A round up of obesity-related discussion at IUPS 2013, Birmingham

News and Views

Caroline Wood
PhD student, University of Sheffield, UK

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https://doi.org/10.36866/pn.96.14

In 2008, the World Health Organisation estimated that over 10% of the global adult population were obese. The corresponding rise in cardiovascular disease, Type 2 diabetes and cancer has caused this trend to be viewed as an ‘epidemic’ of great concern. By bringing together pioneering researchers working on the latest theories and techniques, IUPS provided a unique venue to engage with this issue. A wealth of symposia and keynote lectures explored the physiological impacts of the obese state and how current knowledge could be developed into clinical treatments.

Brown adipose tissue – a potential recruit for weight loss?

Not all fat, it seems, is bad for us. Whilst traditionally ‘unhealthy’ white fat acts as a reservoir of storage lipids, brown adipose cells are stimulated by the sympathetic nervous system to burn fat to produce heat (thermogenesis). Although once thought to be restricted to fetuses and newborns, modern scanning methods have shown that metabolically active brown adipose tissue (BAT) is also present in human adults, prompting researchers to question whether this could be manipulated to facilitate weight loss. In her keynote lecture, Brown adipose tissue: the mammalian prerogative, Barbara Cannon, president of the Royal Swedish Academy of Sciences, outlined how BAT initially evolved as a strategy for cold-survival in mammals. Professor Cannon described how thermogenic ability depends on the mitochondrial channel UCP (thermogenin) and that knocking this channel out in mice prevents cold-stimulated BAT activity. Furthermore, mice lacking UCP are less able to maintain a steady weight on control diets and show greater weight gain on high fat diets, suggesting that BAT may protect against obesity. When radioactive glucose or triglycerides were fed to mice, BAT was found to clear 50 and 75% of these, respectively, implying that this tissue acts to counter hyperlipidaemia and hyperglycaemia, key features of the metabolic syndrome. This raises the question, is obesity promoted by a lack of BAT? Or does obesity reduce BAT because the body has greater insulation? In support of the former view, the UCP-1 channel has a polymorphic enhancer, with the so-called ‘AA allele’ promoting greater mRNA expression. Studies indicate that those carrying this allele burn more calories after a high fat meal and occupy the lowest quartile of population BMI.

The role of brown fat in weight control was discussed further in the symposium What’s hot in brown adipose tissue biology? Dr Tim Schulz (German Institute of Human Nutrition) presented exciting evidence that white adipose tissue could be manipulated to take on a fat-burning brown phenotype. BAT and muscle cells derive from a common Myf5-positive progenitor, with lineage allocation determined by BMP7. White adipose tissue, on the other hand, originates from a separate My5 negative cell. In experiments where BMP receptor 1α was deleted in mice, BAT was ablated yet the white fat remained unaffected. In these mice, sympathetic nervous stimulation to white fat deposits increased, causing them to adopt a brown phenotype. In addition, the mice were found to be resistant to diet induced obesity. Could inhibiting BAT progenitors be a mechanism to combat obesity in humans?

Besides cold temperatures, glucose uptake by BAT is also stimulated by insulin. Dr Saveiro Cinti (University of Ancona) outlined her work investigating how this process is affected by obesity. Her experiments compared the insulin responses of lean mice with individuals fed a high fat diet for 3 months to cause insulin resistance. In the obese animals, downstream insulin signal transduction in BAT (including the AKT pathway) showed reduced activity and insulin-promoted thermogenesis was inhibited. Furthermore, production of the energy storage molecule glycogen was suppressed, suggesting a mechanism by which BAT normally protects against hyperglycaemia. This was found to be due to reduced expression of the protein PTG (which stimulates the enzyme glycogen synthase) in the obese animals. In future work, Dr Cinti hopes to investigate the effect of obesity on other insulin-stimulated pathways, such as triglyceride production. Meanwhile, she described her other research interest: the role of endocannabinoids in regulating BAT. This relatively unexplored pathway uses signalling molecules similar to the active component of cannabis, tetrahydrocannabinol. These compounds are thought to be implicated in the metabolic syndrome due to the weight loss effects of the drug rimonabant. This acts as an inverse agonist of cannabinoid receptor 1 (CB1), i.e. it binds the receptor but induces an opposite effect to the natural agonist. Subcutaneous temperature probe implants indicate that the drug stimulates BAT thermogenesis, but Dr Cinti’s studies found that inhibiting CB1 does not increase the basal glucose uptake in BAT. Specifically, CB1 inhibition increases glucose uptake in response to insulin and improves whole-body glucose–insulin sensitivity. As obesity and diabetes are often characterised by elevated cannabinoids and hyperactive CB1, this could indicate why insulin resistance develops in these conditions. Curiously, when BAT was denervated, Rimonabant failed to activate thermogenesis, suggesting that the endocannabinoid pathway is mediated by the sympathetic nervous system. Could this explain how drugs used to treat mental health that target the sympathetic nervous system can cause weight gain or loss? Although little known at present, endocannabinoids seem sure to assume a more prominent role in obesity research.

