Obesity - Published: April 2010
Interview Date: May 2010
From the Special Topic of
In our recent Special Topics analysis of obesity
research over the past decade, the work of Professor
Philippe Froguel ranks at #9, both by total citations and
by total papers, based on 129 papers cited a total of 8,808
He was also the top-cited researcher in our 2002
Special Topics analysis on diabetes research, and he ranked
in the top 20 in our 2009 re-analysis of the topic. His
2007 paper on the genome-wide association study of type 2
diabetes (Sladek R. et al., "A genome-wide
association study identifies novel risk loci for type 2
diabetes," Nature 445: 881-5, 11 February
2007) was ranked at #1 on the list of most-cited diabetes
papers published in the past two years.
His record in
Essential Science IndicatorsSMfromThomson
Reutersincludes 219 papers, classified under Clinical
Medicine, Molecular Biology & Genetics, and Biology & Biochemistry,
cited a total of 11,713 times between January 1, 1999 and December 31,
Professor Froguel is Professor of Genomic Medicine and Head of the
Department of Genomics of Common Diseases at the School of Public Health of
Imperial College London. He is also Director of the CNRS Research Unit on
Genomics and Metabolic Diseases at the Institut Pasteur in Lille,
Below, he talks with ScienceWatch.com about his highly cited work as it
relates to obesity.
Would you tell us a bit about your
educational background and research experiences?
Originally, I trained as a physician in Endocrinology in Paris hospitals in
the late '80s. At that time I met Jean Dausset, the Nobel Prize laureate,
and Daniel Cohen, Jean Weissenbach and Mark Lathrop, the French pioneers of
the first human genome map, at CEPH (Human Polymorphism Study Centre),
where I established the first lab for the study of a common disease (Type 2
I collected hundreds of diabetic families through a media campaign using
posters in the Paris Metro. And subsequently I identified the first T2D
gene, glucokinase, in 1992, which was the first evidence that this disease
was due to a pancreatic dysfunction (and the first proof of concept that
part of common disorders may be monogenic).
In 1995 I moved my lab to Lille at the Pasteur Institute and in 2003 I also
joined Imperial College London where I currently chair the Department of
Genomics of Common Diseases of the School of Public Health. Half of my
activity is focused on T2D and I was pleased to hear a few years ago that
Clarivate Special Topics found that I was the most-cited researcher
in diabetes research in their 2002 analysis.
What first drew your interest to the field of
T2D is closely linked to obesity, as 80% of diabetic patients are obese.
However, the majority of obese individuals are not diabetic. In the mid
'90s, I decided to develop a project on extreme obesity which led to the
discovery in 1998 of the most prevalent monogenic form of obesity (2% of
obesity cases) due to a mutation in the hypothalamus-expressed melanocortin
4 receptor gene (MC4R).
"Genetics has much to bring to the personalized
treatment of obesity."
I also identified the first mutation in the leptin receptor gene which
evidenced the central role of the leptin-melanocortin pathway in the
regulation of the appetite. We now know that all the obesity genes
identified so far are expressed in the brain or act through the brain (like
leptin) to control food-intake behavior. Importantly, all obesity genes
found so far have a neuroendocrine effect and most the T2D genes regulate
insulin secretion. Although tightly linked, obesity and T2D have distinct
Our analysis suggests that your focus is on the
genetics of obesity. Is this the case, and are there particular
aspects of the topic in which you specialize?
I believe in "extremomics," i.e., in the major interest to work on extreme
(familial) phenotypes to find novel causative DNA abnormalities having
strong effects that can be subsequently analyzed in large general
populations. This strategy recently worked very well in a study I published
in Nature in February 2010 (Walters RG, et al., "A new
highly penetrant form of obesity due to deletions on chromosome 16p11.2,"
We postulated that part of the missing heritability of obesity that was not
explained by the recent wave of genome-wide association studies (GWAS)
using frequent single nucleotide polymorphism (SNP) microarrays can be due
to rare copy number variations (also called genome structure variations,
GSV) that may have a much stronger functional impact than SNPs (by the way,
the obesity risk of the SNP that my group and others found by GWAS range
In order to resolve the issue of causality and statistics I followed a
two-stage approach, screening first children with extreme obesity and
learning disability. Rare GSV that were identified through this approach
were first validated and characterized using several methods. A deletion on
chromosome 16p was found in 3% of these children.
We then re-analyzed our previous GWAS data in 16,000 samples from various
European populations and found that the same GSV was also associated with
common obesity (1% of severe obesity cases). Importantly the risk to be
obese (OR) for deletion carriers was 4300% with a clear age-dependent
effect (virtually all adults with this GSV were obese).
Pending directions of research will include a systematic analyses of GSV in
extreme obesity cases as well a full exome sequencing of obese pedigrees.
Indeed, we need to test the validity of the "frequent disease, rare
mutations" hypothesis (alternative to the "frequent disease, frequent
polymorphisms" that is only partially right).
I postulate that we carry "rare but common mutations" (each specific DNA
variant is very rare, but this type of mutations in indeed common and
widely distributed) that may have serious effect on the regulation of the
body mass. Few of them are enough to make a great difference and possibly
to show some "synthetic associations" prints in GWAS.
