Obesity

Energetics and Obesity

According to the WHO, obesity is the largest health threat facing the western world. Our work on obesity has addressed four aspects of the problem. In addition we have been instrumental in the development of techniques for monitoring body composition, energy expenditure and food intake in both humans and in animal models.

 

The main areas of our work are as follows.

  1. The evolutionary context of our propensity to develop obesity.
  2. Whether the obesity epidemic has been caused more by increases in food intake or decreases in energy expenditure, including physical activity and the causes and consequences of variation in resting metabolic rate. This work includes the SLOSH project.
  3. Diagnosing the effects of various molecular factors in the brain and peripherally on food intake and energy balance.
  4. Evaluating the effects of dietary restriction.

A) The Evolutionary context of our propensity to develop obesity

Why is it that some people get fat, while others seem to have no problems regulating their body weight, and remain quite slim? Most people now agree that these differences have a large genetic basis, and that our propensity to become obese, or not, is rooted deep in our evolutionary history. There is a conundrum however in this interpretation. We know that obesity leads to many serious negative health effects. How is it possible then for natural selection to have favoured genes that predispose us to this clearly very negative trait. This area has historically been dominated by the ‘thrifty gene’ hypothesis originally proposed by James V. Neel in 1962 (Neel, J. V. (1962). Diabetes mellitus a 'thrifty' genotype rendered detrimental by 'progress'? American Journal of Human Genetics 14, 352-353).

Neel suggested that the solution to the conundrum was that in our ancient history genes which enabled us to get fat were advantageous because they facilitated the deposition of fat during periods between periodic famines. Individuals that had such genes and were fat had sufficient energy resources to survive the famines, and therefore passed their fat deposition genes (so called ‘thrifty genes’) to their offspring. In modern society however these genes become disadvantageous because they prepare us for a famine that never comes and the result is widespread obesity and its associated co-morbidities. The ‘thrifty gene’ hypothesis has been widely reiterated in many recent publications as a key factor causing obesity.

The thrifty gene idea however has several fundamental flaws. These include:

  1. Famines are too infrequent, have acted for too short a time period and involve insufficient mortality to select for genes that predispose for obesity.
  2. There is no evidence that fat people survive famines better than lean people, and in fact mortality actually falls mostly on groups such as the very young and very old where differential mortality in relation to body composition is very unlikely.
  3. Observations of modern hunter-gatherer populations do not indicate that in periods between famines they fatten up – and hence suggests they have not inherited thrifty genes.

 Our ideas in this area have grown out of studies we made between 2000 and 2005 on the regulation of body weight in small wild mammals – particularly voles. This work has led us to question the thrifty gene hypothesis and develop a completely novel hypothesis based around the idea that early humans were under tremendous predation pressure. This probably meant that like modern small animals ancestral humans (Australopithecines) probably had a body weight regulation system that prevented the animals becoming too thin to avoid starvation risk, but also prevented them becoming too fat to avoid predation risk. The environment occupied by early hominids changed dramtically about 2 million years ago with the emergence of Homo erectus. Homo erectus was social, invented fire and weaponry. These three factors removed the predation risk, allowing the genes regulating the upper limits of our body weight to randomly drift – the ‘Drifty gene’ hypothesis.

More recently our work in this area has included investigations of mouse and human genetics, including the functional effects of polymorphic variation in the FTO gene, and the role of assortative mating in the epidemic.

Publications in this area

Pdfs for most of the papers in this and following sections are available for free download here

