By Amelia Crowley
A critical analysis piece based on a seminar given by Dr Dyan Sellayah.
Historically, obesity was once a sign of wealth that could only be afforded by the likes of iconic characters such as Henry VIII and Queen Victoria (Sugunendran 2012), whilst the rest of the population suffered from malnutrition (Eknoyan, 2006). However, obesity has taken a counter intuitive evolutionary path, which has led to its current worldwide epidemic. This is continuing to worsen; approximately two billion people worldwide are classified as overweight, and one third of this group are considered obese (Seidell and Halberstadt, 2015). This population, who experience poor diet related pathologies, cost the National Health Service (NHS) £5.8 billion a year in the UK alone, meaning obesity has undeniable detrimental impact on the economy (Scarborough et al., 2011).
Obesity occurs when individuals consume nutriment in excess of requirement, which results in increased adipogenesis, and subsequent weight gain. Adipogenesis results in the formation of white adipose tissue (WAT) and brown adipose tissue (BAT), which function in energy storage and wastage respectively. Adipogenesis can be divided into two categories: Developmental adipogenesis which occurs during early life and adult obesogenic adipogenesis, which occurs in adulthood in response to a high fat diet (HFD). The process begins with a precursor cell that originates from the embryonic reticulo-endothelial primitive organ for the formation of both WAT and BAT (Hausman, Campion and Martin, 1980). In developmental adipogenesis, the adipocyte progenitors form mature adipocytes by organogenesis resulting in most gonadal WAT (gWAT) being formed in early postnatal life. Following this, there is no role for developmental organogenesis in adulthood. Weight gain in adulthood is therefore exclusively mediated by obesogenic adipogenesis, where gWAT expands via hypertrophy. The hypertrophic period is short lived, subsides, and is replaced by adipogenesis (Gregoire, Smas and Sul, 1998).
Despite an early obvious link between a HFD and obesity, scientists began to speculate a potential link between genetics and weight gain. This was investigated and supported by various studies, including work done on twins in as early as 1990. This particular study analysed pairs of identical twins that were subjected to a consistent HFD and exercise plan. Weight fluctuation was then observed and the study concluded that there was at least three times more ‘intertwin’ variation when compared with ‘intratwin’ variation, indicating that genetic factors play a role in energy storage (Bouchard et al., 1990).
Based on such initial evidence for the role for genes in predisposing adipogenic potential, scientists began using animal models in order to locate the gene(s) responsible for this effect. Many studies were conducted that identified a specific gene, known as the fat mass and obesity associated (FTO) gene, which has been linked to obesity. A summary of these previous studies and their respective results can be seen in Table 1.
|Title of paper||Author(s) and Year of publication||Results from the study|
|A common variant in the FTO gene is associated with the body mass index and predisposes to childhood and adult obesity.||(Frayling et al., 2007)||Identification of the FTO gene as a type 2 diabetes susceptibility gene. Predisposes diabetes by increasing body mass index (BMI). Therefore provides initial evidence for the relationship between FTO and weight gain.|
|Variation in FTO contributes to childhood obesity and severe adult obesity.||(Dina et al., 2007)||Concluded that a mutation in the first intron of the FTO gene that enhanced its activity, resulted in early onset and higher incidence of obesity in both children and adults.|
|Genome-Wide Association Scan Shows Genetic Variants in the FTO Gene Are Associated with Obesity-Related Traits.||(Scuteri et al., 2007)||Various different single nucleotide polymorphisms (SNP) in the FTO gene resulted in increased BMI and weight.|
|Inactivation of the FTO gene protects from obesity.||(Fischer et al., 2009)||Demonstrates that knocking out the FTO gene results in growth retardation, a reduction in adipose tissue and a particularly lean body mass.|
|Overexpression of FTO leads to increased food intake and results in obesity.||(Church et al., 2010)||Demonstrates that overexpression of the FTO gene results in a dose dependent body and fat mass increase. First direct evidence for FTO overexpression causing obesity in mice.|
Following the studies in Table 1, as well as various others, the link between FTO gene expression and adipogenesis was evident. This is still relatively new research, and recently scientists have had varying ideas as to exactly how the FTO gene influences adipogenesis. A summary of papers investigating various mechanisms can be seen in Table 2.
