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Overview

Scientific discussion meeting organised by Professor John R Speakman FMedSci FRS, Professor Thorkild IA Sørensen, Dr Kevin D Hall and Professor David B Allison.

Obesity has been described by the WHO as the largest health threat facing mankind. Obesity is manifestly an issue of energy balance. Yet, there is surprisingly little consensus about why such energy imbalance develops. This meeting will include presentations by world experts on the plethora of ideas about the mechanisms underlying obesity, and hence how we may tackle it.

The schedule of talks and speaker biographies are available below. Speaker abstracts are also available below. Meeting papers will be published in a future issue of Philosophical Transactions of the Royal Society B

Attending this event

This meeting is intended for researchers in relevant fields.

  • Free to attend
  • Both in person and online attendance will be available
  • Limited places, advance registration essential

Enquiries: contact the Scientific Programmes team

Organisers

Schedule


Chair

09:00-09:10
Welcome and introduction
09:10-09:25
The genetic subtyping of obesity

Abstract

Obesity is a multifactorial disease, resulting from an intricate interplay between genetic and environmental factors. Yet, it is defined by a simple metric; ie a body mass index (BMI) of 30 kg/m2 or more. Because of the simplicity of this metric, it is no surprise that obesity is a heterogenous condition. Two individuals that have obesity may differ in the underlying causes of their weight gain. They may also differ in the presentation of disease, its prognosis, the complications, and the response to treatment. To account for this heterogeneity, there is a growing interest to subclassify obesity in smaller, more homogenous subtypes.

So far, subclassifications have been predominantly performed based on clinical features in individuals that have obesity (ie phenotypic subclassification). With the increasing number of genetic variants associated with obesity, genetic subclassification has become possible. A key advantage of subclassifications that are based on genetic variants is that they may reveal new insights in the etiology of the disease and its subtypes. In addition, genetic subclassification can be done early on in life, before the onset of disease, allowing for a timely prevention.

Professor Loos will review various approaches to implement genetic information in the subclassification of obesity and will discuss how these subtypes may help reveal new biological pathways. A more precise diagnosis is key to more precise prevention and treatment strategies tailored to the specific subtype, more precise prediction of the obesity subtypes, and more precise prognosis.

Speakers

09:25-09:40
Discussion
09:40-09:55
Insights from the genetics of obesity and thinness

Abstract

Family, twin and adoption studies have consistently shown that body weight is a highly heritable trait. Genome wide association studies have identified hundreds of genetic regions or loci containing common variants which are associated with increased body mass index (BMI) or obesity in multiple populations. In addition, disruption of a single gene is sufficient to cause severe obesity which can present in childhood. The discovery and characterization of these monogenic obesity syndromes in mice and humans has paved the way for understanding the molecular framework which underpins appetite and weight regulation by establishing a key role for the leptin-melanocortin pathway. Several of these disorders can now be treated with rational mechanism based therapies. Genetic factors also contribute to protection from obesity and persistent thinness. New genetic discoveries continue to provide insights into the mechanisms which couple weight regulation to other aspects of physiology and behaviour and reveal molecular targets for weight loss therapy.

Speakers

09:55-10:10
Discussion
10:10-10:25
Genetic variants and human diseases: lessons from FTO

Abstract

Genetic variants associated with complex traits are often in noncoding sequences. Translating these association studies to mechanistic insights into disease has lagged behind. Challenges for the functional follow up of GWAS include: 1) identifying causal variants; 2) establishing the regulatory potential of causal variants; 3) assigning target gene(s); 4) characterizing the phenotypic impact of the variants. The group has developed a comprehensive pipeline to functionally follow up on GWAS signals and used it to dissect loci associated with metabolic traits. Insights from these studies include: 1) the target genes of genetic associations are often far from the causal variants; 2) several variants may contribute to the association on a given locus; 3) multiple regulatory elements harboring variants in a locus may be associated with a trait; 4) these regulatory elements have complex spatial and temporal specificities; 5) multiple genes are often targeted by a single regulatory variant. In this talk Professor Nóbrega will discuss some of the lessons that they learned by dissecting the strongest genetic association with polygenic human obesity, within the gene FTO. Their data posit that the genetic architecture of complex traits may be significantly more complex than previously anticipated, involving pleiotropism, allelic heterogeneity and temporal-specific phenotypic effects of genetic variants.

Speakers

10:25-10:40
Discussion
10:40-11:00
Coffee
11:00-11:15
Body weight regulation from Lavoisier to control theory

Abstract

Animal energetics began in 1780, when Antoine Lavoisier and Pierre-Simon Laplace, using an apparatus combining direct and indirect calorimetry, discovered that respiration and combustion are quantitatively identical oxidative processes. By the mid-19th century it was realized that oxidation and physical activity were forms of a conserved quantity, energy. This permitted the (much later) formulation of the energy balance equation: energy stored = energy intake – energy expenditure.

Claude Bernard and Walter Cannon developed the concept of homeostasis, that animals actively preserve or regulate many characteristics of the cellular environment within narrow limits despite changes in the outer world. Application of this concept to energy exchange developed slowly. John Brobeck (1948) first reviewed food intake, physical activity, heat loss, and weight change as interconnected variables, but did not argue for regulation. Gordon Kennedy (1951) found that “the young rat adjusts its food intake so precisely to its energy needs that its fat stores remain almost constant” – organismic energy homeostasis. A similar regulatory mechanism exists in humans.

In 1868 James Clerk Maxwell published a mathematical analysis of the dynamics of the centrifugal governor that regulated the speed of James Watt’s steam engine. This began negative-feedback control theory. In control-theory models of weight regulation, changes in adipose-tissue mass (the regulated variable) are sensed (negative feedback), activating compensatory control responses that oppose the changes; the strength of these responses (feedback gain) typically determines the dynamics and precision of regulation. Such models can provide useful insights into human weight regulation.

