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Fit-Fat Paradox Holds For People With Severe Obesity

Regular readers will be quite familiar with the findings that cardiometabolic health appears to be far more related to “fitness” than to “fatness” – in other words, it is quite possible to mitigate the metabolic risks commonly associated with excess body fat by improving cardiorespiratory fitness. Now, a study by Kathy Do and colleagues from York University, Toronto, published in BMC Obesity, shows that this relationship also holds for people with quite severe obesity. The researcher studied 853 patients from the Wharton Medical Clinics in the Greater Toronto Area, who  completed a clinical examination and maximal treadmill test. Patients were then categorized into fit and unfit based on age- and sex-categories and in terms of fatness based on BMI class. Within the sample, 41% of participants with mild obesity (BMI<35) had high fitness whereas only 25% and 11% of the participants with moderate (BMI 35-40) and severe obesity (BMI>40), respectively, had high fitness. Individuals with higher fitness tended to be younger and more likely to be female. While overall fitness did not appear to be independently associated with most of the metabolic risk factors (except systolic blood pressure and triglycerides), the effect of fitness in patients with severe obesity was more pronounced. Thus, the prevalent relative risk for pre-clinical hypertension, hypertriglyceridemia and hypoalphalipoproteinemia and pre-diabetes was only elevated in the unfit moderate and severe obesity groups, and fitness groups were only significantly different in their relative risk for prevalent pre-clinical hypertension within the severe obesity group. Similarly, high fitness was associated with smaller waist circumferences, with differences between high and low fitness being larger in those with severe obesity than with mild obesity. Based on these findings, the researchers conclude that the favourable associations of having high fitness on health may be similar if not augmented in individuals with severe compared to mild obesity. However, it is also apparent based on the rather low number of “fit” individuals in the severe obesity category (only about 1 in 10), that maintaining a high level of fitness proves to be more challenging the higher the BMI. @DrSharma Edmonton, AB

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Can Liraglutide Help Grow New Fat Cells?

The human GLP-1 analogue liraglutide is now approved for the long-term medical treatment of obesity in an ever-increasing number of countries. Its safety and clinical effectiveness is now well established and there is no doubt that this is an important addition to the rather limited number of treatment options available to people living with obesity. Interestingly, however, liraglutide has also been shown to promote the differentiation of pre-adipocytes or, in other words, promote the formation of new fat cells. While this may seen worrying or even counter-intuitive, we much remember that having more (smaller) rather than fewer (bigger) fat cells actually has substantial metabolic advantage s- there is indeed ample data showing that large adipocyte cell size and limited capacity to grow fat cells (the extreme case of which is seen in people with lipodystrophy) is actually a key risk factor for metabolic problems including insulin resistance, possible by promoting the accumulation of ectopic fat (e.g. in liver and skeletal muscle). Now, a paper by Yongmei Liand colleagues, published in Molecular Medicine Reports provides additional insight into the cellular pathways involved in liraglutide’s adipogenic effects. Using a series of in vitro experiments, the researchers show that liraglutide does indeed promote the adipogenic differentiation of 3T3-L1 cells (a widely used murine preadipocyte cell line)  through a process that upregulates the expression of C/EBPα and PPARγ at the early phase of adipogenic differentiation, promots the expression of lipogenesis associated genes including aP2, and enhances the accumulated of lipids. At the same time, liraglutide appears to suppress cell proliferation via the Hippo‑yes‑associated protein (YAP) signaling pathway, thereby allowing these cells to transform into mature adipocytes sooner. How relevant these observations are for humans remains to be seen, but certainly the promotion of adipogenic differentiation may hold the potential for improving insulin sensitivity and reducing the metabolic risks associated with excess weight gain. @DrSharma Edmonton, AB Disclaimer: I have received speaking and consulting honoraria from Novo Nordisk, the maker of liraglutide.  

