Body weight is a highly heritable trait and a host of genes have now been identified as playing a role in its regulation. Furthermore, there is evidence that changes in body weight in response to caloric restriction may also be in part determined by genetic factors. This naturally leads to the question whether or not weight loss after metabolic surgery may be predicted by genetic screening. This is the topic of a recent systematic review by Sapana Gupta and colleagues, published in Obesity Surgery. In their analyses of fifty-seven studies that looked at single genes or genetic risk scores in relationship to weight loss after metabolic surgery, they found some (albeit weak) evidence that certain genetic variants (e.g. UCP, FTO, MC4-R) may predict greater or lesser weight loss. However, results were inconsistent and, where stated, of rather modest magnitude (1.5-4.5 kg). Given the host of factors that can potentially influence post-surgical weight loss, this should not be surprising. It is indeed extremely unlikely that a genetic score is likely to reliably predict weight loss in a given individual with sufficient sensitivity and specificity to meaningfully guide clinical decision making. For this, one would need to not only link genetic markers to weight loss but also to the overall potential clinical benefit including prediction of hard outcomes. Thus, the clinical utility of a genetic score that predicts a higher probability of a given patient perhaps achieving a 2 kg less weight loss than the average, is rather limited. At this time, I do not see any value of adding genetic screening to assessing patients’ suitability for metabolic surgery. @DrSharma,Berlin, D
Obesity is now well recognised as an important risk factor for cancers of the GI tract including oesophagus, stomach, colon, gall-bladder, liver, and pancreas. Furthermore, weight-loss interventions, particularly bariatric surgery, have been shown to reduce cancer morbidity and mortality in people living with obesity. Traditionally, obesity related cancer risk has been attributed partly to dietary patterns associated with obesity, as well as insulin resistance (with hyperinsulinemia), increased production of pro-inflammatory cytokines, and changes in sex hormones. Now, a review paper by Maria Angela Guzzardi and colleagues, published in the International Journal of Obesity, discusses the possibility that obesity related alterations in gut hormones may play a hitherto unrecognised role in the etiology of these cancers. Gut hormones play a vital role in a wide range of processes ranging from local influences on GI motility, exocrine function and the bacteriome to systemic influences on appetite, glucose homeostasis, and immune response. As an example, the authors discuss the role of GLP-1: “Recent studies have shown that GLP-1 receptor (GLP-1R) agonists might have a beneficial anti-inflammatory role independent from the glycemic regulatory actions. In fact, GLP-1R agonists modulate enteric immune response by activating intestinal intraepithelial lymphocytes GLP1R, which may influence microbiota composition and intestinal inflammation. Therefore, the blunted GLP-1 secretion in obesity contributes to the obesity-related pro-inflammatory condition.” Similarly, vasoactive intestinal peptide (VIP), “…is a regulator of both innate and adaptive immunity, with an anti-inflammatory role. In fact, in innate immune cells, VIP can inhibit the production of pro-inflammatory factors (e.g., TNF-alpha, IL-6, IL1beta, IL12, iNOS) and promote the production of anti-inflammatory factors (e.g., IL-10 and TGF-beta). In the adaptive immune system, VIP shifts the Th1/Th2 balance during CD4 T cell differentiation in favor of Th2 cells, both in vitro and in vivo, primarily through the vasoactive intestinal peptide receptor-2 (VPAC2).” Based on the observation that neoplastic samples have been shown to express receptors for many gut hormones, the authors also discuss at length the evidence that gut hormones could modulate the proliferation and perhaps invasiveness of a wide range of cancers. However, they also note that, “Overall, existing data are controversial, which might be due to differences between local and systemic effects of the hormone, and among cancer types.” Hopefully this review will prompt further studies exploring the potential role of obesity-related alteration of gut hormones in the pathogenesis of specific tumors, which will open the perspective of new strategies in the… Read More »
Although I have spent the last 25 years helping patients manage their obesity, I have never had obesity myself (at least not based on BMI). Everything I know about what it must be like living with this chronic disease, I have learnt from what my patients have told me. Obviously, this is a biased sample, as I have mainly seen patients with more severe obesity and those fortunate enough to have access to an obesity clinic. So, what is it really like to live with obesity? This is the topic of a systematic review by Emma Farrell and colleagues published in Obesity Reviews. The study included findings from 32 peer-reviewed studies relating to the lived experience of patients with obesity. Overall, fiive “third-order constructs” or themes emerged from their ethnographic analysis related to 1) the development of obesity, 2) a life limited, 3) stigma, judgment, shame, and blame, 4) treatment and 4) experiences of specific or minority groups. Interestingly, the researchers actually involved people living with obesity to inform and validate their synthesis. Thus, once the third-order constructs had been identified and described, the researchers met with the study’s Patient Advisory Board (PAB) to discuss the findings and to provide a “phenomenological nod” if advisory board members could relate to the synthesis, recognizing it as an experience that they have or could have had. With regard to the development of obesity, people living with obesity had a wide range of individual experiences to share. While some reported having been heavy since earliest memory, others reported a steady progression, often in response to a major life event. Other reported contributors ranged from negative emotional states and adverse life experiences to genetic predisposition, social pressures, physical environments and sometimes medications. Virtually all experienced weight cycling, often attributable to dieting. Obesity clearly was a major limiting factor in many people’s lives, leading to social disconnection as well as restrictions in movement, activities, and opportunities. Many participants described a sense of having to put life on hold. Complications of obesity such as diabetes, high blood pressure, and musculoskeletal pain curtailed many participant’s ability to be active and participate in aspects daily life. Judgment, by self and others, was identified as a major contributor to social isolation and the life-limiting effects of obesity. Indeed, experiencing stigma, judgment, shame, and blame was one of the most pervasive and consistent themes to emerge from the analyses. Thus,… Read More »