Speakers

11:15-11:30
Discussion
11:30-11:45
Adipocyte and lipid turnover in human adipose tissue

Abstract

Obesity, defined as an excessive accumulation of body fat, is considered one of the major health challenges facing the world today. White adipose tissue (WAT) mass is determined by the synthesis and removal (ie turnover) of adipocytes and triglycerides. Using a radiocarbon dating strategy the group has shown previously that approximately 10% of subcutaneous abdominal adipocytes are renewed each year throughout adult life. Using the same strategy to measure triglyceride age, they reveal changes in lipid turnover in association with person age, body fat distribution and disease. What has been learned about fat cell and lipid turnover from radiocarbon dating studies, as well as new data on fat cell turnover in omental versus subcutaneous WAT, will be discussed. To explore the implication of these results on the wider issues of energy balance, the group uses a computational model built from an energy-based model (EBM, Hall et al. 2011), which they augment to include physiological regulation as proposed in the carbohydrate-insulin model (CIM, Ludwig et al. 2021), and lipid turnover dynamics. This computational approach will be used to investigate how lipid turnover sets limits on energy partitioning.

Speakers

11:45-12:00
Discussion
12:00-12:15
A unifying pathway for obesity mediated by fructose metabolism

Abstract

Fructose is a unique nutrient that when metabolized by fructokinase C (KHK) activates an energy depletion pathway that resets ATP levels to a lower intracellular level. This process is mediated by an acute consumption, followed by a removal of the AMP substrate by AMP deaminase, with the generation of intracellular uric acid that induces mitochondrial oxidative stress that reduces ATP production coupled with further blockade of ATP by inhibition of AMP-activated protein kinase. This sets off an ‘alarm signal’ that triggers a survival response in which food and water intake are stimulated, calories are preferentially stored, insulin resistance is induced to reduce energy needs, and circulation and excretion are facilitated by increases in systemic and glomerular hydrostatic pressures, respectively. The mechanism stimulating fructose intake includes taste, palatability and craving, but the critical factor driving excess food intake is leptin resistance. Indeed, increased energy intake is primarily responsible for weight gain and reduced energy metabolism plays a minor role. However, other metabolic effects of fructose, such as its ability to induce insulin resistance, hypertriglyceridemia, hypertension and fatty liver occur independently of excessive calories. Fat has a critical role in the process by being the primary food driving weight gain, but only if leptin resistance from fructose is present. While much of the fructose is from the diet, fructose is also generated in the body in response to high glycemic carbs and salty foods, and some umami foods can also activate the survival switch distal to fructose. Indeed, studies suggest a major role for high glycemic carbs in initiating the switch, while fat is a driver of the obese response. Another factor that has not been recognized until recently is the key role of salt in activating the switch, and the critical role for vasopressin in driving obesity through the V1b receptor. Furthermore, several thrifty genes have been identified that can explain why humans are so sensitive to fructose. Finally, new studies suggest that the endogenous fructose pathway may have a critical role in other conditions, including heart disease, obesity-associated cancer, behavioral disorders and dementia. Ultimately, the fructose pathway appears to have a central role in biology and may help explain many of today’s burden-of-life diseases. It also bridges most of the current hypotheses on obesity.

Speakers

12:15-12:30
Discussion

Chair

13:30-13:45
Sex hormones impact ALL aspects of metabolism

Abstract

Oestrogens regulate key features of metabolism including food intake, body weight, energy expenditure, insulin sensitivity, leptin sensitivity, and body fat distribution. The metabolic impact of excess body weight is correlated with the location of fat deposition. The abdominal (visceral) fat depot correlates with diseases associated with obesity while fat deposition in the subcutaneous (SC) depot, by comparison, is relatively benign. Of particular interest is the observation that distribution of body fat varies greatly between men and women. On average, women carry more fat in the SC depot; whereas, men carry more fat abdominally. Hence, there are sex differences with regard to obesity-associated health risks, men being more likely to develop cardiovascular disease, diabetes, and other obesity-related disorders. Given the sexual dimorphism in body fat distribution and co-morbidities, it is likely the mechanisms that regulate body fat compartmentalization are controlled by sex hormones. The group and others have generated data indicating oestrogen receptors (ERs) in the central nervous system (CNS) and directly on adipocytes play important roles in determining fat distribution. Importantly, sympathetic nervous system (SNS) activity has been implicated as a key determinant in body fat deposition. There are two ‘classical’ oestrogen receptors (ERs): oestrogen receptor alpha (ERS1) and oestrogen receptor beta (ERS2). Data further implicate ERS1 in specific postganglionic neurons innervating visceral and SC fat depots is distinct, suggestive of neuroanatomical differences in the regulation of fat compartmentalization populations as being critical for regulating body fat distribution and adipose tissue function. This presentation will focus on how oestrogens regulate the trafficking of sympathetic outflow between fat depots, as well as mechanisms underlying divergent SNS circuits from brain to adipose tissues.

Speakers

13:45-14:00
Discussion
14:00-14:15
Is there a role for higher cognitive functions in the development of obesity?