Thrifty and drifty genes – the predation release hypothesis

  • SPEAKMAN, J.R. (2008)
    Thrifty genes for obesity and diabetes, an attractive but flawed idea and an alternative scenario: the ‘drifty gene’ hypothesis.
    International Journal of Obesity 32: 1611-1617
    This paper was an invited perspective following the presidential lecture/debate presented at the Obesity Society annual meeting in New Orleans during November 2007. A sister paper by Andrew Prentice and colleagues which presents a view defending the Thrifty gene idea is published adjacent to this manuscript in the journal.
    see Prentice AM, Hennig BJ, Fulford AJ. (2008) Evolutionary origins of the obesity epidemic: natural selection of thrifty genes or genetic drift following predation release? Int J Obes (Lond). 32: 1606-1610
  • SPEAKMAN, J.R. (2007)
    A novel non-adaptive scenario explaining the genetic pre-disposition to obesity: the ‘predation release’ hypothesis.
    CELL metabolism 6: 5-11
    This paper was the most downloaded paper at Cell metabolism during July 2007 and the second most downloaded paper during August 2007.
    The paper was recommended at Faculty 1000 Biology by Andries Karlsbeek on August 16th 2007 graded 6.0 as a ‘Must read’. See review here
  • SPEAKMAN, J.R. (2006)
    Gene environment interactions and the origin of the modern obesity epidemic: a novel ‘non- adaptive’ scenario. In T.C. Kirkman, and S.J. Cooper, (Eds) Appetite and body weight:integrative systems and the development of anti-obesity drugs. Elsevier New York
  • SPEAKMAN, J.R. (2006)
    The genetics of obesity: five fundamental problems with the famine hypothesis.
    In G. Fantuzzi, and T. Mazzone, (Eds) Adipose tissue and adipokines in health and disease Humana Press New York
  • SPEAKMAN, J.R. (2006)
    Thrifty genes for obesity and the metabolic syndrome – time to call off the search?
    Diabetes and vascular disease research 3:
  • SPEAKMAN, J.R. (2004)
    Obesity: the integrated roles of environment and genetics.
    Journal of Nutrition.134: 2090-2105S
  • SPEAKMAN, J.R., Stubbs, R.J. and Mercer, J.G. (2002)
    Does body weight play a role in the regulation of food intake?
    Proceedings of the Nutrition Society 61: 473-487

Mouse genetics

  • Rance, K.A., Hambly, C., Dalgleish, D., Fustin, J.M., Bünger, L., and SPEAKMAN, J.R.
    (2007)
    Quantitative Trait Loci for total and regional adiposity in mouse lines divergently selected for food intake
    Obesity 15: 2994-3004.
  • Rance, K.A., Fustin, J.M., Dalgleish, G., Hambly, C., Bünger, L. and SPEAKMAN, J.R.
    (2005)
    A Paternally Imprinted QTL for Mature Body Mass on Mouse Chromosome 8
    Mammalian genome 16: 567-577

Human genetics

  • SPEAKMAN, J.R., Rance, K.A. and Johnstone, A.M. (2008)
    Polymorphisms of the FTO gene are associated with variation in energy intake but not energy expenditure.
    Obesity 16:1961-5
    This paper was the first human study to demonstrate an effect of the polymorphisms of the FTO on food intake.
  • Rance, K.A., Johnstone, A.M., Murison, S., Duncan, J.S., Wood, S.G., and SPEAKMAN,
    J.R. (2007)
    Circulating leptin levels are related to adiposity, age, sex and the A55V
    polymorphism of the UCP2 gene.
    International Journal of Obesity

Assortative mating

  • SPEAKMAN, J.R., Djafarian, K., Stewart, J. and Jackson, D.M. (2007)
    Assortative mating for obesity
    American Journal of Clinical Nutrition 86: 316-23

Assortative mating (AM) occurs when people mate together non-randomly with respect to a given biological or social trait. In this context of obesity risk it is important because the offspring of an obese x obese partnership received a double dose of obesity susceptibility genes.

AM is well known to occur for social factors such as race, religion, social and educational class and smoking habits, and biological factors such as age and height. Prior to our study it had been suggested that there was also assortative mating for obesity, but most of these studies were based only on BMI (Body mass index) and were often poorly controlled for co-variable traits such as social class and age. In our study we examined assortative mating in couples from north-east Scotland using dual energy x-ray absorptiometry (DXA) to objectively measure actual body fatness, and controlled our analysis for social and other factors. The work showed that obese people do indeed mate assortatively with other obese people.

Plump couple
From dailymail.com article reporting on our study

Theoretical models we have developed have shown that assortative mating cannot explain the whole epidemic but can make a substantial contribution to it.

Why assortative mating for obesity occurs is not yet clear. Current work in this area is being performed in collaboration with Dr Phillip Benson of the Dept of Psychology in Aberdeen. We are using software originally developed to assess self perception of body image to explore whether fat people have a tendency to rate other fat people as more physically attractive than lean people, and hence whether assortative mating results from mutual attraction. The alternative model is that people have a universal ideal of physical attractiveness, but choose their partners to match their own level of physical attractiveness to minimize infidelity risks. This has interesting implications for our notions of beauty and how physical attraction is related to evolutionary concepts such as fitness.

Do our ratings of physical attractiveness of potential partners depend on our own level of attractiveness? Is beauty really all in the eye of the beholder? If so does this individual conceptualisation of beauty drive assortative mating for obesity? Or are there universal ideals of beauty and attractiveness?

