significant increase in lymphocyte proliferation of all types measured when incubated with adipocytes. The media in which the mature adipocytes were grown was also analyzed to reveal higher amounts of proinflamatory cytokines compared to anti-inflammatory ones detected. They also found that when distributed throughout a culture containing adipocytes., after only a few hours all of the lymphocytes were arranged close to mature adipocytes rather than evenly distributed throughout the media suggesting that adipocytes also secrete chemo-attractant factors. Potential impact of adipocytes on immunity and even autoimmune disorders is brought to light, as well as the inflammatory potential associated with obesity.
-Blake Eledge
Works Cited
Jiang Y, Jo AY, Graff JM. SnapShot: adipocyte life cycle. Cell. 2012;150:234–234. e232.
Poloni A, Maurizi G, Leoni P, et al. Interaction between human mature adipocytes and lymphocytes induces T-cell proliferation. Cytotherapy (Elsevier Inc.) [serial online]. September 2015;17(9):1292-1301.
Rigamonti A, Brennand K, Lau F, Cowan CA (2011) Rapid Cellular Turnover in Adipose Tissue. PLoS ONE 6(3): e17637. doi:10.1371/journal.pone.0017637
Rosen ED, Spiegelman BM. What We Talk About When We Talk About Fat. Cell. 2014;156(0):20-44. doi:10.1016/j.cell.2013.12.012.
Schmidt SF, Jørgensen M, Sandelin A, Mandrup S. Cross-species ChIP-seq studies provide insights into regulatory strategies of PPARγ in adipocytes. Transcription. 2012;3(1):19-24. doi:10.4161/trns.3.1.19302.
Shi, Xin-E et al. MicroRNA-199a-5p Affects Porcine Preadipocyte Proliferation and Differentiation. Int. J. Mol. Sci. 2014: 15(5): 8526-8538. doi:10.3390/ijms15058526
No comments:
Post a Comment