Abstract

Cognition underpins the flexibility of human eating and disruption to higher cognitive processes, such as inhibitory control and memory, can result in increased food intake, which in the long term could result in weight gain. The aim of this presentation is to provide an overview of the current evidence on the role higher cognitive processes in the development of obesity.  Evidence from meta-analyses supports the suggestion that cognitive function is cross-sectionally associated with obesity even when controlling for a range of confounding variables. However, this association could be explained by reverse causality because there is also evidence that metabolic syndrome and a history of excess western diet consumption alters brain structure and cognitive function. Emerging longitudinal data from large childhood cohorts support a causal effect of cognition on the development of obesity but the effect sizes are small and data is currently lacking on the mechanisms that link cognitive process to specific styles or patterns of consumption and subsequent weight gain. It is concluded that higher cognitive functions likely contribute to development of obesity but exactly how, for whom, and the relative importance of the causal association remain to be determined.

Speakers

14:15-14:30
Discussion
14:30-14:45
High-fat/high-sugar diets rewire dopamine circuits to impact behaviour before the onset of weight gain

Abstract

Adaptive behaviour depends on the capacity to accurately predict future events. It is well established that the neurotransmitter dopamine plays a critical role in optimizing adaptive behaviour by encoding prediction errors during associative learning. Accordingly genetic variations that influence dopamine signalling confer risk for disorders characterized by disturbances in adaptive behaviour such as obesity and substance abuse. There is now also clear evidence from animal models that a diet high in fat and sugar can lead to altered dopamine signalling, even in the absence of weight gain or metabolic dysfunction. Using a short-term dietary intervention protocol coupled with functional magnetic resonance imaging in healthy weight individuals, the group provide evidence that such effects translate to humans. They also extend work in animals by showing that exposure to short term high-fat/high-sugar, energy-dense foods impacts dopamine-dependent prediction error encoding that underlies adaptive behaviour. Finally, using transgenic and viral-mediated strategies in the mouse model, they identify a candidate mechanism by which diet could alter dopamine signalling to impact behaviour and metabolism. Collectively, this work demonstrates that exposure to an energy-dense, high-fat/high-sugar diet in the absence of body weight or metabolic change, can rewire dopamine circuits to increase subsequent overeating and weight gain before the onset of changes in adiposity.

Speakers

14:45-15:00
Discussion
15:00-15:30
Tea
15:30-15:45
Obesity, mitochondrial energy efficiency and insulin secretion

Abstract

The increasing incidence of obesity correlates with insulin resistance, hyperlipidemia, fasting hyperinsulinemia, increasing consumption of highly processed food and potential environmental toxins such as plastics and air pollution. The sequence of appearance and causal relationship between the appearance of each of these potential causes of obesity and the onset of obesity has not been determined. The cause must precede obesity, the consequence, and temporally relate to its rising incidence in different populations. It is unlikely that macronutrients such as carbohydrates or fats cause obesity since these have long been constituents of the human diet. High carbohydrate diets have been common in warm to moderate climates, where agriculture thrives, and high fat diets, in cold climates. Furthermore, food consumption and body weight have been well-regulated in most humans and other species until recent times. Thus, our attention must focus on changes that have occurred in the last half-century and the relationship between such changes and specific populations that are impacted. The hypothesis presented here is that substances that have entered our bodies recently, cause obesity by generating false and misleading information about energy status. The group proposes that this is achieved through changes in the oxidation-reduction (redox) potential of circulating metabolites that are communicated throughout the body. Examples are provided of food additives that generate reactive oxygen species (ROS) and thereby elicit tissue specific functional changes that are inappropriate. Reversal requires the identification and removal of these compounds or preventions of their effects.

Speakers

15:45-16:00
Discussion
16:00-16:15
Leptin and a simple circuit regulating feeding

Abstract

Leptin is an adipose tissue hormone that maintains homeostatic control of adipose tissue mass. This endocrine system thus serves a critical evolutionary function by protecting individuals from the risks associated with being too thin (starvation) or too obese (predation). Mutations in leptin or its receptor cause massive obesity in mice and humans, and leptin can effectively treat obesity in leptin deficient patients. The identification of leptin has thus provided a framework for studying the regulation of feeding behavior and the pathogenesis of obesity.

While most obese patients have high endogenous levels of leptin indicating that they are leptin resistant, obese patients with low endogenous levels show robust weight loss with leptin treatment. Leptin also links changes in nutrition to adaptive responses in other physiologic systems with effects on insulin sensitivity, fertility, immune function and neuroendocrine function (among others). Leptin is an approved treatment for generalized lipodystrophy, a condition associated with severe diabetes, and has also shown promise for the treatment of other types of diabetes and for hypothalamic amenorrhea, an infertility syndrome in females. Studies of leptin gene regulation also suggest that leptin should be an effective treatment for the subset of obese patients with low endogenous levels of the hormone.

The identification of leptin has also advanced our understanding of the neural mechanisms that control feeding. Current research focuses on the function of specific neural populations in the hypothalamus and other brain regions to control feeding behaviour and energy balance. The role of these neural populations is being evaluated by identifying molecular markers for specific subpopulations, and evaluating the effect of modulating their activity. In other studies, the group is studying the transcriptional mechanisms that regulate leptin gene expression as well as the leptin-regulated neural circuits that regulate metabolism.

Speakers

16:15-16:30
Discussion
16:30-16:45
The gut-brain axis and the neural basis of sugar and fat preference

Abstract

Sugar and fat are essential nutrients. Therefore, it is expected that selective circuits be dedicated to seek, recognize and motivate their consumption. Professor Zuker will discuss the group's recent work on the neural basis of sugar and fat preference, and the gut-to-brain circuits driving their consumption, craving and appetite.