|Title of paper||Author(s) and Year of publication||Ideas suggested by the study, as well as results|
|Loss-of-function mutation in the dioxygenase-encoding FTO gene causes severe growth retardation and multiple malformations.||(Boissel et al., 2009)||That the FTO gene must regulate body weight and fat mass because a mutation in R316Q (catalytic domain of FTO) resulted in growth retardation. Therefore the paper suggests that R316Q is what regulates adipogenesis.|
|A link between FTO, ghrelin, and impaired brain food-cue responsivity.||(Karra et al., 2013)||Suggests that the neural response to food is indirectly modulated by the FTO gene. The paper demonstrated that people who are homozygous for the ‘obesity-risk’ version of the FTO gene have disregulated levels of acyl-ghrelin, which usually modulates appetite via neural pathways.|
|Obesity-associated variants within FTO form long-range functional connections with IRX3.||(Smemo et al., 2014)||Idea that it is not solely the FTO gene that regulates adipogenesis. Paper proposes that a second gene, adjacent to FTO, named IRX3 also plays a role in its regulation. Results suggest that the FTO gene regulates IRX3, which both work in synergy to regulate adipogenesis.|
|Hypomorphism for RPGRIP1L, a ciliary vicinal to the FTO locus causes increased adiposity in mice.||(Stratigopoulos et al., 2014)||Following on from Smemo et al., 2014 (above), this paper suggest that yet another gene, named RPGRIP1L, is also involved in regulating adipogenesis. Results indicate that mice with decreased RPGRIP1L activity are more overweight and hyperphagic (large appetite). These results indicate that RPGRIP1L may be partly responsible, along with FTO and IRX3, in regulating adipogenesis.|
|FTO-dependent demethylation of N6-methyladenosine regulates mRNA splicing and is required for adipogenesis.||(Zhao et al., 2014)||FTO demethylates N6methyladenosine (m6A). Therefore, when this process occurs, as levels of FTO fall, levels of demethylated m6A increase. This increase then promotes an increase in the RNA binding ability of SRSF2. RUNX1T1 is a target for SRSF2, therefore increased activity of SRSF2 results in increased RUNX1T1 activity, which is why adipogenesis is stimulated when FTO is expressed. This paper therefore concludes that FTO potentially acts indirectly, via RUNX1T1 in order to stimulate adipogenesis (in vitro).|
The ideas explored in Table 2 demonstrate how scientists were coming closer to elucidating the mechanism(s) as to how FTO gene expression influences adipogenesis. However, despite this, the process was still unclear. Dr Dyan Sellayah’s work in 2015 provides the latest novel mechanistic insight into how the FTO gene regulates adipogenesis in vivo. His work provides evidence that FTO influences adipogenesis by increasing the levels of the short isoform of the RUNX1T1 protein (RUNX1T1-S) in early adipogenesis. This increase in RUNX1T1-S stimulates various cyclins involved in regulation of the cell cycle, which subsequently function to increase the rate of mitotic clonal expansion (MCE). MCE is a process that occurs within the first 48 hours following adipogenic induction. This stimulation event by heightened levels of RUNX1T1-S results in the increased formation of mature adipocytes from preadipocytes and fibroblasts by adipogenesis, and therefore FTO expression indirectly leads to the stimulation of adipogenesis (Merkestein et al., 2015). His work also demonstrates that there is no role for FTO in adipogenesis following the MCE stage. Since Sellayah’s work demonstrates many other experiments, analyses and respective results, Table 3 has been created in order to compartmentalise his work. The eight experiments carried out in Sellayah’s paper together form a story that leads to the latest, newest research in the field.
|Experiments/Analyses conducted (with detail)||Result from each experiment|
|1) Experiment demonstrating that FTO promotes adipogenesis in vitro. Mouse embryonic fibroblasts (MEF) were taken and the FTO gene was either knocked out (FTO-KO) or overexpressed (FTO-4). FTO-KO and FTO-4 were given IBMX, dexamethasone and insulin to induce adipogenesis. The ability to undergo adipogenesis was then assessed in each group.||FTO-KO cells showed a reduced ability to undergo adipogenesis. This was also accompanied by a reduction in FABP4, C/EBPα, PPARgamma and PLIN1 mRNA levels (which, in normal physiology, have important roles within the process of adipogenesis). PLIN1 and FABP4 protein levels were also lower in FTO-KO cells when compared with a WT control.
