Obesity, depression, phobia and genes

The prevalence of clinical depression is about one third higher among obese versus non-obese subjects and there is conflicting evidence as to whether it is depression that brings on obesity or the reverse, where obesity brings on depression. To study this conundrum, a recent research project examined data from a longitudinal study of 18, 558 British individuals born in 1958[1]. This cohort was followed up at 7, 11, 16, 23, 33, 42, 45 and 50 years. Subjects were rated as underweight, normal weight over weight or obese. Those that were underweight had 1.3 to 2.3 times the risk of being depressed compared to those of normal weight. There was no evidence of a tendency toward depression among the overweight but among the obese, the risks of depression were between 1.5 and 2.3 times that of normal weight subjects. The data were then examined to see how either one of the conditions (obesity or depression), in prior years influenced the likelihood of the other condition subsequently developing. Being underweight predicted subsequent depression in both males and females (25% higher that those of normal weight) and depression predicted subsequent underweight in males only  (84% higher risk). Obesity predicted subsequent depression in females only (34% higher risk). However, depression did not predict subsequent obesity. In all these calculations, confounding factors such as social class, physical illness and ethnicity were controlled for.  The authors reflect on the fact that the treatment of obesity should also include an examination of possible depression but they ignore the elephant in the room, which is the stigmatization of the obese. By and large, the overweight and obese are seen by society, including health professionals, as having themselves to blame. They are seen as lazy, dishonest, untidy, lethargic, unreliable and so on. Sympathy with the overweight and obese is a rare occurrence.

A second paper[2] looking at a related topic, namely phobic anxiety, obesity and genes is also worth considering. Phobic anxieties relate to a wide range of fears that some people experience and the level of anxiety is measured on the Crown Crisp Index, which includes, for example, measures of claustrophobia fear of heights and crowds or hypochondriac traits. The subjects were participants in the Harvard based Nurses Health Study (5,911 females) or the Health Professional follow-up Study (3,697 males). They used genetic data on 34 genes linked to obesity. One was the FTO gene, which is the most widely studied such gene and another was the gene for a brain receptor involved in appetite regulation (MC4R). The remaining 32 genetic variants had been previously identified as increasing the risk of obesity in another study and were termed obesity risk genes. One of these 32 genes was also the FTO gene and these 32 genes had an additive effect on the risk of obesity. Average phobic anxiety scores were more 43% higher in women, which agrees with the general literature. The relationship between genetic factors and BMI was strong for the FTO gene, the MC4R gene and the 32 obesity risk genes. Higher BMI values increased the risk of phobic anxiety only among those carrying the common FTO genetic variant. After adjusting to an average BMI value, the FTO gene variant still had a direct association with phobic anxiety. Taken together, these data show that there is a common genetic link between obesity and phobic anxiety. The authors ask that their findings should be treated with caution and their hypothesis should be studied in larger samples. The finding that the collection of genes that had a linear rise in the risk of obesity did not link with anxiety suggests that obesity per se is not a cause of phobic anxiety and that the two conditions, obesity and phobic anxiety simply share a common genetic pathway

All in all, these two papers highlight the need for the study of the psychological conditions associated with obesity and they further highlight the need to study the reverse: how do psychological conditions contribute to energy imbalance

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[1] Geoffrey, M and Power C (2014) Psychological Medicine, 44, 2461-2652

[2] Walter S et al (2014) Psychological Medicine, e publication  ahead of print: PMID: 25065638

The Human Microbiome ~ Myth and mystery

In the 1990’s, antioxidants were the big fashion in food and health. These antioxidants were mainly vitamins (C and E), pre-vitamins (beta-carotene) and plant constituents of various kinds (e.g. coumarin, flavonoids, thymol). Studies showed that rates of cancers across many countries were directly correlated with plasma levels of antioxidants. Laboratory studies showed that the damaging effect of pro-oxidant metals such as copper could be reduced with the addition of antioxidants. Every disease imaginable was included in the antioxidant Klondike. And of course we had the race to the finish culminating in a trial of Chinese smokers (smoking is pro-oxidant) with antioxidant supplements which showed the opposite to what was hoped for - cancer rates were increased! Many other trials were conducted but to date, little evidence exists to support the theory that taking antioxidant supplements reduces any disease risk. Of course that doesn’t bother the health food industry and to some extent the food industry from hyping up the antioxidant myth.  This blogger learned one lesson from the antioxidant saga namely that any nutritional theory that is putatively related to many diseases, is a theory about to be shelved.