Speakers

16:45-17:00
Discussion

Chair

09:00-09:15
Competing obesity paradigms: the energy balance vs carbohydrate-insulin models

Abstract

Conventional treatment for obesity, based on the First Law of Thermodynamics, assumes that all calories are metabolically alike, and that to lose weight one must ultimately 'eat less and move more'. However, this prescription rarely succeeds over the long term. Calorie restriction elicits predictable biological responses, including increased hunger and reduced energy expenditure, that oppose ongoing weight loss. The carbohydrate-insulin model proposes a reversal in causal direction: overeating doesn’t drive body fat increase over the long term; instead, the process of storing excess body fat drives overeating. High intakes of processed carbohydrate raise the insulin-to-glucagon ratio and elicit other hormonal responses that shift energy partitioning toward storage in adipose, leaving fewer calories available for metabolically active and fuel sensing tissues. Consequently, hunger increases, and metabolic rate slows in the body’s attempt to conserve energy. A small shift in substrate partitioning favoring fat storage, as hypothesized by this model (10 – 20 kcal/d average), would account for the slow but progressive weight gain characteristic of common forms of obesity. From this perspective, the conventional calorie-restricted, low-fat diet amounts to symptomatic treatment, destined to fail for most people because it does not target the underlying predisposition toward excess fat deposition. A dietary strategy aiming to lower insulin secretion may increase the effectiveness of long-term weight management and chronic disease prevention.

Speakers

09:15-09:30
Discussion
09:30-09:45
Protein leverage and human obesity

Abstract

Global obesity has been driven principally by increasing consumption of fats and carbohydrates, with the relative contributions of each of these differing among populations. Meanwhile, protein intake has remained more stable and less variable, indicative of its intake being regulated and prioritized over other forms of energy intake, as has been demonstrated in a range of other animal species. This led us to propose that protein has the power to leverage food intake in humans and to drive increased energy intake and predispose to obesity when protein in the diet is diluted by non-protein energy, as has occurred throughout the development of the obesity epidemic with the incursion of industrially processed foods and beverages into the global food system. A specific appetite for protein is universal among animal species and the underlying mechanisms are being increasingly understood. Evidence from randomised clinical studies and from more realistic ecological settings indicate that protein prioritisation is a feature of human nutritional biology. The authors argue that the interaction between the strong human protein appetite and the changed food environment has been an important contributor to the obesity epidemic and may also explain a range of other phenomena in human nutritional biology and health.

Speakers

09:45-10:00
Discussion
10:00-10:15
Dietary fat, energy density and energy intake

Abstract

Absolute energy from fats and carbohydrates and the proportion of carbohydrates in the food supply have increased over 50 years.

Fat usually contributes more to dietary energy density (ED) than other macronutrients. Protein, carbohydrates and fat exert hierarchical effects on satiety in the order protein > carbohydrates > fat. When the ED of different foods is equalised, the differences between fat and carbohydrates are far more subtle. Experimental evidence for fat-specific effects on EI independent of ED, and of fat structure (chain length, esterification, saturation and novel structures) is fragmentary and limited. Such effects may be additive, synergistic or cancel each other out in the real world.

Experimentally increasing dietary ED with fat, carbohydrate and mixed macronutrients elevates EI, producing weight gain. Increased ED has a large effect on increasing EI; decreased ED, a more modest effect at decreasing longer-term EI. Human energy balance regulation appears more tolerant of positive than negative energy balances. In more naturalistic situations where learning cues are intact, there is more (albeit incomplete) compensation for elevated ED. There is considerable individual variability in response. Dietary ED is primarily driven by the water and fat content of foods. Food liking, wanting and learning are central factors shaping energy intake (EI). Foods containing mixtures of readily assimilated fats and carbohydrates and caloric beverages also elevate EI through hedonic and physiological mechanisms.

Effects of specific macronutrients (eg fat) on EI should be considered in the context of dietary ED, and how macronutrient combinations (especially fats and short-chain carbohydrates) in foods and drinks contribute to learned patterns of food selection determining EI.

Speakers

10:15-10:30
Discussion
10:30-11:00
Coffee
11:00-11:15
Do ultra-processed foods cause obesity?

Abstract

The substantial increase in obesity prevalence over the past half century is believed to be driven primarily by changes in the food environment. While some models of obesity focus on macronutrient content, a nutrition classification system called NOVA largely ignores nutrient content and instead categorizes foods according to their purpose and extent of processing, with the highest category labeled 'ultra-processed foods' (UPFs). UPFs are formulated using a series of industrial processes and include ingredients rarely used in home kitchens, or classes of additives whose function is to make the final product palatable or more appealing. UPFs are affordable, convenient, shelf stable, palatable, and highly marketed products that now represent more than 50% of the food supply in many industrialized countries. 

Observational studies have shown that increased availability and consumption of UPFs are associated with obesity, but randomized controlled trials have been lacking. The group completed an inpatient random order crossover study to investigate whether people eat more calories when exposed to a diet with >80% of calories from UPFs compared a diet without UPFs. The two test diets were matched for daily presented calories, sodium, sugar, carbohydrates, fat, fibre, glycemic load, and energy density. Participants were instructed to eat as much or as little as they wanted and consumed ~500 kcal/d more during the UPF diet period resulting in weight gain and body fat accumulation. These results suggest that UPFs cause excess energy intake and weight gain, although the mechanisms remain uncertain and will be the subject of future research.