FTO-4 cells from gWAT tissue showed higher triglyceride accumulation when compared with a WT control, and therefore demonstrated increased adipogenic potential. This was also accompanied by 70, 55 and 50 fold increases in PLIN1, PPARgamma and FABP4 mRNA levels respectively. Protein levels of FABP4 were elevated when compared with a WT control.
|2) Experiment disproving the work done by Stratigopoulos et al., 2014 (see Table 2). FTO, IRX3 and RPGRIP1L mRNA expression was measured in WT gWAT cells and MEF’s (FTO-KO and FTO-4).||FTO expression was higher than both PRGRIP1L and IRX3 expression in WT gWAT and MEF’s.
Significant differences in expression of IRX3 and RPFRIP1L were not observed in FTO-KO MEF’s, FTO-4 MEF’s or FTO-4 gWAT. This demonstrates that differences in adipogenic potential observed for FTO-KO and FTO-4 are independent of both RPGRIP1L and IRX3.
|3) Experiment confirming the role of FTO in adipogenesis. This was achieved by assessing the rates of proliferation after applying the induction cocktail and waiting 24 hours. The proliferation rates of FTO-KO and FTO-4 MEF’s were each compared with their respective controls.||When compared with a control, FTO-KO MEF’s showed a decreased rate of proliferation.
When compared with a control, FTO-4 MEF’s showed an increased rate of proliferation.
|4) Experiment demonstrating that FTO regulates MCE in a demethylation-dependent manner. Ie demonstrates that FTO only plays a role in adipogenesis during MCE, and not at any other later point in the process. The FTO gene was knocked down in FTO-4 MEF’s before adipogenic induction, which was then compared with FTO knockdown 48h after induction of adipogenesis.||FTO knock down in FTO-4 MEF’s before the induction of adipogenesis resulted in reduced expression of FABP4, C/EBPα and PPARgamma, when compared with expression before the knockdown event.
On the other hand, knocking down the FTO gene 48h after adipogenic induction had no effect on the expression of FABP4, C/EBPα or PPARgamma.
These results indicate that FTO solely has a role in initial stages of adipogenesis, specifically during MCE which occurs within the first 48 hours.
|5) Experiment that supported the role of FTO in MCE (above). The expression of CCND3 and CCND1 were assessed, as these two genes are involved cell cycle progression, and their levels are therefore increased following adipogenic induction. FTO-4 MEF’s were transfected and therefore activity was downregulated. This was compared with a FTO-4 MEF’s that were transfected with a control – ie were not altered.
The cyclin gene expression was also assessed in WT MEF’s that were overexpressing FTO.
|Transfected FTO-4 MEF’s showed significant downregulation in CCND3 and CCND1 expression at 40h and 24h after adipogenic induction respectively. The control did not demonstrate the same pattern of downregulation.
WT MEF’s that were overexpressing FTO demonstrated increased CCND1 expression 24 hours after induction of adipogenesis.
This demonstrates that FTO potentially increases the activity of genes that are responsible for regulating cell cycle progression and therefore more FTO expression results in faster cell cycle progression.
|6) Experiment assessing whether adipocyte proliferation is definitely dependent on the demethylase activity of FTO, which was an idea suggested by Zhao et al., 2014 (see Table 2). FTO-KO cells were either transfected with WT FTO (restoration of FTO function) or were transfected with FTO that was catalytically inactive. The proliferation rates of the two subgroups were compared.||Only the FTO-KO MEF’s that received WT FTO, and therefore had restored function, showed increased rates of proliferation. Transfection with FTO that was catalytically inactive resulted in no increase in cell proliferation.
This experiment demonstrates that FTO only has a role in MCE if its demethylation activity remains intact.
|7) Zhao et al., 2014 previously suggested that FTO influences adipogenesis by stimulating the production of the short isoform of RUNX1T1, which functions to stimulate adipogenesis. Therefore Merkstein et al, 2015 evaluated this claim. This involved measuring the expression of both the long (L) and short (S) isoforms of RUNX1T1 in FTO-KO, FTO-4 MEF’s and standard MEF’s.||In standard MEF’s, L isoform expression was much greater than S isoform expression. A decrease in the S isoform was observed in FTO-KO MEF’s, yet an increase in S isoform levels were observed in FTO-4 MEF’s.
Levels of L isoform expression were also decreased in FTO-KO MEF’s, but this was a smaller decrease than that of the S isoform. In FTO-4 MEF’s, the L isoform levels did not differ when expression was compared with a control.