Intergenerational effects – blame the mother?

Is obesity simply the consequence of personal choice or do intergenerational effects play a role? This was explored in Monday’s symposium, Obesity: Intergenerational programming and consequences. Professor Lucilla Poston (King’s College London) opened the session by describing early studies on Pima Indians which found that individuals exposed to maternal diabetes in utero had a higher BMI than siblings born before the mother developed the condition. Since then, a wealth of studies have indicated that children have a 2- to 3-fold increased risk of becoming fat when the mother is overweight. Furthermore, a high pre-pregnancy BMI is also associated with birth defects and miscarriages. Professor Poston stressed, however, that this does not necessarily indicate a causal link and that confounding factors, such as poor household diets, should be taken into account. Nevertheless, siblings born following bariatric surgery in the mother show reduced incidence of obesity, improved lipid profiles and higher insulin sensitivity. Furthermore, 5698 genes are differentially regulated in offspring born before/after surgery. Professor Poston outlined her work in the ongoing UPBEAT trial which is investigating the effects of intervention with a low GI diet and physical exercise in obese pregnant women. The results of this comprehensive study, which will have a sample size of 1546, will no doubt prove illuminating in the near future. Meanwhile, Poston’s research on mice has provided insight into intergenerational mechanisms for obesity. In general, overweight mice give birth to fatter offspring which show an increased food intake and are resistant to the appetite-suppressive effects of the hormone leptin. Intriguingly, the mice showed an increased response to leptin-induced hypertension, showing that leptin resistance is selective. These offspring also exhibited a fatty liver phenotype reminiscent of humans with non-alcoholic fatty acid liver disease. Future studies will investigate whether these observations translate to humans born to obese mothers.

Professor Kimberley Bruce (The Scripps Research Institute) presented evidence that circadian rhythms may also be involved in intergenerational effects. Mice exposed to high fat diets in the uterus and postnatally showed dysregulation of key clock gene components, including sirtuins and bma1. Directly disrupting circadian rhythms in flies has been shown to have implications on diet and appetite. Knocking out the cyc clock gene, for instance, causes flies to consume larger meals but less frequently, implying an impaired ability to sense metabolic status.

The work of Dr Kevin Grove (Oregon Health and Science University) also suggests that nutrient signalling is disrupted in the obese state. His studies found that the activity of serotonin, a key regulator of energy homeostasis, was reduced in non-human primates exposed to high fat diets in utero. These primates also exhibited altered food preferences and a tendency to ‘binge’ when presented high-sugar food. More disturbingly, they also showed increased anxiety and withdrawal behaviour, similar to autistic-like spectral disorders in humans.

