Obesity is
emerging as the leading cause for morbidity and mortality around world, and it
is defined as a disproportionate body weight for height with an excessive
accumulation of adipose tissue that is usually accompanied by mild, chronic,
systemic inflammation. Obesity is associated with many diet-related chronic
diseases including diabetes mellitus, cardiovascular disease, stroke,
hypertension and certain type of cancers. (Williams et al. 2015). The convenient supply of high calorie food and decreased physical
activity have contributed to a rapid increase of obesity in developing
countries, such as Sri Lanka. This will be a double sword attack on developing
countries as the developing country has to deal with over and under nutrition.

 

Lifestyle
modification through behavioral counselling by an interventionist is considered
as the first step in the management of obesity, as the cost and complications
are low. However 5-8% weight reduction is observed and patients tend to regain
the weight after cessation of behavioral counselling (Anon 2014). Pharmacotherapy is advised as adjunct to a reduced-calorie diet
and increased activity for long-term weight management. Number of anti-obesity
drugs were brought to the market, but withdrawn later due to adverse
complications. This cause unpleasant situation among patients and prescribed
for short term. The seriousness of the situation and failing to find a solution
urge for new therapeutic strategies.

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Recent advances
in genetics have showed that the body mass index (BMI) is heritable. Twin and
adoption studies estimating the heritability of fat mass to be between 40 and 60%
(Raman 2002). The Genome Wide Association Studies (GWAS); a study that compares
DNA markers across the genome in people with a disease or trait to people has
identified that the Fat mas and obesity – related transcript (FTO) is associated
with Type 2 Diabetes, but further analysis confirmed that the FTO is associated
with BMI. Thirteen independent cohort studies have confirmed the association of
FTO with BMI (Frayling et al. 2007).  Further analysis of GWAS revealed
that Single nucleotide polymorphisms (including rs9939609, rs17817449,
rs3751812, rs1421085 and rs9930506) in the intron 1 of FTO are associated with
obesity (Scuteri et al. 2007). Homozygous of above alleles weigh 3kg more than the baseline and
it is estimated that 1 billion of us share the homozygous allele (Leibel 2008).

 

Mechanistic information of the FTO protein

In 2007, Schofield’s
group has done a bioinformatic sequence analysis studies and predicted that FTO
protein contains a double-stranded beta-helix (DSBH) fold that is homologous to
those of Fe(II) and 2-Oxoglutarate (2OG) oxygenases (Gerken et al. 2007). 2OG oxygenases regulate wide range of functions including: DNA
repair, posttranslational modifications, the regulation of the hypoxic
response, and fatty-acid metabolism (Trewick et al. 2002). In 2007, Schofield’s group demonstrated that using recombinant
murine Fto catalyses the Fe(II)-and 2OG-dependent demethylation of
3-methylthymine in single-stranded DNA, with concomitant production of
succinate, formaldehyde, and carbon dioxide. Studies on the wild type indicated
the Fto mRNA is abundantly expressed in arcuate nucleus, which regulate the
feeding and fasting (Gerken et al. 2007). Recent studies have showed that FTO gene might represent an
important regulatory site for both FTO, as well as RPGRIP1L (retinitis
pigmentosa GTPase regulator-interacting protein-1 like), whose transcriptional
start is located in the opposite direction of and close to the first exon of
FTO (Stratigopoulos et al. 2008).

 

Structure of FTO protein

The protein
structure of the FTO is important to develop inhibitors using the strategy of
Structure-based drug design. Crystallo- graphic analyses reveal inhibition by
2OG cosubstrate or primary substrate competitors as well as compounds that bind
across both cosubstrate and primary substrate binding sites (Aik et al. 2013). Further studies have showed that FTO protein has preference for
number of substrates (Han et al. 2010). Schofield’s group possess large number of small molecules those
are related 2OG oxygenases, which can be used to evaluate the structure of FTO
protein.

 

Small molecule inhibition

Small molecule
inhibition is vital for unrevealing, either in
vitro or in vivo biological
mechanisms, as obtaining crystallographic structures are difficult. Simple
inhibition studies such as differential scanning flurometry can be performed to
identify inhibitors. As the Schofield group possess large number of potential
small molecules, it would be interesting to evaluate the inhibition potential
of those. (McMurray et al. 2015)

 

Experimental Plan:

·        
Molecular biology studies will be conducted to
unravel the linkage between FTO gene and obesity by incorporating knockout
mouse or small interfering RNAs (siRNA).

 

·        
Comprehensive studies on FTO regulation in food
intake and energy expenditure using animal models – in vivo models.

 

·        
Inhibition studies: Use the differential
scanning flurometry based assay to screen 2OG analogues and metal chelators to
identify the most potent inhibitors for the FTO protein.

 

·        
Efforts will be made to obtain crystals of
FTO-small molecule complex and solve them.