Regulation of body weight and adiposity in small wild rodents

  • Tidhar, W.L., Bonier, F., and SPEAKMAN, J.R. (2007)
    Sex- and concentration-dependent effects of predator feces on seasonal regulation of body mass in the bank vole Clethrionomys glareolus
    Hormones and Behaviour
    52: 436-444.
  • Król, E., Tups, A., Archer, Z.A., Ross, A.W., Moar, K.M., Bell, L.M., Duncan, J.S., Mayer, C., Morgan, P.J., Mercer, J.G. and SPEAKMAN, J.R. (2007)
    Altered Expression of SOCS3 in the Hypothalamic Arcuate Nucleus during Seasonal Body Mass Changes in the Field Vole, Microtus agrestis.
    Journal of Neuroendocrinology 19: 83-94
  • Krol, E. and SPEAKMAN, J.R. (2007)
    Regulation of body mass and adiposity in the field vole, Microtus agrestis: a model of
    leptin resistance
    Journal of Endocrinology 192: 271-278
  • Król, E., Duncan, J.S., Redman, P., Morgan, P.J., Mercer, J.G. and SPEAKMAN, J.R.
    (2005)
    Photoperiod regulates leptin sensitivity in field voles, Microtus agrestis
    Journal of Comparative Physiology B 176: 153-163
  • Król, E., Redman, P., Thomson, P.J., Williams, R., Mayer, C., Mercer, J.G., and
    SPEAKMAN, J.R. (2005)
    Effect of photoperiod on body mass, food intake and body composition in the field vole, Microtus agrestis
    Journal of Experimental Biology 208: 571-584
  • Peacock WL, Krol E, Moar KM, McLaren JS, Mercer JG & SPEAKMAN, J.R. (2003)
    Photoperiodic effects on body mass, energy balance and hypothalamic gene
    expression in the bank vole.
    Journal of Experimental Biology 207: 165-177
  • Peacock, W. and SPEAKMAN, J.R. (2001)
    Effect of high-fat diet on body mass and energy balance in the bank vole.
    Physiology and Behavior 74: 65-70.

B) Energy expenditure or food intake

Most researchers agree that obesity is a consequence of chronic energy imbalance. People either eat too much, expend too little, or do both. Debate about the causes of the obesity epidemic, and whether the blame is to lie with excessive consumption or slothfulness have tended to vary over time. However since the turn of the millennium there has been a broad consensus that food intake may actually have declined slightly since the 1980s, and the main problem is that this reduction in energy intake has been more than outstripped by a reduction in levels of physical activity. This opinion was dominated by the highly influential paper ‘Obesity: gluttony or sloth?’ published by Prentice and Jebb in the 1990s. Certainly there have been enormous changes in our physical activity behaviour patterns over time – including for example increases in computer use, sedentary occupations and television viewing. A key question is whether these changes have really had an impact on our levels of energy expenditure.

Is our increased sedentary lifestyle to blame for the obesity epidemic?

Our work in this area has involved studies of both animals and humans and has led us to reach the opposite conclusion that in fact changes in physical activity have not driven the obesity epidemic. Key observations in this area include our collaboration with Klaas Westerterp (right) from the University of Maastricht to show that our energy expenditure since the 1980s has been virtually constant (Westerterp and Speakman, 2008).

 

Our work suggests that increased intake of food seems more likely to have fuelled the obesity epidemic than reduced physical activity

In 2006 we initiated a project to explore the interactions between food intake, physical activity levels and various health markers in Scottish school children. This study is called the SLOSH study. SLOSH stands for Scottish Lifestyle Organised Sports and Health. 

In the SLOSH study we are looking at the behaviour and health of primary school children 

between the ages of 5 and 11. So far we have recruited about 300 children into this study.  

Publications in this area

Activity or food intake

  •  Jackson, D.M., Djafarian, K., Stewart, J., and SPEAKMAN, J.R. (2009)
    Increased TV viewing is associated with elevated body fatness but not lower energy expenditure.
    American Journal of Clinical Nutrition89: 1-6

    In this paper we showed that in pre-school children the more TV they watch the fatter they are. Figure shows body fatness (corrected for fat free mass) against time watching TV.