Speakers

11:15-11:30
Discussion
11:30-12:30
Panel discussion

Speakers


Chair

13:30-13:45
FFM and RMR are strong determinants of energy intake: integration into a theory of appetite

Abstract

Any explanation of appetite control should contain a description of physiological processes that could contribute a drive to eat alongside those that inhibit eating. However such an undertaking was largely neglected until 15 years ago when a series of independent research programmes investigated the physiological roles of body composition and appetite. These outcomes demonstrated that FFM, but not FM, was positively associated with objectively measured meal sizes and daily EI. This relationship is extremely robust and has been replicated in more than 12 countries in diverse participant groups including new born babies and elderly adults. These findings have been accompanied by demonstrations that RMR (strongly influenced by FFM) is also positively associated with EI. Modelling work has confirmed that the influence of FFM is largely mediated by RMR. These findings reintroduce the role of drive into models of appetite control and indicate how this can be integrated with processes of inhibition. The determinants of EI fit into an evolutionary perspective in which the energy demands of HMROs and skeletal tissue constitute a need state underlying the drive to eat. Moreover this work has indicated both direct and indirect components of FM on EI. This approach should lead to the development of integrated models of appetite that include components of body composition (FFM) and energy expenditure (RMR) as tonic biological signals alongside traditional tonic inputs from adipose tissue and episodic signals from the GI tract.

Speakers

13:45-14:00
Discussion
14:00-14:15
Does eating less or exercising more to reduce energy availability produce distinct physiological responses?

Abstract

Both Jack and John wish to lose weight, and to achieve this they have two options: either increase energy expenditure or decrease energy intake. It is believed that one of the reasons weight loss is often hard to achieve and in particular maintain is because the body decreases cellular metabolism in response to the reduction in availability of endogenous energy. Is the metabolic response by the body to reduced energy availability the same or different depending on whether that reduced availability is caused by increased activity or decreased energy intake? Metabolism can be considered the result of the body’s many physiological processes; if Jack commits to losing weight by increasing his activity levels and John by decreasing his food intake, what metabolic and physiological differences would we observe between them after, say, 6 months?

This review, a work in progress when writing this abstract, will first address whether adaptive metabolic suppression really occurs. Beyond that, one approach to investigating potential differences in metabolic rate in response to reduced energy availability as a result of lowered food intake versus heightened activity is to compare the relationships between weight change and whole-body metabolic adaptation. For participants on lowered food intake, those exhibiting greater weight loss might exhibit greater metabolic suppression because weight loss drives metabolic adaptation. For participants on increased activity, those exhibiting greater weight loss might exhibit less metabolic suppression because those exhibiting greater metabolic suppression experience more of a limit on their weight loss. Professor Halsey reports on these findings gleaned from analysis of (relatively scant) data in the literature.

Speakers

14:15-14:30
Discussion
14:30-14:45
Paleolithic perspectives on human diet and cardiometabolic health

Abstract

Obesity is a modern pandemic caused by environmental changes in our recently industrialized environments. One approach toward identifying the most salient environmental factors is to work with extant hunter-gatherer and farming societies as case studies in non-industrial diet and lifestyle, and to interrogate the archaeological record to understand how humans lived in the deep past. Work with hunter-gatherers and farmers shows that bodyweight remains stable at healthy weights through adulthood, in contrast to steadily increasing bodyweight among industrialized societies. Daily energy expenditures are not elevated among hunter-gatherers and farmers, pointing to diet as the root cause of energy imbalance and obesity among industrialized countries.

Diets among hunter-gatherers and farmers, both today and in the archaeological record, are remarkably diverse across time and geography, challenging notions of any singular 'Paleo' or natural human diet. Further, carbohydrate intake among these groups is considerable, often higher than those of industrialized populations, challenging the hypothesis that carbohydrate intake underlies the modern obesity pandemic. Hunter-gatherer and farming societies typically eat foods that are less energy dense and contain more fibre than foods consumed in the industrialized world, and traditional diets are completely devoid of ultraprocessed foods that dominate diets in developed countries. These dietary changes, brought about through industrialization and the growth of mass produced, low cost, shelf-stable, and hyper-palatable foods, appear to contribute substantially to the obesity pandemic.

Speakers

14:45-15:00
Discussion
15:00-15:30
Tea
15:30-15:45
Direct weight sensing and regulation of body weight: the gravitostat

Abstract

Gravity is among the most important and well-studied phenomena in physics, including by a former President of the Royal Society (1703–1727), Sir Isaac Newton. Gravity affects all living organisms on planet earth. However, most articles on the biological consequences of gravity concern extreme conditions such as microgravity during space flights. Moreover, existing literature on biology and gravity on earth mostly concerns how to avoid the negative consequences of gravity. For instance, in land living animals, damages caused by falling are possible to avoid through physiological processes of proprioception and balance. Moreover, bone fracture may be avoided by developing stronger bone tissue. 

In 2018, the authors proposed that the size of land living animals is regulated by a homeostatic loop, coined the 'gravitostat' (PNAS, PMID: 29279372). They found that increased loading of mice and rats (achieved through the implantation of capsules of differing weights in the abdomen or subcutaneously), decreased the biological body weight and fat mass partly via reduced food intake. They found that the gravitostat mechanism acts independently of the well-established fat-derived hormone leptin. Of note, loading suppressed body fat was more effective in obese mice, while leptin was more effective in lean animals, consistent with the existence of dual intervention points. Knockdown of osteocytes prevented this regulation of body weight and body fat mass by loading, in line with a homeostatic weight sensing by weight bearing bones. 

They hypothesize a negative feedback system for regulation of body weight and fat mass that takes advantage of gravity, the gravitostat. 

Speakers

15:45-16:00
Discussion
16:00-16:15
Brown adipose tissue: does it keep you slim?