In today’s world of food and health, that role is played by the human gut microbiota. The front covers of The Economist, the New York Times magazine, Nature, Scientific American and others have highlighted articles with titles such as “Microbes maketh man” or “Our other genome”. There are wow statistics that journalists love: 100 trillion bacteria in our gut accounting for 1.5 kg of our bodyweight with 100 times more genes than we have (“We” are referred to as “Hosts”!). To journalists, it is an astonishing mystery that bacteria, previously thought to be bad for health were in fact our single most important protection against an array of diseases.  A search of the PubMed database shows the term “Gut microbiome” is associated with the following diseases (number of published papers in brackets): obesity (628), cancer (381), diabetes (350), allergy (260), depression (48) and autism (33). I stopped there but I’m sure I could go further. The point is that the gut microbiota is the new unifying theory of life and death.

A very welcome paper in this week’s Nature bears the title “Microbiome science needs a healthy dose of sceptism”[1]. The author’s first point of criticism is that the techniques used to characterise the microbiota genome often lack direct links to known functions. He points out that his team has shown that vaccination eliminated 30% of known pneumococcal strains in a human population but only because they knew which genes to focus on. In the case of the human microbiota genome, we might know that it differs between say normal weight and obese subjects. But that’s all we know. We cannot tell what part of the microbiota genome is directly linked in a causal manner to obesity.  His second criticism is linked to this in that cause and effect are misinterpreted when looking at gut microbiota. He cites a paper, which shows that changes in the human microbiota correlate with measures of frailty in older persons. So too did dietary patterns. The conclusion was that poor diet altered the gut microbiota and thus led to frailty. The opposite was not considered, namely, that frailty led to poor diets that in turn altered gut microbiome patterns. His third criticism is that most of the studies lack any mechanistic explanation based on experimental investigation. In that respect the field is similar to nutritional epidemiology where correlations dominate and shape policy in the absence of any experimental proof. So if we consider the microbiome-diet-frailty issue, a simple test would be to take a cohort of frail persons and through physiotherapy, counseling and nutritional support reduce their frailty. If a significant improvement in frailty had no effect on the microbiome, we can dismiss that theory. Alternatively, frail persons could receive faecal transplants to modify their microbiota and examine the effect of improved microbiota on frailty. His fourth criticism relates to the quality of the data on the microbiota and health vis-à-vis the real world. He highlights the fact that many of the studies that show the importance of the gut microbiota are conducted in germ-free mice. Such mice live in an aseptic bubble that makes them generally ill and with poor food intake. Finally he asks if there might be a confounding factor such that the real force driving the disease is one thing and the altered microbiota simply an observer, equally effected by the true driver.

In his paper, Professor Hanage who works in Harvard, cites a blog by Professor Jonathan Eisen of the University of California at Davis in which he makes an award for “Overselling the microbiome”[2]. He shows how research results are manipulated by university press offices and swallowed easily by journalists. Two collaborating Swedish university research groups published a paper in Nature Communications[3] and they wrote thus:

“Our finding of enriched levels of phytoene dehydrogenase in the metagenomes of healthy controls and its association with elevated levels of β-carotene in the serum may indicate that the possible production of this anti-oxidant by the gut microbiota may have a positive health benefit”.

In the press release[4] we read the following:

“Our results indicate that long-term exposure to carotenoids, through production by the bacteria in the digestive system, has important health benefits. These results should make it possible to develop new probiotics. We think that the bacterial species in the probiotics would establish themselves as a permanent culture in the gut and have a long-term effect”. “By examining the patient's bacterial microbiota, we should also be able to develop risk prognoses for cardiovascular disease", says Fredrik Bäckhed, Professor of Molecular Medicine at Gothenburg University. "It should be possible to provide completely new disease-prevention options".

The present fashion of the microbiota has a powerful scientific dimension but it is over-hyped and under-studied at the human experimental level. Whist many good human experiments are done to study the human microbiota, most are poorly constructed, observational and in rodents, normal or germ free.

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[1] Hanage WP (2014) Nature 512, 247

[2]http://phylogenomics.blogspot.ie/search/label/overselling the microbiome award

[3] Karisson FK et al (2012) Nature Communications 3, Article 1245

[4] http://medicalxpress.com/news/2012-12-gut-bacteria.html

School lunches: Measure twice - cut once

“History doesn’t repeat itself, but it does rhyme” Mark Twain

Maureen Ogle, in her book “In meat we trust”, reminds us that school lunches have always been on the menu of food controversies. In 1926, the New York School Board banned frankfurters from school lunches. She writes that: “The board’s lunch director explained that the food was unsuited to students’ nutritional needs” The director went on to say that: “The sausage was so heavy that when children ate it, they neglected to eat green stuff and milk”. And you’ve guessed it – no data were gathered upon which to construct evidence based policy. The director simply looked into his or her heart in search of wisdom. The issue of school lunches lingers on and whilst I want to end on a positive note, I will cite three studies which all show that poorly informed or misinformed interventions in food choice to improve nutritional balance in school lunches can back fire.