    However, TV viewing was NOT associated with differences in energy expenditure. Figure shows PAL (Physical activity level which is daily energy expenditure divided by Resting metabolic rate)
  • Westerterp, K.R. and SPEAKMAN, J.R. (2008)
    Physical activity energy expenditure has not declined since the 1980s and matches energy expenditure of wild mammals
    International Journal of Obesity 32:1256-63

    In this paper we showed by compiling measurements made using the DLW method that date back to the 1980s that energy expenditure on physical activity has been unchanged for the past 20 years or so.
  • Simončič, M., Horvat, S., Stevenson, P.L., Bünger, L., Holmes, M.C., Kenyon,C.J., SPEAKMAN, J.R. and Morton, N.M. (2008).
    Divergent physical activity and novel alternative responses to high fat feeding in polygenic fat and lean mice.
    Behaviour genetics 38: 292-300
  • Bünger, L., Forsting, J., McDonald, K.L., Horvat, S., Duncan, J., Hochscheid, S., Baile, C.A.,
    Hill, W.G. and SPEAKMAN, J.R. (2002)
    Long-term divergent selection on body fatness in mice indicates a regulation system that is independent of leptin production and reception
    FASEB J 16:U463-477

Causes and consequences of variation in RMR

  • Johnston, S.L., Erwin, S.S., Souter, D.M., Tolkamp, B.J., Gordon, I.J., Illius, A.W.,
    Kyriazakis, I. and SPEAKMAN, J.R (2007)
    intake compensates for resting metabolic rate variation in female C57BL/6J mice fed high-fat diets.
    Obesity 15: 600-606
  • Johnstone, A.M., Murison, S.D., Duncan, J.S., Rance, K.A. and SPEAKMAN, J.R (2005) Factors influencing variation in basal metabolic rate include fat-free mass, fat mass, age, and circulating thyroxine but not sex, circulating leptin, or triiodothyronine. American Journal of Clinical Nutrition.82: 941– 8.
  • Hambly, C., Adams, A.C., Fustin, J.M., Rance, K.A., Bünger, L. and SPEAKMAN, J.R.
    (2005).
    Mice with low metabolic rates are not susceptible to weight gain when fed a high fat diet.
    Obesity Research 13: 556-566
  • SPEAKMAN, J.R. and Selman, C. (2003)
    Physical activity and resting metabolic rate.
    Proceedings of the Nutrition Society 62: 621-634

C) Molecular regulation

Our understanding of the molecular basis of weight regulation has exploded over the past 15 years since the discovery of leptin (Zhang et al 1994: Nature). We now know that leptin interacts with many systems in the brain notably in the hypothalamus and brainstem. Our contributions in this area have been principally to explore the impact of various putative factors on regulation of body weight and food intake using the ICV infusion of target compounds into the brains of mice, or acute/chronic peripheral infusion of compounds, followed up by detailed exploration of the energy balance and food intake.

A typical example of our work is the study of galanin null mice (Adams et al 2008) where we used mice with global absence of galanin to show that galanin plays a critical role in the selection of fat in the diet. By repleting galanin direct into the brain of null mice we were able to reverse the fat avoidance phenotype.

Publications in this area

  • Adams, A.C., Wynick, D., Clapham, J.C. and SPEAKMAN, J.R. (2008)
    Feeding behavior in galanin knockout mice supports a role of galanin in fat intake and preference
    Journal of Neuroendocrinology 20: 199-206
  • Valle, A., Hoggard, N., Adams, A.C., Roca , P., and SPEAKMAN, J.R. (2008)
    Chronic central administration of apelin-13 over ten days increases food intake, body weight, locomotor activity and body temperature in C57BL/6 mice.
    Journal of Neuroendocrinology 20: 79-84.
  • Hoggard, N., Bashir, S., Cruickshank, M., Miller J.D.B. and SPEAKMAN, J.R.
    (2007)
    Expression of Neuromedin B in adipose tissue and its regulation by changes in energy
    balance.
    J. Mol. Neuroendocrinology 39: 199-210.
  • Claret, M., Smith, M.A., Batterham, R.L., Selman, C., Choudhury, A.I., Fryer, L.G.D.,
    Clements, M., Al-Qassab, H., Heffron, H., Xu, A.W., SPEAKMAN, J.R., Barsh, G.S., Viollet, B., Vaulont, S., Ashford, M.L.J., Carling, D. and Withers, D.J. (2007)
    AMPK is essential for energy homeostasis regulation and glucosesensing by POMC and AgRP Neurons.
    Journal of Clinical Investigation 117: 2325-2336
  • See also commentary on this paper “AMPing up” our understanding of the hypothalamic control of energy balance. By Kevin W. Williams, Roberto Coppari, and Joel K. Elmquist
    Journal of Clinical Investigation. 117: 2089-2092.
  • Choudhury, A.I., Heffron, H., Smith, M.A., Al-Qassab, H., Xu, A.W., Selman, C., Simmgen,
    M., Clements, M., Claret, M., MacColl, G., Hisadome, K., Diakonov, I., Moosajee, V., Bell, J.D., SPEAKMAN, J.R., Batterham, R.L., Barsh, G.S., Ashford, M.L.J. and Withers, D.J. (2005)
    The role of insulin receptor substrate 2 in hypothalamic and beta cell function
    Journal of Clinical Investigation 115: 940-950
  • Hoggard, N., Rayner, D.V., Johnston, S.L. and SPEAKMAN, J.R. (2004)
    Peripherally administered [Nle4, D-Phe7]-aMSH increases resting metabolic rate, while peripheral AgRP has no effect, in wild type C57BL/6 and ob/ob mice.
    Journal of Molecular Endocrinology 33: 693-703
  • Mercer, J.G. and SPEAKMAN, J.R. (2001)
    Hypothalamic neuropeptide mechanisms for regulating energy balance: from rodent models to human obesity.
    Neuroscience and Biobehavioral Reviews 25: 101-116.