Following this, Dr Lisa Nicholas (University of South Australia) described her elegant experiments investigating the specific influence of obesity exposure in the peri-conception period. In these studies, sheep embryos were transferred from obese ewes to a control mother; in half of the cases, the obese mother was made to lose weight prior to the transplant. Many of the adverse effects in the offspring, including impaired insulin signalling, were ablated when the mother underwent weight loss. Given that an estimated 93% of pregnant women attempt to lose weight before pregnancy, these results are of considerable relevance. Questions remain regarding whether in utero effects are caused by alterations in blood flow, nutrient transfer or the profile of cytokines secreted by the placenta. Evidence for a model of enhanced nutrient transfer in obese mothers was discussed in the Tuesdayafternoon symposium, Mother, placenta, fetus and lifelong health. Here, Professor Theresa Powell (University of Texas Health Science Center, San Antonio) described how fatty acid transporters (such as FATP2) and the glucose transporter GLUT1 are expressed more highly in the basal placenta membrane of obese mothers. Maternal obesity also appears to stimulate the mTOR signalling pathway in the placenta, promoting nutrient uptake. In addition, maternal obesity is associated with decreased expression of the protein adiponectin, which is thought to normally inhibit placental nutrient transfer. Professor Powell’s studies found that infusions of adiponectin in obese pregnant mice was able to return fetal birth weights to control levels, suggesting a mechanisms by which excess nutrient transfer to the foetus can be restricted.

Alternate day fasting – a celebrity diet that works?

A considerable audience gathered to hear Dr Krista Varady’s lecture, Alternate day fasting: a novel dietary restriction regimen for weight loss in humans, which described the results of an 8 week pilot study in the USA. This involved placing 20 obese males and females on a regime which limited their dietary intake to 25% of their needs on three days a week. On the remaining days, the participants were free to choose what they ate. In the first 4 week block, the participants were control fed 500 calorie meals on the ‘fast days’, but in the second half of the trial the subjects prepared these themselves, using dietary advice. Only four participants dropped out of the study and these did so at a fairly early stage. The rest lost an impressive average of 5.6 kg with the rate of weight loss being fairly steady throughout the study period. In conventional restrictive diets (especially those involving no additional exercise) this loss is usually lean muscle, rather than fat, which reduces the amount of metabolically active tissue, making it even harder to lose weight. The key finding for this study however, was that about 90–95 % of the weight loss was fat. The subjects also lost about 4 cm of their waistline, lowered their systolic blood pressure by 6 mmHg and reduced their LDL cholesterol levels by 20–25%. Subject compliance, as assessed through feeding diaries, was 87%. Although one might presume that the participants would ‘binge’ on the non-fasting days, the subjects were found to only consume 110% of their energy needs and so didn’t make up the deficit. Many of them were even happy to carry on the diet with Dr Varady stating that ‘after the initial two weeks most have no problem with the fast days’. Some of the audience were sceptical about the long term effects and Dr Varady admitted that the rate of weight loss did seem to drop after 24 weeks. Nevertheless, this approach certainly gives food for thought…

Exercise – we know it’s good for you, but how does it work?

Another popular session was the plenary lecture, Health-promoting effects of exercise in diabetes and obesity: from molecular mechanisms to clinical action, given by Professor Juleen R. Zierath (Karolinska Institutet, Sweden). Exercise has been established as an effective strategy for weight loss and this talk explored how exactly these beneficial effects are translated. Professor Zierath described how glucose uptake capacity varies across different muscle fibre types and is particularly enhanced in slow-twitch oxidative fibres, due to greater expression of components of insulin-stimulated signalling pathways. When one of these components, calcineurin, is over-expressed in mice fed high-fat diets, insulin-stimulated glucose uptake is increased and the mice are less likely to develop insulin resistance. In a human study where diabetic patients underwent a week-long exercise programme, most improved their glucose tolerance apart from those with the Type 1 condition (characterised by low insulin production). This suggests that exercise acts at the level of improving insulin sensitivity of muscle cells, rather than increasing insulin production through β cell activation. Sensitivity is mediated in part by the availability of the GLUT4 glucose transporter on the plasma membrane; this translocates to the cell surface when the energy sensor AMPK is stimulated. Physical exercise appears to enhance AMPK signalling activity through increased expression of diacyl-glycerol kinase (DGK), an enzyme which converts diacylglycerol to phosphatidic acid. In DGK deficient mice, glucose uptake and lipid oxidation are impaired and the metabolic response to fasting or high fat diets is blunted. These mice also show reduced AMPK activation and are prone to becoming insulin resistant on high fat diets. In humans, Type 2 diabetes can be improved with exercise and this is associated with raised DGK levels. Professor Zierath suggested that treatment strategies should focus on exercise regimes or drugs that promote DGK, and hence AMPK, activity. But how does exercise induce changes in protein expression? Professor Zierath cited studies which found that humans on high fat diets show genome wide changes in DNA methylation that were not easily reversed. In addition, muscle biopsies taken after acute exercise have reduced promoter methylation for genes encoding enzymes involved in the exercise response; this hypomethylation allows more efficient recruitment of the transcription machinery and hence greater protein expression. A further study indicated that hypomethylation is more extensive following 35 minutes of high intensity exercise (80% of VO2 max) compared with 75 minutes of lower-intensity exertion (40% of VO2 max). This gives credence to claims that short intense bursts of exercise can be more beneficial than longer, aerobic workouts. As we understand more about how exercise induces physiological changes, our ability to tailor weight-loss programmes can only improve.

