Why Do We Get Fat?

Biology ︱ Professor John Speakman and Dr Sumei Hu

One version of this framework states that animals have certain protein demands they need to meet. Consequently, Why do we get fat? if the protein content of the diet Evidence from a large diet trial in mice decreases, the animal must eat more to reach its protein goal and this then leads to overconsumption of energy. This is Professor John Speakman, besity is a global health issue. intake drives weight gain, then decreased called the ‘protein leverage hypothesis’. who is a 1000 talents ‘A’ A World Health Organization fat intake will increase weight loss. Fast The Atkin’s and ketogenic diets may professor at the Chinese Oreport in 2014 estimated there forward several years, into the 1980s and work because they provide high amounts Academy of Sciences, Institute were 1.9 billion overweight adults in the 90s, and the main culprit was claimed to of protein that mean individuals stop of Genetics and Developmental world, with 600 million of those having be refined carbohydrates and hence diets consuming food before their energy Biology,Beijing and a Professor obesity. It is well known that having focussing on fibre and low glycaemic requirements are met. An alternative at the University of Aberdeen, obesity is strongly associated with many index foods became the most popular idea is the energy regulation model. In UK, is interested in factors other health risks, such as cardiovascular methods to reverse obesity. Then in the this case, the suggestion is that animals Speakman (seated centre) with some of the research team that performed the large mouse diet study. controlling energy balance problems, type 2 diabetes and some new millennium, there was a shift back to eat primarily to meet their energy and in particular which aspects forms of cancer. high-fat diets, before the more recent rise demands. If the protein content of the The group made over 100,000 body intake for the mice on a 5% protein of diet have the biggest of the anti-carb movement and ‘ketogenic’ diet decreases, as long as the diet meets weight and food intake measurements diet at both high and low-fat contents, influence on weight gain Despite the ever-increasing number diets. This latter movement has revolved their energy demands, they will not over- and measured the fat levels of the mice this did not directly translate to weight and obesity. His recent work of people now living with obesity, there around the so-called ‘carbohydrate-insulin’ consume food but may risk ingesting using a micro MRI machine. They also gain. On the high-fat diet, body weight involved a study using over is still much that remains unknown. model of energy balance which suggested insufficient protein. investigated gene expression in adipose and adiposity (obesity) increased, 1000 mice and 100,000 body For example, which foods contribute that carbohydrates in the diet generate (fat) tissue and in a region of the brain regardless of the protein content of weight measurements and the most to weight gain and which a surge of insulin which promotes fat OF MICE AND MEN associated with control of food intake the diet. Hypothalamic hunger pathways, showed that fat, not protein or One major issue is how to test between and metabolism, the hypothalamus. which regulate appetite and energy carbohydrate, causes increased these different hypotheses. Whilst usage, were unresponsive to dietary weight gain in mice. If these data are translatable to humans, the ideal scenario to study which diet EXPERIMENT 1 protein content. Overall, there was is most likely to lead to obesity would The mice were fed either a diet with no impact of the protein content of recommendations for preventing weight be a definitive randomised controlled varying protein levels and a high-fat the diet on weight gain, apart from gain from a lean starting point would be to trial, this is never going to become reality. content or a diet with varying protein in one mouse strain, and even there levels and a low-fat content. Although the effect was small. These data did not eat a lower fat diet (<20% fat by calories). Firstly, ethical permission to do this on there was a slight increase in energy support the ‘protein-leverage’ hypothesis. human subjects would not be granted. foods are protective is still a matter storage and further calorie intake. Today, It would never be an option to expose BODY WEIGHTS (G) of considerable dispute and debate. many diets seem to focus also on protein people to diets which would give them intake, inferring that a high protein obesity and hence compromise their Professor John Speakman, from the diet may be protective against hunger health. Secondly, it would be extremely Chinese Academy of Sciences, wants and weight gain. challenging to persuade people to to understand which dietary components volunteer for a study which involved being contribute most to weight gain. One It is generally accepted that obesity kept in confinement and eating only argument is that high-fat diets cause cannot happen without a positive energy one type of food for several years. weight gain and hence low-fat diets balance, i.e. more calories entering might reverse this process. This the body than are being used up. Therefore, Professor Speakman and his was challenged in the 1970s However, understanding that it is due group set out to do what turned out to by the emergence of the to positive energy balance is insufficient be one of the biggest studies in mouse Atkins Diet, which suggested to explain the phenomenon. We need nutrition for at least 50 years. They used that carbohydrates may to understand the exact mechanisms over 1000 mice, comprising of 5 different drive weight gain and that that lead to excess energy consumption. strains, and exposed them to 29 different consequently, weight loss This is still under debate. The ‘nutritional diets, which varied in their protein, fat may be best induced through geometry’ approach aims to provide and carbohydrate content. The protein increasing fat and protein a macronutrient framework, where content varied from 5% to 30% with fixed intake. However, the processes nutritional behaviour can be understood fat content (experiment 1), fat content of weight gain and weight loss as animals trying to reach optimum varied from 8.3% to 80% with fixed DAY ON DIET are not always symmetrical, nutritional targets that have been protein content (experiment 2), and the i.e. it is not necessarily the defined by evolution, for example, sucrose (sugar) content varied from 5% The patterns of change in body weight of one of the mouse strains on the 24 different diets. Although the mice start with similar weights there is an enormous difference in how much weight they gain over case that if increased fat the energy demands required to 30% with fixed fat (high) and protein the 90-day long experiment, with some diets causing virtually no weight gain but others causing the for reproduction or hibernation. contents (experiment 3). mice to increase by 50%.