Abstract

The realization by Rothwell and Stock in 1979 that the heat production of brown adipose tissue could also be seen as a way of burning excess calories and thus counteracting the development of obesity has inspired a large interest in the possibility of activating brown adipose tissue in order to control body weight. The issues thus are whether this type of diet-induced thermogenesis really exists, whether (if it exists) it is mediated by brown adipose tissue and thus via UCP1, and whether the phenomenon would occur in humans. Initial studies of mice lacking UCP1 did not indicate any effect of its absence on obesity development. However, it was successively realized that any such metabolic effects would be overrun by enhanced metabolism for heat production in mice living under normal animal house conditions (ie in reality in constantly cold-stressed mice). Thus, when mice were instead examined at thermoneutral conditions, several laboratories reported clear although modest effects of the absence of UCP1: an increased adiposity. Correspondingly (although perhaps at first sight somewhat paradoxically) adiposity was associated with an increased amount of UCP1 (and when this UCP1 was omitted, the obesity was further pronounced). Although many studies have confirmed the existence of UCP1-mediated diet-induced thermogenesis, there are also now a series of investigations that cannot identify such a role. Though several of these perhaps can be 'explained' as being due to experimental details (single versus group holding, type of diet used, strain of mice), it is a disturbing issue if this potentially important process is easily overrun by small technical shifts in experimental conditions. Thus, the actual significance of UCP1 and diet-induced thermogenesis for obesity development is still unsettled.

Speakers

16:15-16:30
Discussion
16:30-16:45
Questioning the foundations of the gut microbiota and obesity

Abstract

The potential causal role of the gut microbiota in shaping body weight has become a prominent area of research and received significant public attention and funding. This was based largely on animal studies and has yet to translate into successful interventions in people; more recent attempts to do so have been unsuccessful. This talk will look at some key animal studies that initiated this area of research and whether later follow-up research supported earlier conclusions. In particular, this talk will examine the role of germ-free mice in both initiating interest in the function of the gut microbiota in body weight regulation and their role in determining cause and effect as a recipient in studies of microbiota transfers. This talk will then consider the outcomes of recent randomised controlled trials of microbiota transfer in human participants that have failed to show beneficial effects on body weight and whether this lack of effect could have been foreseen from pre-existing animal research. Dr Dalby will suggest that early studies on this subject were not considered critically enough and that this has led to an unfounded level of optimism about the role of the gut microbiota in shaping our body weight.

Speakers

16:45-17:00
Discussion

Chair

09:00-09:15
Early life impacts of maternal obesity: a window of opportunity to improve the health of two generations?

Abstract

Over half of women in the UK are overweight or obese during pregnancy. This is concerning as in addition to immediate detrimental consequences to mother and baby, children born to obese women are more likely to be obese and develop cardio-metabolic dysfunction. This transmission of poor cardio-metabolic health between mother and child is in part mediated by genetics and shared current environmental factors. However, evidence indicates that developing in utero in an obesogenic environment also impacts on long-term cardio-metabolic health. The strongest evidence from humans to support such a 'programmed' risk of cardio-metabolic disease comes from the study of siblings born before and after maternal bariatric surgery. These studies revealed that the sibling born after weight-loss surgery had reduced adiposity, lower blood pressure and increased insulin sensitivity compared to their sibling born prior to maternal weight-reducing surgery. The group used a mouse model of maternal diet-induced obesity to show that this relationship is causal and as a tool to define underlying mechanisms. Obese dams are insulin resistant and develop impaired glucose tolerance in late gestation. Their offspring develop insulin resistance, increased adiposity, cardiac dysfunction, hypertension and fatty liver and are more susceptible to diet-induced obesity. They identified maternal hyperinsulinaemia as a key programming factor that mediates effects of maternal obesity (independently of obesity per se) on long-term health of the offspring. These findings suggest that maternal insulin resistance may represent an important target of interventions to reduce the inter-generational transmission of poor cardio-metabolic health from mother to child.

Speakers

09:15-09:30
Discussion
09:30-09:45
Behavioural Susceptibility Theory: the role of appetite in rapid infant weight gain, obesity and eating disorders

Abstract

Rapid weight gain (RWG) during the first two years of life is a well-established risk factor for later obesity, yet its causes are poorly understood. Dr Llewellyn's group developed Behavioural Susceptibility Theory (BST), which hypothesises that infants who inherit a set of genes that confer greater responsiveness to food cues and lower sensitivity to satiety, are more susceptible to overeating and developing obesity, and that these processes begin soon after birth. In 2007, Gemini was established to test BST; it is the largest population-based twin birth cohort (n=4808) ever set up to study genetic and environmental influence on early growth. Gemini has demonstrated that variation in early appetite: (i) is highly stable and heritable; (ii) is associated with patterns of overconsumption; (iii) predicts prospective infant weight gain; and (iv) shares common genetic factors with weight. Other cohorts of children/adults have also shown that appetite is highly heritable and that BMI-related genetic variants are associated with appetite. More recently, they extended BST to study eating disorders (EDs); parallel analyses in Gemini and another large population-based cohort (Generation R) have both shown prospective associations between food cue responsiveness in early childhood and the onset of ED symptoms in adolescence. Together, these studies suggest that food cue responsiveness is an early marker of behavioural susceptibility to RWG, obesity and EDs. Parents are often blamed when their children develop health problems that are poorly understood, such as RWG. However, infants are not born on a ‘level playing field’; some have an avid appetite and are highly demanding with regard to milk feeds and, subsequently, food. Infants and toddlers with avid appetites present considerable feeding challenges for parents and may also be at increased risk of later problems including obesity and EDs.