Too much of a good thing – the physiological effects of a hedonic diet

The physiological changes induced by excess calorie consumption were explored in the Wednesday morning symposium, Peptide modulation of hedonic food intake. Professor Suzanne Dickson (The Sahlgrenska Academy at the University of Gothenburg, Sweden) introduced the session by outlining the central role of the hormone ghrelin in activating reward pathways. During fasting periods, this is produced by oxyntic glands in the stomach and activates the GHS-R1A receptor in the brain to stimulate increased food intake. The hormone also mediates the reward response by promoting dopamine release into the nucleus accumbens. Directly injecting ghrelin into various areas of the brain stimulates feeding behaviour. Professor Dickson’s work, however, has demonstrated that ghrelin mediates its effects through an orchestra of different neurone types, besides the opioid compounds. Curiously, inhibiting different ghrelin-activated pathways can cause differential effects. Suppressing neuropeptide Y (NPY) neurones, for instance, decreases food intake but not food motivation (assessed by how many times a mouse is prepared to pull a lever to obtain a food pellet). Inhibiting the opioid system, meanwhile, reduces food motivation but not overall intake. Reward–response pathways were explored further by Professor Roger Adan (University Medical Centre, Utrecht), who described experiments where ventral tegmental area (VTA) neurones were engineered to fire in response to injections of clozapine. Stimulating these neurones (which release dopamine in the nucleus accumbens) was found to increase food-motivated behaviour in mice. Professor Carlos Dieguez (University of Santiago de Compostela) meanwhile outlined the emerging role of opioids in modulating ghrelin-induced feeding stimulation. Ablating or inhibiting opioid receptors can reduce long term food intake and protect against obesity induced by high-fat diets. Specifically, antagonists against the kappa opioid receptor impair ghrelin-stimulated food intake, with hypothalamic transcription factors normally unregulated by ghrelin (such as bsx and pCREB) showing reduced expression. This implies that an active opioid pathway is essential to potentiate the feeding-stimulation effects of ghrelin.

Dr Stephanie Fulton (University of Montreal) moved the discussion to leptin, an antagonist of ghrelin which inhibits dopaminergic and GABA neurones in the VTA to induce satiety and suppress food intake after a meal. Ablating leptin receptors in VTA neurones causes mice to increase food intake, leading to obesity. Dr Fulton described her recent work where Stat3, a downstream effector of leptin signalling, was knocked out in mice to suppress leptin signalling in dopaminergic neurones. The mice were trained to adopt a ‘hedonic feeding pattern’ where they consumed their daily intake within a 4 hour window. When the mice were given an extra hour of access to high fat food (the so-called ‘dessert test’), there was no differential intake between the Stat3 knockouts and control groups, suggesting that food-related reward pathways were unchanged. On the other hand, the Stat3 knockouts showed greater voluntary running behaviour, indicating that the ‘euphoria effects’ of exercise were enhanced. This indicates that different neurone populations mediate the effects of leptin on reward pathways and that GABA, rather than dopaminergic, neurones may act to suppress food intake.

