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Gene Variants for Obesity and Type 2 Diabetes – A Shared Aetiology?
Obesity Further insight into the function of these genes may yield valuable
Overweight and obesity result from a long-lasting imbalance clues for lifestyle intervention and therapeutics.
between food intake and energy expenditure, leading to storage
of excess calories as body fat. Control of energy balance involves Genome-wide Association Studies
the integration of satiety signals from the gastrointestinal tract, Give Insight into Shared Disease Aetiology
adipose tissue and nutrient-related signals. Adiposity signals So far, results from the recent GWA studies do not point towards
provide feedback information from body energy stores to various obesity and type 2 diabetes having an increased risk from shared
disease susceptibility loci. It seems that the susceptibility genes
for obesity are involved at the start of the trait (energy imbalance)
and those for type 2 diabetes at a later stage of the disease
Studies show that SH2B1 regulates
(β-cell defect).
energy balance, bodyweight, peripheral
The initial finding of association between the FTO gene and type 2
insulin sensitivity and glucose
diabetes was subsequently shown to be entirely due to an obesity
homeostasis, at least in part by
risk. The gene was found to be highly associated with type 2
diabetes in several study populations
27
but failed to replicate in
enhancing hypothalamic leptin sensitivity.
studies where they matched the cases and controls on BMI or
selected relatively lean cases.
7,9
The loci near GNPDA2, BDNF and
TMEM18 that were associated with obesity were also found to be
hypothalamic regions and are mediated via the circulating weakly associated with type 2 diabetes.
11,13
Follow-up studies
hormones leptin and insulin and others. As a result, bodyweight should explore whether these associations with type 2 diabetes
remains remarkably stable most of the time in most people, but any mainly act through an effect on weight regulation. They need to
defects in this system can lead to a deregulation of bodyweight. take into account not only BMI but also other measures of obesity.
It is known that hypothalamic defects in either insulin or leptin Recently, it has become clear that not only is the amount of body
signalling are associated with increased food intake and/or fat important but especially its distribution in determining disease
heavier bodyweight.
16,17
risk. Independently of BMI, a larger waist circumference (as a
measure of abdominal obesity) is related to chronic disease risk,
Many of the recently established obesity susceptibility loci are such as type 2 diabetes.
28
However, because there are still many
located near genes that are highly expressed in the brain and/or more obesity and type 2 diabetes genes to discover, we cannot rule
have been shown to have a function in neuronal development or out that the susceptibility for developing type 2 diabetes and
activity. These suggest a key role for the hypothalamic pathways in obesity is partly due to shared underlying genetic factors.
regulating food intake and energy homeostasis in the architecture
of obesity. The role of BDNF, MC4R and SH2B1 genes in obesity In a previous study we compared all the published genome scans
pathogenesis is well known from functional studies. MC4R is the for type 2 diabetes and obesity and identified five overlapping
key signalling neuropeptide, inhibiting food intake and increasing chromosomal regions for both entities.
29
However, the shared
metabolic rate.
18
BDNF decreases food intake in response to genetic effect may be smaller than we initially thought, or obesity
nutritional status and MC4R signalling.
19
Studies show that SH2B1 could simply be a non-genetic risk factor for type 2 diabetes
regulates energy balance, bodyweight, peripheral insulin sensitivity because it provokes insulin resistance.
and glucose homeostasis, at least in part by enhancing
hypothalamic leptin sensitivity.
20
The roles of the other recently
identified loci in obesity pathogenesis are not yet clear. FTO is
suggested to participate in the central control of energy
The next challenge is to go from the
homeostasis, where it is regulated by feeding and fasting.
21
NEGR1
and
statistical association of the markers to a
TMEM18 are involved in neural development,
11,13
whereas NPC1
is involved in endosomal cholesterol trafficking in the central
functional link between the genomic
nervous system, liver and macrophages.
22
region and type 2 diabetes and obesity.
Because satiation signals influence how many calories are eaten
during individual meals, it is interesting to further explore the effect
of obesity susceptibility variants on total and nutrient-specific
dietary intake. Although total energy intake is a vital aspect of food Follow-up of Confirmed Associations and
intake, macronutrient composition or diet patterns may be equally Alternative Gene-hunting Approaches
important factors underlying the development of obesity. Common The next challenge is to go from the statistical association of
variants near the FTO and MC4R genes were recently found to be the markers to a functional link between the genomic region and
associated with total energy intake, and a variant near MC4R was type 2 diabetes and obesity. The associated single nucleotide
also found to be associated with dietary fat.
23–25
In addition, in a polymorphism (SNP) will either be the disease-causing variant or
study population of 1,700 Dutch females, the susceptibility loci near strong linkage disequilibrium (LD) with the causal variant, i.e. the
NEGR1, TMEM18, BDNF, MTCH2 and SH2B1 showed association associated SNP and the causal variant are inherited together.
with macronutrient intake.
26
It can be argued that the genes Re-sequencing of the susceptibility loci is needed to establish the
associated with food intake play a role in satiation signalling. causal genes. This will be a daunting task because the LD blocks can
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