Speakers

09:45-10:00
Discussion
10:00-10:15
Natural selection and human adiposity: crafty genotype, thrifty phenotype

Abstract

To date, genetic perspectives on obesity have focused on the heritability of body composition, and on identifying putative ‘obesity alleles’, namely those associated with variability in body mass index or markers of fat distribution. However, both absolute adiposity and its anatomical distribution change substantially through the life course, while also responding to diverse ecological stresses and stimuli. For example, the thrifty phenotype hypothesis emphasises that exposure to undernutrition in utero life may impact how the body responds to weight gain at later ages. Professor Wells suggests that selection has favoured a ‘crafty genotype’ in our species, namely a genetic basis for accommodating variability in the ‘fitness value’ of body fat depending on the endogenous and exogenous characteristics of each individual throughout the life course. This framework allows the thrifty phenotype hypothesis to be reconsidered, as a developmental strategy to reorganise the allocation of metabolic resources in ways that maximise survival and fitness. The thrifty phenotype reduces early investment in organ and muscle tissue, which has implications for longevity. If energy supply subsequently increases, it may be allocated disproportionately to earlier maturation, to reproduction in females, or to defence (promoting immune function) which may favour a more central fat distribution. These strategies may increase Darwinian fitness, but at a cost to longevity. This approach shifts attention from the notion of a ‘static’ predisposition to obesity, and instead highlights fitness-enhancing plastic responses as a key characteristic of our species. In turn, this helps understand the sensitivity of body fatness to environmental factors through the life course.

Speakers

10:15-10:30
Discussion
10:30-11:00
Coffee
11:00-11:15
Obesity and mental health

Abstract

The links between obesity and mental health have been contested for many decades. While most authorities argue that depression and anxiety are increased among individuals with obesity, another research tradition has championed the ‘jolly fat’ hypothesis which proposes that obesity is associated with better mental health. The causal sequence relating obesity and mental health has also been contested. Stress and depression may contribute to obesity risk, while individuals with obesity may experience increased distress, stimulated in part by stigma and discrimination. Methodological factors may account for some of these discrepancies, while cultural factors surrounding perceptions of higher body weight may also be relevant. The strongest evidence comes from large longitudinal population studies in which bidirectional associations can be tested. A recent investigation pooling more than 57,000 individuals from 15 population cohorts clearly showed positive associations between obesity and depressive symptoms, adjusting for demographic characteristics and chronic illness. In longitudinal analyses, obesity predicted future depressive symptoms but not vice versa. The relationships were strongest for a subset of depressive symptoms. It is likely that inflammatory pathways play an important role in these associations, with cytokines expressed by adipocytes having effects on the central nervous system. Shared genetic underpinning of obesity and depression, and other biological pathways such as cortisol dysregulation and comorbid physical illnesses may also be relevant. Teasing out these processes will promote a better understanding of aetiology, while the wellbeing of people with obesity will be enhanced by reducing weight stigma and avoiding weight shaming.

Speakers

11:15-11:30
Discussion
11:30-11:45
Obesity and environments external to the body

Abstract

Studies of environment and obesity usually use epidemiologically-tractable measures that are proxies for energy balance measures of intake and expenditure, including access to physical activity resources, walkability of neighbourhoods, geographic areas and access to healthy food. It is mostly to identify individual behavioural changes to prevent or reduce obesity rates, or to inform policy. Alternatively, environment and obesity research focusses on individual food consumption, the brain and the regulation of energy balance, usually with implicit goals of individual behavioural or biomedical interventions. Social, political and technological change has disrupted many of the traditional approaches to obesity and environment. Such change includes: new knowledge of how human microbiomes form an environment straddling the body internal and external; epigenetics that frame the foetus within an internal maternal bodily environment; the new sociality that Web 2.0 has created; and near-universal neoliberal political systems that promote individualism and competition but also generate increasing inequality, insecurity and stress. There are new environmental ways to produce obesity and to ameliorate it. This presentation examines the construct of ‘environment’, a western nineteenth century romantic individualist idea of humans in nature, in relation to obesity studies in the twenty-first century when most people in the world live in built contexts. It examines disruptions in environments external to the body (that is not the microbiome, not epigenetics) in relation to obesity production, focusing on built, food and social environments and their intersections.

Speakers

11:45-12:00
Discussion
12:00-12:15
Decoding weight gain defence mechanisms: a critical foundation for future obesity treatment

Abstract

There is evidence to suggest that body weight is biologically defended around an upper and a lower 'intervention point'. These boundaries reflect the respective levels of body weight at which physiological mechanisms are actively engaged to defend against excessive weight gain or weight loss and in between these two boundaries of adiposity, fat mass can fluctuate more 'passively' depending on socio-environmental factors and less so on physiological forces.

This model implies that individuals with a genetic predisposition to obesity are characterized by an elevated upper intervention point, thus explaining why they easily drift upwards in weight as a consequence of living in an obesogenic environment. During weight gain, the lower intervention point appears to drift upwards as well, ensuring fierce biological protection of fat mass, despite it being in excess. The fact that pathological levels of body fat are homeostatically protected, represents a primary obstacle for successful obesity treatment. This also explains why weight lost through lifestyle or drug interventions is typically regained over time. While the food intake promoting effect of reduced plasma leptin is a key mechanism that defends against weight loss, it is unknown what mechanisms mediate the protection against weight gain at the upper intervention point.

It is clear, however, that experimental overfeeding elicits a homeostatic response that effectively counteracts weight gain.  Uncovering the molecular mechanisms that mediate this response holds promise to fill a major knowledge gap in the science of energy homeostasis and is likely to provide inspiration for new anti-obesity agents.