The role of perivascular fat in the interplay between obesity and cardiovascular health

The mechanisms by which obesity affects cardiovascular health were explored in Tuesday’s symposium, Perivascular fat: Role in metabolic and cardiovascular disease. Perivascular adipose tissue (PVAT) accumulates around blood vessels and is metabolically active, secreting a range of cytokines, hormones and chemokines – together known as ‘adipokines’. Aortas with a covering of PVAT show a reduced constriction response to the vasoconstrictor noradrenaline; this is termed the ‘anti-contractile’ effect. Professor Anthony Heagerty (University of Manchester) described how the anti-contractile effect is lost in the metabolic syndrome and that this is thought to be due to inflammation of PVAT. In studies where mice were fed a high-fat diet, glucose tolerance was improved in animals that were additionally subjected to tape-worm induced eosinophilia. Eosinophils function to reduce proinflammatory cytokines; in their absence classically activated macrophages promote an inflammatory response which reduces adipokine secretion from PVAT. Additionally, eosinophil loss causes hypertension, suggesting that obesity-associated hypertension may be mediated in part by the protective effect of eosinophils on PVAT. Curiously, anti-contractile activity can be restored in patients who undergo bariatric surgery, which generally improves systolic blood pressure. This opens a door to future work investigating the role of macrophages, eosinophils and other inflammatory cells in mediating the effects of obesity.

The importance of gut microbiota…you are what your microbes eat…

Professor Graham Dockray’s (University of Liverpool) well attended keynote lecture, Gastrointestinal hormones and the dialogue between gut and brain, provided a lively introduction to the myriad components that affect feeding behaviour in response to nutrient status. The second part of his talk, however, focused on how imbalances in the gut microbiome can deregulate this dialogue. Bacterial populations are usually a balance between the bacteroidetes and the firmicutes, yet high-fat diets increase the proportion of the latter. This promotes lipo-polysaccharide production, inducing inflammation and increasing gut permeability. Professor Dockray presented results showing that mice infected with helicobacter showed increased expression of plasminogen activated inhibitor 1 (PAI1), which attenuates satiety signalling pathways. This adds another realm of complexity to the interaction between inflammation, obesity and the hormonal control of feeding behaviour.

Does hypoxia in the womb increase susceptibility to obesity?

The influence of the fetal environment was explored further in the keynote lecture New insights into the fetal origins of adult cardiometabolic disease, given by Professor Sandra Davidge (University of Alberta). Her studies have found that placing pregnant mice under hypoxic conditions (17% oxygen) during their third trimester causes the offspring to show a ‘prematurely aged cardiovascular system’. These mice showed reduced diastolic filling, left ventricular hypertrophy (males only) and decreased pulmonary tension, yet the phenotype only manifested at 12 months, suggesting it requires a ‘second hit’ of ageing. At 4 months, the mice were identical to the controls unless challenged with induced myocardial infarction; in this case, the hypoxia-exposed individuals showed considerably impaired recovery. More recently, Professor Davidge has investigated whether perinatal hypoxia increases susceptibility to obesity caused by a high fat intake. When mice were fed high fat diets, those exposed to perinatal hypoxia exhibited increased intra-abdominal fat, reduced glucose tolerance and greater insulin resistance. Critically, there was no difference in these parameters between hypoxia-exposed and control mice fed normal diets, demonstrating that hypoxia per se does not promote obesity, but requires a second challenge to manifest a phenotype. This raises the question of whether drugs that improve placental blood flow (and thus oxygen delivery) can protect against hypoxia-induced obesity susceptibility that may be caused by pregnancy complications. In hypoxia-exposed mice fed high fat diets, treatment with the vasodilator resveratrol improved many aspects of metabolic syndrome, suggesting that this could be an effective preventative measure in humans.

Another reason to avoid stress…

Perinatal influences were also discussed in the session Peptide modulation of hedonic food intake. Here Dr John Menzies (University of Edinburgh) described how subjecting rats to stress increases their preference for palatable food. To see if this can be translated gestationally, pregnant mothers were subjected to ‘social defeat’ scenarios over an extended period. The offspring showed enhanced stress responses with increased plasma corticosterone levels, besides a greater motivation towards palatable food. Curiously, a potential mechanism was proposed in the Wednesday Research Symposium Gastrointestinal flexibility: Ecology, evolution and microbial symbiosis. In this session, Dr Gaelle Boudry (INRA, France) described how exposing neonatal rat pups to stress caused an increase in early gut permeability and increased inflammation in adult life. As chronic inflammation is associated with leptin and insulin resistance, it is pertinent to ask if our high-stress modern lifestyles are contributing to the obesity epidemic.