Case 1. A group from Tufts University examined the effect of three years of intervention in the US National School Lunch Programme to reduce total fat and saturated fat intake[1]. They observed that as the % of calories in lunches decreased, the % of calories from fat increased. This is known as the sugar-fat seesaw. Basically, if one reduces the level of fat in a child’s energy supply, children will compensate for the loss of fat by eating higher amounts of other foods and time after time, it has been shown that as you lower fat, you raise sugar. So, in today’s terms where sugar is popularly perceived to be utterly toxic, would one describe the reduction in total fat and saturated fat intakes as a success or would the increase in % energy from sugars be seen as a failure. This writer would deem it a success as fats and especially saturates are directly implicated in elevated plasma cholesterol on the basis of dozens of randomised controlled feeing studies while almost none exist for sugar at the normal or even slightly normal levels of intake.

Case 2. Fruit and vegetable intake are common targets in school lunch programmes and the general belief is that because they have a low energy density (fewer calories per unit weight) that higher intakes will reduce energy intake. Researchers from the University of Wiscanson-Maddison studied food choice in school canteens using digital imaging to identify foods selected and portion size[2]. They studied schools taking part in the Farm to School project. They found that whereas fruit and vegetable intake increased, the intake of other foods decreased such that energy intake remained constant. Thus if the objective was to reduce energy intake, the project failed. But a higher intake of low-salt, low fat fruit and vegetables would reduce overall the negative targets of foods (fats, saturates etc.) and thus the project should be deemed a success.

Case 3: Brian Wansink and his colleagues at Cornell University, reported on a pilot study evaluating the consequences of banning chocolate milk in school cafeterias[3]. Chocolate flavoured milk represents about two thirds of all mile in the US school cafeteria system. In 11 Oregon schools, chocolate flavoured milk was banned from the lunch menu and the group from Cornell used data gathered in the National School Lunch Program to assess the success or otherwise. Total milk sales fell by 10%. White milk increased but some 29% of this non-flavoured milk was wasted, that is unfinished by the students. In all, the numbers of children using the School Lunch Program fell by 7%. Success or failure? Once again I would say the outcome could have been predicted if someone had invested funds in attitudinal research, which would have saved a lot of money and effort. My father, a carpenter, always used the phrase: “Measure twice – cut once”. In effect, these school lunch managers, in all three cases never measured even once. But they were all mad keen to cut!

Which brings us to a major recent study from the University of Chicago, which carried out a survey of 557 representative schools to assess the impact of the updated standards of the National School Lunch Program[4]. The ratio of “agree”/ “agree strongly” to “disagree”/ “disagree strongly” that “students generally seem to like the new school lunch” was about 70:30. This contrasts with the opinion: “At first, students complained about the new lunch” where 57% agreed or agreed strongly. So, slowly the students absorbed the newer healthier lunches. About 2/3 students have fewer complaints about the new lunches and the same number doesn’t seem concerned about the changes. One main area of complaint was the withdrawal of pizzas from some school menus. Students were happy with healthier pizzas but not happy with the absence of any pizza option. So this is a positive note for innovation school lunches. However, the more that innovation is built on a priori data, the more likely it is to be successful and, regrettably, the general trend is to cut and not measure in advance.

Here in the EU, where national policies on school lunches differ according to member state, the Commission has published a very useful overview of existing practices and has set the scene for future joint action to help improve the nutritional quality of school lunches[5].

One area of public health nutrition that is badly missing is the measure of the impact of school lunches on the student’s overall daily dietary performance. In other words, for how many children does the school lunch counter balance poor dietary practices at home and outside the home and school environments? For how many pupils is the home driving most the student’s daily intake of nutrients to optimal. Such data are very important to understand the true social impact of school lunches.

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[1] Dwyer JT et al (2003) Journal of Adolescent Health, 32, 428–435

[2] Bontrager Yode AB et al (2014) Childhood Obesity July 2, e-pub ahead of print

[3] Hanks AS et al (2014) PLOS ONE, 9, (4), e91022

[4] Turner L and Chaloupka FJ (2014) Childhood obesity, 10, number 4

[5] EU School lunch mapping publication