D) Effects of dietary restriction and compensation

Dieting – reducing the intake of calories below energy demands, is the most frequent self- and physician prescribed treatment for obesity. Diets work in the short term, but in the long term they tend to be unsuccessful, because people are generally unable to maintain their restricted intake. We are looking at the factors that drive the propensity to eat and to break diets with a view to the development of pharmaceuticals that may assist people to use dieting successfully.

Publications in this area

  • Hambly, C., Mercer, J.G. and SPEAKMAN, J.R. (2007)
    Hunger does not diminish over time in mice under protracted caloric restriction.
    Rejuvenation Research 10: 533-540.
  • Hambly, C., Simpson, C.A., McIntosh, S., Duncan, J., Dalgleish G.D., and SPEAKMAN, J.R. (2007)
    Calorie-restricted mice that binge show less ability to compensate for reduced energy
    intake Physiology and Behaviour 95: 982-992.
  • Hambly, C.and SPEAKMAN, J.R. (2005)
    Contribution of different mechanisms to compensation for energy restriction in the
    mouse. Obesity Research 13: 1548-1557

Methodology development

In addition to our work on the development of the doubly-labelled water technique (see the DLW resource centre) we have also worked extensively on method development for other components of energy balance and body composition, in both animals and humans.

Publications in this area

Food intake

  • Fyfe, C.L., Stewart, J., Murison, S.D., Jackson, D.M., Rance, K., SPEAKMAN, J.R.,
    Horgan, G.W. and Johnstone, A.M. (2009: in press)
    Measuring food intake in free-living subjects - when to record and for how long?
    Public Health Nutrition

Body composition

  • Tidhar, W.L. and SPEAKMAN, J.R. (2008: in press)
    An evaluation of four non-destructive methods for predicting body composition of a small rodent.
    International Journal of Body Composition Research
  • Visockiene, Z., Johnstone, A.M., SPEAKMAN, J.R. and Broom, J.I. (2007)
    Body composition measurement in obese patients with and without type 2 diabetes:
    comparison of methods
    Acta medica Lithuanica14: 301-308
  • Johnston, S.L., Peacock, W.L., Bell, L.M., Lonchampt, M. and SPEAKMAN, J.R. (2005)
    PIXImus DXA with Different Software Need Individual Calibration to Accurately Predict Fat Mass
    Obesity Research 13: 1558-1565

Resting or basal metabolic rate

  • Jackson, D.M., Pace, L. and SPEAKMAN, J.R. (2007)
    The measurement of RMR in pre-school children.
    Obesity 15: 1930-1932

Diane jackson (right) performing mask respirometry on school child.

 

  • Johnstone, A.M., Rance, K.A., Murison, S.D., Duncan, J.S. and SPEAKMAN, J.R. (2006)
    Taking additional anthropometric measures may improve the predictability of Basal Metabolic Rate in adult subjects
    European Journal of Clinical Nutrition 60: 1437-1444.
  • Arch, J.R.S., Hislop, D., Wang, S.J.Y., and SPEAKMAN, J.R. (2006)
    Some mathematical and technical issues in the measurement and interpretation of open
    -circuit indirect calorimetry in small animals
    International Journal of Obesity 30: 1322-1331