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Semaglutide Continues To Hold Promise For Obesity Treatment

This week, the Lancet published the results of the SUSTAIN7 trial, an open-label, parallel-group, phase 3b trial done at 194 hospitals, clinical institutions or private practices in 16 countries. Eligible patients with type 2 diabetes (HbA1c 7·0–10·5% on metformin monotherapy, n=1201), were randomised to once-weekly injections of the GLP-1 analogues semaglutide 0·5 mg, dulaglutide 0·75 mg, semaglutide 1·0 mg, or dulaglutide 1·5 mg. Over the 40 weeks of treatment, participants on semaglutide had a greater reduction in HbA1c than participants who were on corresponding doses of dulaglutide. More interesting, in the context of this blog, semaglutide was also almost twice as effective in lowering mean body weight than dulaglutide. Thus, bodyweight was reduced by 4·6 kg with semaglutide 0·5 mg compared with 2·3 kg with dulaglutide 0·75 mg and by 6·5 kg with semaglutide 1·0 mg compared with 3·0 kg with dulaglutide 1·5 mg. As expected, the most frequent adverse effects were gastrointestinal. Given that this was not actually a trial designed to maximise weight loss (as would have been attempted in a study primarily designed to study semaglutide as a treatment for obesity), these changes in body weight are certainly quite impressive. These findings no doubt hold promise for the further development of semaglutide as an anti-obesity medication. @DrSharma Edmonton, CA Disclaimer: I have received speaking and consulting honoraria from Novo Nordisk, the maker of semaglutide

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New European Guidelines on Medical Management After Bariatric Surgery

The European Association for the Study of Obesity (EASO) had now released the new OMTF guidelines Practical Recommendations of the Obesity Management Task Force of the European Association for the Study of Obesity for Post-Bariatric Surgery Medical Management. The guidelines provide the latest guidance on nutritional management, micronutrient supplementation, managing co-morbidities, pharmacotherapy, psychological management, and prevention and management of weight regain. The guidelines also address the issue of post-bariatric surgery pregnancy. Not covered are issues related to dealing with excess skin and rehabilitation (e.g. return to work, reintegration in social activities, education, etc.), both of significant importance, especially in people with severe obesity. As the authors note, “Bariatric surgery is in general safe and effective, but it can cause new clinical problems and it is associated with specific diagnostic, preventive and therapeutic needs. Special knowledge and skills of the clinicians are required in order to deliver appropriate and effective care to the post-bariatric patient. A post-bariatric multidisciplinary follow-up programme should be an integral part of the clinical pathway at centres delivering bariatric surgery, and it should be offered to patients requiring it” These guidelines are now available open access in Obesity Facts. @DrSharma Edmonton, AB

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Reducing Cardiovascular Risk In Adolescents With Bariatric Surgery

Given the limited effectiveness of “lifestyle” interventions and the lack of access to medical treatments, many adolescents struggling with severe obesity are left with no option but to consider having bariatric surgery. Now, a paper by Marc Michalsky and colleagues on behalf of the Teens LABS Consortium, in a paper published in Pediatrics, describes the effect of bariatric surgery on cardiovascular risk factors in adolescents undergoing these procedures. The study includes 242 adolescents (76% girls, 72% white, mean age 17 ± 1.6 y,  median BMI 51) undergoing bariatric surgery (Roux-en-Y gastric bypass (n = 161), vertical sleeve gastrectomy (n = 67), or adjustable gastric banding (n = 14)), at five centers. At 3 years following surgery, weight was significantly lower in all groups (28%, 26%, and 8% for RYGB, VSG, and AGB, respectively). Hypertension, observed in 44% of participants, declined to 15% at 3 years. Dyslipidemia observed in 75% of participants, declining to 27% by 1 year and 29% by 3 years. This improvement was largely due to decrease in triclycerides and increases in HDL cholesterol. Baseline diabetes was present in 13% of participants with major metabolic improvement (0.5%) by 3 years. Similarly, baseline impaired fasting glucose (26%) and hyperinsulinemia (74%) dramatically improved by year 3 (4% and 20%, respectively). Improvements in these parameters were related to the degree of weight loss. Remission rates were negatively correlated to higher age and positively correlated to female sex and white race. Overall, the authors conclude that this study documents the improvements in cardiovascular risk factors in adolescent bariatric surgery. Unfortunately, the study does not present any information on surgical complications or reoperation rates, an obvious matter of concern when it comes to surgery in this young population. While there may well have been no alternative to surgical treatment in these kids, we can only hope that eventually medical treatments will become available for this population, hopefully with similar outcomes. Unfortunately, that may well still be a long way off. @DrSharma Edmonton, AB

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