Clinical trials have consistently documented the weight-loss effect of treatment with the GLP-1 analogue liraglutide. These studies have also generally reported a significant reduction in waist circumference, a simple surrogate measure for visceral obesity. But, does this finding hold up with more precise measures of ectopic fat? That is apparently the case, based on a study by Ian Neeland and colleagues published in The Lancet Diabetes and Endocrinology. The researchers randomised 185 volunteers with a BMI of at least 30 kg/m2 or BMI of at least 27 kg/m2 with metabolic syndrome but without diabetes to 40 weeks of treatment with once-daily subcutaneous liraglutide 3·0 mg or placebo, in addition to a 500 kcal deficient diet and guideline-recommended physical activity counselling. At the end of the trial, visceral adipose tissue, assessed with MRI, was reduced by 12.5 % with liraglutide compared to 1.6% with placebo. Interestingly, this difference was substantially underestimated by changes in waist circumference, which only reduced by 7% with lirgalutide vs. 4% with placebo. Perhaps, even more remarkably, while liver fat reduced by 12% with liraglutide, it actually increased by 21% in the placebo group. Adverse effects were typical of those expected with liraglutide (largely transient GI-related). Thus, the authors note that, “The relative effects of liraglutide on fat reduction were two-times greater in the abdominal viscera and six times greater in the liver than seen on overall bodyweight. The treatment effect seemed consistent across race–ethnicity and baseline BMI categories, and among those with or without baseline prediabetes” Moreover, “Although individual body fat depot reductions were highly correlated with overall bodyweight loss, VAT, and to a greater degree liver fat, were less well correlated with weight loss. This could suggest a partially weight-independent effect of GLP-1 receptor agonism on body fat distribution.” In summary, it certainly appears reassuring that treatment with liraglutide indeed results in a marked reduction in visceral and ectopic fat, as these fat depots have been associated with increased metabolic and cardiovascular risk. @DrSharmaBerlin, D Disclaimer: I have received honoraria as a consultant and speaker from Novo Nordisk, the maker of liraglutide.
Obesity is a heterogeneous complex chronic disease that generally requires patients to make changes to their lifestyles and perhaps deal with various psychological aspects of their mental health. But so is diabetes, hypertension, coronary artery disease, chronic lung disease, or, for that matter, almost any chronic disease that is routinely managed in clinical practice. Obviously, if you have a team of allied health specialists including dietitians, exercise physiologists, behavioural psychologists, occupational therapists, health educators, etc. you could probably do a much better job of managing patients with any of these diseases, than if your were sitting in your office by yourself with no more than 5-8 minutes to dedicate to each patient. And yet, that is exactly how doctors routinely manage the vast majority of patients presenting with these diseases in their real-world practices. And to be fair, most docs do a fairly reasonable job of managing these diseases without having the luxury of working in extended multidisciplinary health teams with support from an army of allied health practitioners. So, why when it comes to obesity, do we suddenly expect them to harness all these resources in order to provide even the most basic obesity care? Why, for example, do we think that it is more important to have a dietitian on my team for managing obesity, than say for managing a patient with diabetes or hypertension or dyslipidemia? Why is it more important to have an exercise specialist on my obesity team, than for my patients with coronary artery disease or heart failure? In fact, why is it more important to have a psychologist on my team for managing obesity, than it is for managing my patients with depression or anxiety disorder? Obviously, patients with any of these conditions would likely benefit from being managed by a multidisciplinary team of experts, but somehow, we manage to provide acceptable care even without all this support. Why, in obesity care, do we often take the “all or nothing” approach? Frankly, I cannot recall the number of times I have heard colleagues tell me that the most important reason they cannot offer obesity treatments, is because they simply do not have the allied health resources they need. And they justify this attitude towards managing obesity, by highlighting the importance that is generally given to multidisciplinary management in obesity guidelines. In fact, reading these guidelines with their emphasis on lifestyle and behavioral interventions,… Read More »