This experiment provides clear evidence supporting there is a greater role for the RUNX1T1 S isoform in early adipogenesis when compared with the L isoform, and that FTO regulates the expression of the S isoform of RUNX1T1.
|8) Experiment aimed to investigate whether increased FTO expression results in a fatter phenotype. Weight gain was measured in mice with an FTO-4 genotype and in WT mice with functioning FTO after both being subjected to the same standard chow diet after the same amount of time.
The same experiment was conducted again, but the standard chow diet was replaced with a high fat diet (HFD).
|Mice with the FTO-4 genotype showed increased weight gain when compared to WT mice when both exposed to a normal chow diet.
The same results were found when both subgroups were subjected to a HFD, but the weight gain was more extreme.
Lean mass remained constant, with only fat mass being responsible for the weight gain observed. Results conclude that increased FTO expression does result in a fatter phenotype in mice.
Each experiment conducted by Sellayah and his team (Table 3) necessitated using chemicals in order to induce adipogenesis. The chemical cocktail selected included dexamethasone, insulin and IBMX. Although this chemical cocktail is successful in inducing adipogenesis, it is known to produce adipocytes that are smaller and more immature when compared with the wild type equivalent (Pantoja, Huff and Yamamoto, 2008), and are therefore not representative of human adipocytes. A recent study conducted in September 2015 has discovered a brand new cocktail capable of inducing adipogenesis that includes rosiglitazone and dexamethasone (Contador et al., 2015). These chemicals induce the production of fully functional, regular sized adipocytes that are therefore much more representative of conditions within the human body. Unfortunately for Sellayah and his team, literature stating the preference for the new chemical cocktail was released after the publication of his work. Therefore, in order to improve the work done by Sellayah, the same experiments should all be conducted again, but the standard induction cocktail should be replaced with rosiglitazone and dexamethasone. This will hopefully verify that FTO affects fully functional adipocytes using the same mechanism as seen in smaller, immature adipocytes.
The C57BL/6 murine model is susceptible to obesity induced by HFD, and therefore represented a sensible model organism for not only Sellayah’s work in Merkstein et al, but also other studies investigating genes involved in adipogenic regulation such as the study by Stratigopoulos et al in 2014 (Details can be found in Table 2). Seven substrains of the C57BL/6 strain exist, and the particular substrain selected by Sellayah is referred to as the C57BL/6J substrain. Although various C57BL/6 substrains are used in adipogenic research, literature has noted that scientists often select their substrain without realising the fundamental differences that exist between them (Mekada et al., 2009). The C57BL/6J substrain used by Sellayah naturally possesses a five exon deletion in the nicotinamide nucleotide transhydrogenase (Nnt) gene (Huang, 2006). This results in a reduction in insulin secretion and therefore a mouse that is glucose intolerant (Freeman et al., 2006). This mutation therefore means that the mice will naturally gain less weight than standard mice given the same diet (Matsui et al., 2010). Although this does not present an issue for experiments one to seven (Table 3), experiment eight in Table 2 aimed to investigate how much more weight was gained in mice overexpressing FTO compared with a WT control when exposed to varying diets. However, seeing as members of the substrain are intolerant to glucose, and subsequently unable to gain weight in a normal way, the weight gain observed by Sellayah may be dramatically underestimated. In order to improve experiment eight, a mouse strain should be used that does not naturally possess a mutation in the Nnt gene. This would allow observation of weight fluctuation that is due to the FTO gene only, without considering the fluctuation caused by glucose intolerance.
The work done by Sellayah and his team has provided the most recent information on how the FTO gene influences adipogenesis, which in itself is exciting research. However, every single conclusion documented in his paper is based on the study of female mice only. This means the novel conclusions ascertained by the study are therefore ambiguous as the FTO gene may not influence adipogenesis in the same way in male mice. In order to unequivocally determine how FTO effects the whole population of mice, experiments one through to eight must be repeated using male mice to see if the results run parallel.
Dr Dyan Sellayah and his team have claimed to provide firm evidence for novel mechanistic insight into how the FTO gene influences adipogenesis. The in vitro work was based on small, immature adipocytes; while in vivo studies were based solely on female mice of a murine strain that already possess other genetic mutations that may alter the role of FTO in adipogenesis. Since this is the case, I believe it is an invalid claim to suggest that the results presented in this paper are representative of a whole population of standard mice, let alone applicable to a human population. Despite this, I do believe that the work has provided excellent foundation for further work to support research into whether this is also the case in male mice, and therefore is potentially the mechanism that occurs during human adipogenesis.
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