Elucidating their contribution is not easy as the exome sequencing (1% of
the genome) currently shows thousands of potentially "novel" mutations in
each individual. Large sequencing efforts such as the 1000
genomes, familial and functional analyses etc., are necessary to
evaluate the deleterious potential of each of them in order to establish
Many of your papers, including the 2005 Nature
Genetics paper "Variants of ENPP1 are associated with childhood
and adult obesity and increase the risk of glucose intolerance and
type 2 diabetes" (Meyre D, et al., 37: 863-7, August
2005), link type 2 diabetes and obesity. What has current research
told us about this link, and what are the implications?
This paper is the only success story of the familial positional cloning of
obesity genes, a strategy combining genome-wide linkage analysis and
candidate gene studies. ENPP1 is a natural inhibitor the insulin receptor
which is associated with insulin resistance and thus to T2D. Furthermore,
insulin is a strong anorexigenic hormone, and a defect in insulin action
may contribute to obesity.
"We now know that all the obesity genes identified so
far are expressed in the brain or act through the brain
(like leptin) to control food-intake behavior."
More recently GWAS and GSV analysis reported another protein of this kind,
SH2B1 (part of the insulin receptor pathway) which also contributes to both
obesity and insulin resistance
Last year, you published a paper in the
Journal of Molecular Medicine, "Combined effects of MC4R and
FTO common genetic variants on obesity in European general
populations" (Cauchi S, et al., 87: 537-46, May 2009).
Would you talk a bit about this paper—its findings and
Our GWAS identified a new gene that we called FTO (FaT and Obesity
associated gene) where SNP associate with a 50% increase of the risk for
obesity (Dina C, et al., "Variation in FTO contributes to
childhood obesity and severe adult obesity," Nature Genetics
39: 724-6, June 2007).
Shortly thereafter, we contributed to the discovery of frequent SNP located
500 Kb apart from the MC4R gene (the same gene responsible for monogenic
obesity) that increases the risk for obesity by 20%. Both loci additively
increase body fat in general populations and both have an effect on food
intake: we found that MC4R SNP associate with abnormal food intake
For FTO the effect seems to be different and related to a higher hunger.
That illustrates the different facets of energy consumption and their
relationship with obesity.
How reasonable is it at this point to expect that
current genetics-based research will have a significant effect on the
treatment and prevention of obesity?
The dogma in the late '90s was the central role of fat (and the energy
expenditure and storage) as a causal factor for obesity. Surprisingly
perhaps, genetics have shown that obesity may be more a neurobehavioral
Furthermore the recent discoveries of obesity genes (or regions such as the
chromosome 16p) strongly link obesity with mental development and learning
disorders as some of the identified genes are involved in neuronal
development. That reinforces the hypothesis that obesity is indeed a
comportment disease with strong implications for prevention and treatment
especially in children.
Comportment-based therapies may be more useful than usual diets that worsen
deleterious food-intake habits. We are still missing drugs that can target
obesity genes without serious side effects.
How far would you say obesity genetics research
has come in the past decade? Where do you see it going in the next 10
The role of genetic factors in obesity is now seriously considered.
Although the impact of the environment is major at the level of the entire
population, it is now accepted that each individual has a different level
of vulnerability to the obesogenic environment which is genetically driven.
We need to make progress in the understanding of this genetic background
and I believe that "rare but common" DNA variations that greatly increase
appetite and/or decrease satiety are important. The development of
whole-exome and whole-genome sequencing will greatly help.
However, the biggest challenge is elsewhere: nearly half a million
individuals received obesity surgery in 2009 (half in the US) but this
aggressive treatment has significant side effects and needs very
sophisticated medical follow up. On the other hand, bypass obesity surgery
unexpectedly cures T2D in up to 70% of morbidly obese diabetic patients.
As it is not possible to propose obesity surgery to the 1.2 billion obese
human beings on Earth, there should be studies to define who the best
candidates for obesity surgery are, and what the best procedure is for each
patient. Genetics has much to bring to the personalized treatment of
Professor Philippe Froguel, M.D., Ph.D., FMedSci
School of Public Health
Imperial College London
London, United Kingdom
Institut Pasteur de Lille
Philippe Froguel's current most-cited paper in Essential
Science Indicators, with 1,629 cites:
Yamauchi T, et al., "The fat-derived hormone adiponectin reverses
insulin resistance associated with both lipoatrophy and obesity,"
Nature Med. 7(8): 941-6, August 2001. Source:
Essential Science Indicators from
KEYWORDS: OBESITY, GENETIC FACTORS, TYPE 2 DIABETES, T2D GENE, GLUCOKINASE,
COMMON DISEASES, GENOMICS, MELANOCORTIN 4 RECEPTOR (MC4R) GENE, LEPTIN
RECEPTOR GENE, HYPOTHALAMUS, APETITE REGULATION, NEUROENDOCRINE EFFECT,
EXTREMOMICS, GWAS, SNP, GSV, DELETION CARRIERS, ENPP1, INSULIN, FTO GENE,
COMPORTMENTAL BASED THERAPIES, RARE BUT COMMON DNA VARIATION, OBESOGENIC