Bariatric surgery-induced significant weight reduction. The patient collective, consisting of 105 severely obese patients displayed an average BMI of 48.0 kg/m2. This average BMI is classified according to the WHO as super obesity and meets the highest obesity classification, the class III obesity (BMI ≥ 40) (WHO 2014). Six month after bariatric surgery of either sleeve gastrectomy or the Roux-en-Y gastric bypass (RYGB) the obese patient significantly reduced they average BMI to 38.5 kg/m2which implies class II obesity (35 ≥ BMI ≤ 40). Later time points revealed a further general but slower BMI decline resulting in average BMI of 35.5 kg/m2 after 2 years, being close to class I obesity (30 ≥ BMI ≤ 35). These significant BMI reductions are in accordance with other bariatric surgery studies showing consistent results in extensive weight reduction. For instance, the most common bariatric surgery, the RYGB, resulted in an initial BMI loss of 20 to 40 % (Cummings et al. 2004).
After 1 or 2 years the weight loss in another study revealed a weight reduction of 24 to 40 % (Sjostrom et al. 2007). The sleeve gastrectomy or also known as duodenal switch caused BMI declines of 18 % or even 80 % after 24 month (Hess & Hess 1998; Buchwald et al. 2004). We also observed median BMI decreases of 20 % to 25 % to 26 % after 6, 12 and 24 month post-OP, respectively and thus it is assumed that our obese patients gained life quality similar as described by others. This included the complete loss of the disease diabetes mellitus type 2, hypertension, dyslipidemia, obstructive sleep apnea (Buchwald et al. 2004; Huerta et al. 2007), cardiomyopathy (McCloskey et al. 2007), polycystic ovary syndrome, male obesity-associated secondary hypogonadism (Escobar-Morreale et al. 2017), psychological body image disturbance (De Panfilis et al. 2007), or the improvement of economic productivity (Hawkins et al. 2007). Overall, the long-term total mortality after gastric bypass surgery was significantly reduced in comparison to obese non-operated persons (Adams et al. 2007).
Hyperleptinemia induces inflammatory pathways and triggers the production of IL-6, TNF-α and activates macrophages and monocytes (Tilg & Moschen 2006; Ceci et al. 2007; Beltowski 2012). The resulted increased oxidative stress seen in blood samples of obese people was also reduced by bariatric surgery-induced weight reduction. Horn and co-workers showed a reduction of carbonylated protein, reduced glutathione, thiobarbituric acid reactive substance and an ascorbic acid level 6 month post-RYGB (Horn et al. 2017).
For that reason, the successful reduction of body weight caused through bariatric surgery in our obese patient cohort should have reduced the psychological and physiological stress following by an improvement of the quality of life.
93 BMI of class III obesity does not correlate with telomere length. Pervious work connected obesity to shorter telomeres and Müezzinler and co-workers suggested an inverse relationship between BMI and telomere length by peforming a meta-analysis between obesity and telomere length (Muezzinler et al. 2014). In their summary they ignored gender and not all included studies revealed statistical significance and heterogeneity in characteristics of population size, methods and age. One year later also Mundstock and colleagues supplied such a meta-analysis with a more moderate conclusion of just a tendency of negative correlation between obesity and telomere length (Mundstock et al. 2015).
Unfortunately, linear TL-BMI regressions were rarely represented in the included studies and most of the studies compared LTL of obese vs. non-obese groups. By the latter approach, if overweight and obese patients were compared to normal-weight subjects a significant decline of LTL was received in adipose patients (Lee et al. 2011). Kim and colleagues compared a normal weight, an overweight and a class I obesity population with each other. Depending on the adipose classification LTL was shorter with increasing weight (Kim et al. 2009). This data were confirmed by Strandberg and co-workers;
however, their data did not reach significance (Strandberg et al. 2012).
Comparing our class III obesity population with our normal weight population we could confirm the previous findings, nevertheless, our two populations were differently methodical conditioned and for that reasons, a comparison of both groups is critical. If we correlated by linear regression the BMI of class III obesity to the PBMC telomere length no TL alteration with increasing BMI was obtained.
However, after bariatric intervention followed by increased weight loss a tendency of shorter telomeres with increasing BMI could be seen. This raised the question, if the level of being obese or being overweight might influence the TL-BMI correlation.
So far, we found studies correlating with linear regression the BMI of normal weight and overweight cohorts and a significant inverse BMI-TL associated was only found for women (Nordfjall et al.