www.researchfeatures.com BODY FATNESS RESPONSES OF C57BL/6 MICE TO CHANGES IN CARBOHYDRATES AND FAT IN THEIR DIETS. Behind the Research

Professor John Dr Sumei Hu Speakman Body Fat (proportion) Fat Body Body Fat Content (p)

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Outcome 1: Mice were thinner when they had more carbohydrate Outcome 2: The fat content of the diet was the major driver of body fatness. in their diets. Fatness reached a peak when the fat content was between 40 and 60%. Research Objectives References EXPERIMENT 2 A World Health Organization report in Professor Speakman’s work at the Chinese Academy of Hu et al., Dietary Fat, but Not Protein or Carbohydrate, In the second part of the study, mice Sciences and the University of Aberdeen focuses on energy Regulates Energy Intake and Causes Adiposity in Mice, Cell were fed either a diet with 10% protein 2014 estimated there were 1.9 billion balance, including food intake and energy expenditure, Metabolism (2018) 28: 415-431, https://doi.org/10.1016/j. cmet.2018.06.010 and varying fat content or 25% protein and the consequence of dysregulation of this balance and varying fat content. Fat intake overweight adults in the world, with 600 on obesity. John Speakman’s research page. Available at https://www.abdn. and hence energy intake was related million of those having obesity. ac.uk/energetics-research/speakman/ [accessed 30th July 2018]. to increasing fat content in the diet, regardless of the protein content. The no upregulation of white adipose tissue diets on subjects which began the trial Detail body weights increased as fat in the diet browning, a mechanism by which already obese. Furthermore, in this John Speakman Personal Response increased to 50-60%, but then the mice animals may avoid obesity by burning particular study, the sugar in the diet Institute of Biological and Environmental Sciences, consuming higher levels of fat in their diet off excess energy. was administered in the food rather than University of Aberdeen The obvious question is ‘what next’? Will you go on to actually put on slightly less weight than via the drinking water. There is some Zoology building, Tillydrone Ave, try and validate these findings in people, or will you do those with the 50-60% diet, potentially EXPERIMENT 3 evidence from previous studies that this Aberdeen, further animal work to provide additional support for suggesting that there is a maximum Increasing sucrose levels in the diet route of consumption of sucrose may AB24 2TZ, Scotland. your conclusions? weight gain resulting from fat in the diet. showed no effect on food intake or affect weight gain. Although this was a massive study comprising about five Interestingly, increased physical activity obesity, energy intake remained constant, Sumei Hu years worth of work and a team of about 20 people, at the was observed in the mice fed on a 10% with no significant differences observed The conclusions of Speakman’s work State Key Laboratory of Molecular Developmental Biology end of the day, in many respects it is woefully incomplete. protein, lower fat diet compared to the between the varying levels of sucrose. appear contradictory to previous studies Institute of Genetics and Developmental Biology We only used one mix of fats, one type of protein and one mice fed on a 10% protein, higher fat This may have been because the other of the protein leverage hypothesis across Chinese Academy of Sciences mode of delivery. Plus, we were only able to study male mice of one age. Most scientists who recognise the effort that diet. The pattern of the effect of dietary carbohydrate components were already a wide range of species. However, how 1 beichen