{My new book "Ever seen a fat fox ~ Human obesity explored" which has a chapter and section on diet and genes is due out mid May}
The Harvard School
of Public Health has a recent web article on genes and obesity bearing the
somewhat negative title: “Genes are not
destiny” [1].
From my standpoint, this review is in fact defensive of a School where genomics
appears to be low on their nutrition research agenda. This brief review of the
Harvard position is written by a blogger who works both in public health
nutrition but also in molecular nutrition.
The overview (hardly
a review) begins by pointing out that obesity conditions linked to a single
gene defect such as the Prader-Willi Syndrome are utterly rare. Equally, common
ordinary everyday obesity is linked to so many genes that looking for one is
like looking for a needle in a haystack. However, needles can be found in
haystacks and we now know that high blood pressure is dramatically reduced in
individuals marginally deficient in the B-vitamin, riboflavin, when given dietary
riboflavin supplements but this applies only to those carrying a single variant
of a gene we all have, the natural variant of the folic acid-related FTHFR.
That variant isn’t rare. One in 10 of us carry it[2]. So
lets not throw the baby out with the bath water as they say.
Equally, the web article goes on to make the
case that modern gene analysis technology allows us to explore how multiple
sets of genes might explain common obesity. The more such complex sets of genes
explain obesity, the fewer people we find with such a unique blend of genes and
even at its best, this technology can explain only a few percentage points of
the obesity problem. So far I am in full agreement with the Harvard team and I
remain somewhat in agreement when they write:
“So if
our genes have stayed largely the same, what has changed over the past 40 years
of rising obesity rates? Our environment: the physical, social, political, and
economic surroundings that influence how much we eat and how active we are.
Environmental changes that make it easier for people to overeat, and harder for
people to get enough physical activity, have played a key role in triggering
the recent surge of overweight and obesity.”
Its here I start to divert from the Harvard dons’ views.
According to the US Center for Disease Control[3],
about 1 in 3 adults is classically obese while the same figure for children
(2-19 years) is 1 in 6 (35% and 17% respectively). The figure rises if we consider overweight but
obesity is the sharp end of the problem in the Harvard analysis. Now if 1 in 3
US citizens are obese, then 2 out of 3 are not. They share as stated above, the
same “environment: the physical, social,
political, and economic surroundings that influence how much we eat and how
active we are”.
So why isn’t everyone obese? Why some, not others. The answer
is of course genes and we’ve known this for years. The Harvard review pays simple
lip service to twin studies, the extensive literature on which tell us that
obesity is about 70% heritable (only 20% in non-identical twins who do not
share an exact genome as identical twins do). In their simple reference to twin studies, the
Harvard Dons reveal a deep prejudice when they write:
“The
strong correlation for BMI between monozygotic twins and its attenuation with
lesser degrees of shared genes suggest a strong genetic influence on BMI.
However, this conclusion is based on the assumption that identical and
fraternal twins have the same degree of shared environment-and it’s an
assumption that may not hold in practice.”
The literature is peppered with outstanding scientific
papers, old and new, which this overview sweepingly ignores. They completely
fail to refer to the studies of twins raised apart for periods of almost 50
years in radically different environments and still showing an obesity
heritability of >70%. They completely fail to refer to metabolic studies
where identical twins were subject to 1000 additional calories per day[4]
or a reduction in caloric balance through bouts of intense cycling[5].
Take for example the former. Some twin pairs showed a dramatic gain in weight
with the extra calories while others didn’t. Different genomes predispose more
or less to obesity. However, whatever one identical twin did, the other followed
exactly. With weight loss experiments the same conclusions held.
In summary, we do know of some instances where a very common single
gene variant can determine dietary responsiveness to a complex phenotype such
as high blood pressure. We do know that identical twins show a 70% heritability
of obesity (this exceeds the heritability of height, alcoholism and depression for
example) and we know that identical twins raised apart for very long periods
also show a very high obesity heritability[6].
Metabolic studies also explain variation in obesity heritability both between
and within identical twin pairs. So, the case for optimism is huge and not so
futuristic, as the Harvard dons would suggest.
One of the main flaws in the diet-obesity-gene link is the
constant belief that it is to reductionist biology that we must turn to
understand this problem. Metabolic pathways of fat and carbohydrate metabolism
including fat cell, liver cell and muscle cell biology dominate. For me, the
future is the genetics of food choice. Why are some people sensitive to the
external cues to food intake – its sight, smell, ambiance, availability, time
of day, etc? Why are some apparently more self restrained, less sensitive to
genetic cues? Applying advanced neurobiological techniques to study
neurobiological determinants and responses to food cues are the start. I would then move to twin studies to rank the
heritability of such neurobiological indices of appetite. In time I’d find more
and more examples of heritable neuronal regulators and her I’m talking complex
neuronal patterns. I don’t need to go to genes at this stage. Moreover, I’d be looking not for determinants
of individual behaviour but membership by individuals of clusters of neuronal
networks as we currently apply to metabolomics.
[1] http://www.hsph.harvard.edu/obesity-prevention-source/obesity-causes/genes-and-obesity/
[2]
Mahmud N et al (1999); Gut 45:389-394
[3] http://www.cdc.gov/obesity/data/index.html
[4] Bouchard, C et al. (1990) ‘The response
to long-term overfeeding in identical twins’. The New England Journal of Medicine, 322:1477–82.
[5] Bouchard, C et al. (1994) ‘The response
to exercise with constant energy intake in identical twins’. Obesity Research, 2: 400–10
[6] Stunkard, A. J et al. (1990) ‘The body
mass index of twins reared apart’. The
New England Journal of Medicine, 322: 1483–7.