2008). However, by correlating BMI and leukocyte TL of an overweight population (25 ≥ BMI ≤ 30) no association was seen. (Farzaneh-Far et al. 2010; Tiainen et al. 2012; Appleby et al. 2017) In class II obesity an inverse association of BMI and TL in whole blood samples was also only obtained in women so far (Al-Attas et al. 2010), whereas, no association between BMI and telomere attrition was seen in a class III obesity population (Laimer et al. 2016). These findings from Laimer et al. are in accordance of our data, as we also saw no correlation between BMI and TL in class III obesity samples and additionally, further subdividing into genders did not lead to a significant linear regression between TL and BMI.
Interestingly, depending on the approach for the investigation of obesity and TL relationship, different findings were obtained. If the TL of obese people is compared to the TL of normal weight people shorter telomeres are found in the obese group. If BMI data are correlated by linear regression with TL data, no BMI-TL association could be found. Thus, it could be, that regression analysis might not reveal significance if just small ranges of BMI in one group are connected with TL. This leads to the assumption that body weight itself just might have a small biological effect on TL and a linear
Discussion
94 regression between BMIs ranging from normal weight (18.5 ≥ BMI ≤ 25) to class III obesity (BMI ≥ 40) is needed.
Bariatric surgery-induced weight reduction increased telomere length of severely obese patients So far, two interventional studies with bariatric surgery exist, which investigated the telomere length alteration in human blood over time. In 2014, Formichi and co-workers investigated the leukocyte TL of obese patients, They followed the patients over 1 year after bariatric surgery by measuring TL all 3 month and a continuous significant telomere length decrease (of 6.4, 10.6, 13.8, and 16.0 % at 3, 6, 9, and 12 month afterwards, respectively) was seen after bariatric surgery (Formichi et al. 2014). These findings are in contrast to our results. At 6 month we saw no telomere length change (meanTSI +0.76
%) was received, which was also not changed after 12 month (meanTSI +1.8 %).
Formichi et al. had a similar patient cohort but a different methodic setup. Their subjects showed a mean BMI of 46.5 kg/m2 and in our study the average BMI was 48 kg/m2, however telomere length was measured with the qPCR and in leukocyte samples including granulocytes. Furthermore, they included subject receiving several different surgeries like sleeve gastrectomy, gastric bandings, gastric bypasses, biliopancreatic diversions, and gastric plication. Furthermore, with their data they could not show the telomere shortening effect with increasing age (Formichi et al. 2014).
Additionally, we also investigated for the first time the TL of human PBMCs at 24 month post-bariatric surgery. Most importantly, at this time point we were able to show a significant TL increase of +5.6 %, revealing a possible starting point for telomere lengthening after bariatric surgery-induced weight reduction. Subdividing these data for gender affiliation we also received a +5.6 % TL increase for women. Due to the low number of male participants no further assumption for men could be made.
Besides Formichi and co-workers, a second study indicated recently TL regulation in bariatric-aided obese humans. Here, Laimer and colleagues indicated with a prospective intervention study a 2.3 % increase of telomere length for obese women 10 years after weight reduction surgery (Laimer et al.
2016) while a normal weight control population revealed over the same period a telomere length decline of 4.9 %. Different from our study, their cohort received either a gastric banding or a RYGB, while our patients received either a sleeve gastrectomy or RYGB and TL was measured in leukocytes with the qPCR method. The starting mean BMI of their cohort was 41.4 kg/m2 and thus lower but a similar weight reduction was indicated as we have seen (- 21 %).
Here, we showed for the first time a TL increase 24 month after bariatric surgery-induced weight reduction and demonstrated that this is the time of beginning TL increase. Conflicting results up to 1 year post-surgery between Formichi et al. and our data might be due to the post-surgical state and its changed metabolism until catabolism discloses stability. So it could be that these radical changes also led to a disordered TL regulation after the first month of surgery receiving TL variations, underlining, that adipose tissue is known for bioaccumulation of lipophilic environmental substances (Durante et al. 2016). The stored toxins may be released during weight loss and become released back into the
95 metabolism causing additional negative effects to human health and imbalanced TL regulation.
Reaching a weight balance and a stable environment for catabolites and hormones, the weight reduction might have induced a positive effect on physical and psychical state and together with the 10 year study this suggest, that upon intervention TL in obese people increases and that this effect is long lasting.