xilu, Chaoyang, Beijing 100101, went into the study have made very positive comments about fat was replicated in all five mouse strains; what would be regarded as refined – like protein leverage is calculated is critically People’s Republic of China its contribution. In contrast, most members of the general dietary fat regulates energy intake and corn starch and maltodextrose. important. In the paper, a method is public who have encountered the study in news articles have adiposity, even in mouse strains normally developed to calculate the magnitude Bio responded very negatively – asking why we didn’t test this considered ‘obesity-resistant’; although CONCLUSIONS AND LIMITATIONS of protein leverage and in these mice, John Speakman has been at the Chinese Academy of that and the other. This really highlights the complexity of the the absolute levels of fat gain did differ If the data are translatable to humans, it varied between 0 and 11%. Although Sciences as a 1000 Talents professor since 2011. He is a Fellow nutrition problem. To answer all these details we would need between the strains. recommendations for maintaining a previous studies of mice have claimed of the Royal Society, the Academy of Medical Sciences and to study millions of mice – and even then, one could argue healthy weight should advocate a lower that intake and adiposity were driven the Royal Society of Edinburgh that the findings are irrelevant (as many of the general public have done) because mice are not little humans. However, The study also showed that in the fat diet. However, the extent to which by protein leverage when the data from despite these problems, I think probably the largest gap hypothalamus the dopamine, opioid these findings will extrapolate to human these studies were recalculated they Funding to plug is to see what happens in female mice and serotonin pathways were all health is unclear. Professor Speakman gave the same answers as the current Chinese Academy of Sciences of the same age. stimulated by fat intake. These pathways thinks that because mice and humans study. Protein leverage doesn’t seem are involved in hunger signalling and share many things in common the to be important in mice – but still could Collaborators food reward. It appeared that when big picture might remain the same, but be in other species (including humans). • Some studies were conducted in collaboration with the diet contained more fat the mice the smaller details may not. The study Quansheng Liu and the team at the Guangdong Institute of found it rewarding to eat and hence also only included male mice of a specific Despite the limitations, Speakman Applied Biological Resources, Guangzhou. they over-consumed it. Interestingly age, whereas female mice or older/ and colleagues’ work adds valuable • Sumei Hu, a post-doc in Professor Speakman’s group at the the actual weight of food consumed younger mice may respond to different information to what is already known Chinese Academy of Sciences, was involved in the analysis on the high-fat diets was lower but this diets in alternative ways. The mice used about the relationships between nutrients of the data on energy intake and body composition in mice. wasn’t enough to compensate for its in the study were naturally lean to begin and body composition in a way that She has also investigated lifestyle and genetic factors which greater energy density. Measurements with leaving the door open for future would be impossible to achieve in studies predispose individuals to being lean. She is first author on of gene expression in fat tissue showed studies to look at the impact of these of human nutrition. the publication concerning this work in Cell metabolism.