As for many chronic diseases, there is certainly a role for dietary and other behavioural measures in the management of obesity. But let us not kid ourselves. According to all of the available evidence, diet and exercise (often described as “lifestyle” interventions) simply do not come close to measuring up with medication or surgical treatments for obesity. Nevertheless, we continue to see overly enthusiastic reports on the efficacy (not effectiveness!) of lifestyle interventions, which not only tend to oversell the benefits but also ignore the reality that most of these interventions that may work more or less in clinical trials, would be almost impossible to implement with any degree of fidelity in routine clinical practice. Case in point, the Look AHEAD study. This was certainly one of the most ambitious and best-resourced randomized controlled trials of intensive lifestyle intervention, designed and run by the leading experts in the field with the aim of once and for all demonstrating the benefit of weight loss on cardiovascular morbidity and mortality (albeit in elderly patients with type 2 diabetes). Indeed, not only was running the trial (till its abandonment for futility) a major logistical feat, but there were certainly several indicators of benefit, even if not in the primary endpoint of the study. These benefits are now nicely summarized and highlighted in a paper by Rena Wing on behalf of the Look AHEAD Research Group in a recent issue of OBESITY. While the paper highlights a number of secondary outcomes that were apparently improved in the intensive lifestyle intervention (ILI) group, the article also notes that, “…several important outcomes (cardiovascular morbidity and mortality, cancer, and cognition) did not show significant differences between ILI and control, and frailty fractures occurred more often in ILI than in control.” As much as the many post-hoc analyses discussed in this paper suggest health improvements in various aspects in the ILI group, the authors also state that, “There were also some subgroups that appeared to have poorer outcomes in ILI relative to DSE, most notably those who had the highest BMI at the start of the trial and those with poorer initial health, including a history of CVD and more health deficits at baseline.” Based on these findings, the authors conclude that, “it would seem best to recommend ILI early in the course of diabetes, when individuals are younger, hopefully have less obesity, and before they have developed… Read More »
The reason that medications and surgery work so much better for managing obesity than behavioural interventions alone, is because they change the underlying biology that drives weight gain and defends against weight loss. Thus, rather than relying on willpower, these treatments change ingestive behaviour by modifying the complex neuroendocrine pathways that regulate food intake. So what exactly do people who undergo bariatric surgery experience in terms of wanting and liking foods and how does their dietary intake change following surgery? This is the topic of a systematic review and meta-analyses of food preference modifications after bariatric surgery by Erika Guyot and colleagues from the University Laval, Quebec, Canada, published in Obesity Reviews. Apart from the homeostatic control of energy intake, the authors remind us that, “Food intake is partly under the control of the reward system (tonsil, ventral tegmental area, hypothalamus, limbic system, and prefrontal cortex). This system assigns a hedonic value to food and generates motivation for food intake. Food reward has been shown to have two distinct components. The first component is “liking” and is related to the pleasure and the sensory properties of foods. The second component is “wanting”, which is related to the motivation and is defined as an implicit drive to eat.” Both of these components of food intake have been reported to be altered in patients post-surgery and imaging studies have shown a decrease in the potential of palatable foods’ ability to activate the relevant areas of the brain in post-surgical patients. The authors included 57 studies in their review (47 studies were prospective, 8 were cross-sectional, and 2 were longitudinal retrospective) that included 2,271 patients with RYGB and 903 patients with SG. As expected, there was significant heterogeneity amongst the studies, which used a total of 16 different methods to assess food intake and preferences, with the majority being based on food records (N = 24), Food Frequency Questionnaires (FFQ) (N = 12), and food recalls (N = 11). Likewise, time points for assessment ranged from days to months post-surgery all the way up to 10 years later. Despite these methodological differences, a couple of important themes emerged. Overall, despite a marked reduction in caloric intake, there was a significant increase in protein intake (from baseline), with a reduced intake of calories from fat. Carbohydrate intake, as a proportion of overall caloric intake, was largely unaltered. Perhaps more interestingly, several studies also described differences in food preferences. Thus,… Read More »
Over the past decades, numerous neuromodulation therapies have been proposed to alter several of the physiological processes underpinning obesity, ranging from the brain control of food intake, satiety, and compulsive eating, to gastrointestinal responses. These neuromodulation approaches include deep brain stimulation [DBS], transcranial magnetic stimulation [TMS], transcranial direct current stimulation [tDCS], percutaneous neurostimulation [PENS], vagus nerve stimulation [VNS], and gastric electrical stimulation [GES]. So far, none of these treatments have made it into routine practice, and according to a review by Flavia Gouveia and colleagues, published in Obesity Reviews, there are probably good reasons for this, the principle one being lack of effectiveness. Thus, their review of 60 trials that had weight loss as an outcome, including 7 DBS, 5 TMS, 7 tDCS, 17 PENS and VNS, and 24 GES in over 3,000 participants, yielded a seemingly consistent pattern. Initial promising results in open label studies and case reports, followed by double-blinded randomized clinical trials that generally failed to reach their primary endpoints, with no technique inducing a striking long-term reduction in body weight. As the authors note, both the case reports and randomised trials were fraught with important sources of bias or lacked details of important confounders. While the authors remain cautiously enthusiastic about the future of neuromodulation, it is fair to say that at this time these approaches must be considered experimental and should probably not be used outside of well-controlled clinical trials. @DrSharmaBerlin, D