Speakers

12:15-12:30
Discussion

Chair

13:30-13:45
Understanding the ‘food insecurity-obesity paradox’: evidence from humans and birds

Abstract

Food insecurity is a construct originally developed by social scientists that captures uncertainty about access to food and deficiencies in the quality and quantity of food consumed. While severe food insecurity leads to weight loss, mild to moderate food insecurity is associated with weight gain and obesity, a phenomenon referred to as the ‘food insecurity-obesity paradox’. In humans, food insecurity is also associated with greater chances of depression, communicable and non-communicable disease and shorter life span. Professor Bateson hypothesises that this suite of impacts is the output of biological mechanisms present in many vertebrate species that evolved as protection against starvation. While the association of food insecurity with obesity might seem paradoxical, there is a well-developed body of theory in evolutionary ecology showing that animals should increase body fat as insurance against starvation when access to food is unpredictable. In support of this insurance hypothesis the group has shown that experimentally exposing European starlings to limited and unpredictable food causes rapid weight gain. Intriguingly, the food insecure birds put on weight despite reduced overall food intake, suggesting increased energetic efficiency. Their work suggests that the birds achieve this via multiple mechanisms, including absorbing more energy from food, reducing energy expenditure and diverting energy from somatic maintenance and repair into building fat stores. Professor Bateson reviews evidence that food insecurity in humans also causes reductions in metabolic rate. She concludes that the increasing levels of food insecurity present in high-income countries are a likely contributory factor driving the human obesity epidemic and associated declines in health and wellbeing.

Speakers

13:45-14:00
Discussion
14:00-14:15
From the social life through the psyche and the brain to the epidemic expansion of the adipose mass

Abstract

Irrespective of the multifrequency, irregular fluctuation of homeostatically regulated energy balance, obesity may develop through a steady retainment of a tiny fraction of the energy intake (<1%) as fat in the adipose tissue, usually accompanied by growth of the metabolically active, hence energy demanding, lean body mass. Availability of the additional energy supplies by persisting abundance of food may be considered a permissive condition for the obesity epidemic, which then most often develops among people genetically predisposed and/or living under various social challenges. To synthesize this, Professor Sørensen proposes an evolutionary-based theory, claiming that human survival and reproduction depend on social abilities supporting collaboration in gathering and sharing of food, combined with anticipatory precautionary measures against failing supplies. It implies a body system, dependent on thousands of genes, that can sense and react to threats of future lack of food by building a reserve of energy. Social insecurity, deprivation and adversities are unconsciously perceived by the psyche as such threats, which activate the brain to instigate, by neuro-hormonal signaling, growth of fat and lean mass. If the perceived threats and food abundance continues, the process continues, eventually leading to more obesity. Numerous mutations have disturbed the system alongside with its development, producing the diversity in genetic predisposition and reactions to the perceived threats. The theory offers explanation of the obesity epidemic and its heterogeneity, and may pave the way for coherent conjectures about the missing evidence and hopefully for opportunities of intervening without restricting food availability.

Speakers

14:15-14:30
Discussion
14:30-14:45
The dual-intervention point model for body fat regulation

Abstract

Physiologists have long regarded body fatness as a regulated trait defined by a set-point. The discovery of the hormone leptin, which is produced by and reflects levels of body fat, provided an appropriate potential sensor of fat levels, which is a prerequisite for such a regulatory system. Moreover, the high contribution of genetics to the explained variance in fatness is also consistent with physiological regulation of adiposity. However, other features of the obesity phenomenon are less compatible with such a regulatory system. In particular, the existence of the pandemic itself, and the impacts of many environmental factors linked to levels of stored fatness, point to a more complex aetiology than is captured by the notion of set-points. These effects have been characterised in a passive regulatory system called a ‘settling point’ model. The dual intervention point (DIP) model is an attempt to capture the useful aspects of both models. It posits upper and lower intervention points that bound a zone of indifference. Within the zone there is no physiological regulation and environmental impacts dominate in a ‘settling point like’ manner. Beyond the intervention points physiology kicks in to stem further gain or loss. Leptin seems likely used at the lower but not the upper intervention point. Such a system may have evolved in response to the evolutionary pressures relating to different levels of fat storage. The lower point defined by the risk of disease, and the upper point defined by the risk of predation.  Humans may have enormous variation in levels of stored fat because for the past 2 million years since we effectively eliminated predation risk mutations in the system have been drifting. This ‘drifty gene’ interpretation of obesity is consistent with the absence of strong signatures of selection at loci linked to fat storage. Despite explaining a lot of the existing phenomena the DIP model struggles to explain resistance and adaptation to fat loss, and day to day autocorrelation of body weight and intake, both of which are more consistent with a strict set point model. Professor Speakman's talk will describe the DIP system and its evolution, and attempt to provide some explanations for these latter phenomena.

Speakers

14:45-15:00
Discussion
15:00-15:30
Tea
15:30-15:45
The causal effects of X vs the cause(s) of Y: causal models, causal modelling, identifiability and identification

Abstract

Discussing causes in science, if we are to do so in a way that is sensible, must as with most endeavours begin at the root. We jump into specific postulated causes, but do not first consider what we mean by causes of obesity, and how we discern whether something is a cause; we jump in the pool before we define water. Let us begin with definitions. In this session, Dean Allison will address what we mean by a cause, what might and might not constitute a reasonable causal model in the abstract, offer some speculation about what the causal structure of obesity might be like overall and the types of things we should be looking for, and finally, delve into methods for evaluating postulated causes and estimating causal effects. He will offer the view that different meanings of the concept of causal factors in obesity research are regularly being conflated leading to confusion, unclear thinking, and in some cases non-sense. He will emphasize the idea of different kinds of studies for evaluating different aspects of causal effects. Experimental methods, assumptions, and evaluations will be discussed. Analogies from other areas of research will be utilized to express the plausibility that only inelegant solutions will be truly informative. Finally, he will offer some comments on some specific postulated causal factors.

Speakers

15:45-16:00
Discussion
16:00-16:45
Panel discussion

Speakers

16:45-17:00
Closing thoughts