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Tuesday, 21 January 2020

Adipogenesis – the making of fat

How Are Fat Cells Formed?


Our entire bodies originate from a single cell. Once it starts dividing, it kick-starts a multiplication process that lasts our whole lives. This ‘starter’ cell is a stem cell; a biologically programmable template for any other cell. They are responsible for everything, including our hearts, minds and waistlines.

Wait, waistlines?

Yes, this is determined by adipocytes, or white fat cells, in a process known as adipogenesis. There are six roughly defined phases of adipogenesis, but within them are a multitude of molecular processes, and explaining how they work poses a considerable challenge to scientists.

Fat, by Bigplankton via Wikipedia Commons.

Adipocytes and Adipose Tissue


Let’s start off with the adipocytes themselves. Together, these white fat cells form a tissue: the fat store of energy for our bodies. For a long time, it was thought we only had two types of fat cell and so tissue: brown and white. Our brown fat cells are a natural defence against the cold, and burn energy to produce heat, especially when we’re babies. Adipocytes found in white fat tissues, on the other hand, are for storing energy and are considered the less healthy of the two; high levels have been associated with diabetes and obesity[1]. Then, in 2009, a third type of fat was discovered: beige[2]. This was originally described as a type of brown fat, but its purpose was not to convert energy to heat; instead, it converted white fat to brown. It has taken six years for researchers to establish that this beige fat is genetically unique[3], and there are still questions about the formation and function of all three tissues. In particular, researchers are keen to work out how beige fat processes white to brown: this could be used to treat obesity. It wuld also help to find out how and where adipocytes and white fat tissues are made, which is where the study of adipogenesis comes in.

Adipogenesis


During fat cell formation, a stem cell turns into an immature preadipocyte, before that matures to a differentiated adipocytes with a specialised function like energy storage. These two steps have been described as adipocyte determination and differentiation[4]. However, the two titles are a generalisation of at least six important steps.The first stage involves ‘mesenchymal precursors’; these are the stem cells. Once they are preadipocytes, there are several stages of growth and multiplication before terminal differentiation into mature adipocytes. Scientists studying this production process consider each step as an equally valuable research focus, though some believe the commitment of preadipocytes to their mature state is key, especially if an obesity therapy were to be developed.

Transcriptional Cascades


For a stem cell to decide to become an adipocyte, it needs some encouragement. There is an overwhelming number of potential factors that may have an influence on adipogenesis, but a few have drawn our attention recently as new information emerges[5]. A little encouragement prompts a transcriptional cascade, where the activation of some genes leads to the expression of others. In a relationship akin to the chicken and egg, gene expression is regulated by transcription factors, but transcription factors are encoded by genes. So once a primary transcription factors is expressed from a gene, that activates the expression of a second, which regulates and activates the expression of another gene for a tertiary factor... and so on and so forth. Imagine the transcription factors are dominoes in a line; when the last one falls, a protein is made, but many other dominoes need to fall in the correct order to knock down the last one. This is how the body regulates which proteins are produced and when.

The Protein Families


DNA, © ynse (CC BY-SA 2.0).

Proteins come in families, and the combination of two of these is generally regarded as one of the most important interactions in adipogenesis. Two protein families are considered to be the "driving forces" behind adipogenesis: C/EBPs and PPAR[4]. Several C/EBPs activate a PPAR as part of a transcriptional cascade, and this combination promotes the maturation of adipocytes.

Going back to the dominoes, for adipogenesis to be activated and then remain in that state, they collapse in a slightly different way. The final dominoes still fall, the C/EBPs and PPAR proteins are made, but they collapse in a circle, making a loop. This is not a perfect analogy, because adipogenesis goes on and on – and we can’t build an infinite domino circle.

In mouse models, inhibiting either of these two protein families stopped white fat tissue being formed. That being said, it has been shown that if a cell lacks C/EBPs, more PPARs can be expressed to compensate, and differentiation still takes place, but without PPARs, no fat cells are detected at all, regardless of C/EBPs overexpression[4][6]. Consequently, we don’t know exactly if or how both families play an equal role.

The FTO Region


A new mechanism has been uncovered that gives new weight to an entirely different part of the genome, called the FTO region[5]. This area has been studied intensely in an attempt to link it to fat cell production and obesity.

Previously, research focussed on connecting FTO genes to the brain, implying it was influenced by “circuits that control appetite or propensity to exercise”, but concluded the FTO has nothing to do with the brain. Instead, genetic differences in the area may be responsible for variations in fat stores; for example, one cellular pathway specifically decides whether a cell will burn fat or store it. The study discovered that with just one nucleotide mutation (we have over six billion nucleotides in total) in the FTO region, heat production could be ‘switched off’ and the cells would store fat instead of burning it. This change activated two regulator genes. Once switched on and the fat burning switched off, fats quickly accumulate and could lead to the onset of obesity. As a result, the researchers classified two types of FTO regions as risk or non-risk, where the risk type contained the mutated nucleotide.

Amazingly, researchers already have the technology to reverse or induce the nucleotide mutations in cells, offering major potential for a therapeutic treatment for obesity. However, whether this is the only regulation mechanism for heat production isn’t clear. Additionally, though there has been success in mice and isolated human cells, whether a treatment could be developed that works naturally in the human body remains to be seen.


This article was written by Joshua Fleming, a biological sciences student from the University of Leicester conducting a summer internship as a science writer at TWDK.

Josh and the TWDK team would like to thank Michael Pepper, Director of the Institute for Cellular and Molecular Medicine and a professor in the Department of Immunology in the Faculty of Health Sciences at the University of Pretoria, whose help was invaluable. Professor Pepper is currently working on single adipocyte cells whilst also contributing to The Conversation on stem cells.



References
why don't all references have links?

[1] Jeffery, Elise, et al. Rapid depot-specific activation of adipocyte precursor cells at the onset of obesity. Nature cell biology 17.4 (2015): 376.
[2] Cypess, Aaron M., et al. Identification and importance of brown adipose tissue in adult humans. New England Journal of Medicine 360.15 (2009): 1509-1517.
[3] Shinoda, Kosaku, et al. Genetic and functional characterization of clonally derived adult human brown adipocytes. Nature medicine 21.4 (2015): 389.
[4] Ali, Aus Tariq, et al. Adipocyte and adipogenesis. European journal of cell biology 92.6-7 (2013): 229-236.
[5] Claussnitzer, Melina, et al. FTO obesity variant circuitry and adipocyte browning in humans. New England Journal of Medicine 373.10 (2015): 895-907.
[6] Farmer, Stephen R. Transcriptional control of adipocyte formation. Cell metabolism 4.4 (2006): 263-273.

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