Introduction
Bariatric surgery is considered an effective way for weight loss in the short and long term. It can help patients decrease the risk of obesity-related diseases [
1,
2]. There are strong evidences supporting the safety and effectiveness of bariatric surgeries [
3]
. Most pathologic co-morbidities associated with obesity including diabetes, hypertension, sleep apnea, and dyslipidemia could improve after the bariatric surgery. Further, these surgeries could improve life expectancy and also the quality of life [
4]. Mechanisms behind the effects of bariatric surgery on weight loss are poorly understood. Most of the studies focused on the changes in the brain-gut axis and neuropeptides or factors such as ghrelin, NPY, glucagon-like growth factor, and so on. All of the aforementioned changes could finally regulate food intake, appetite, glucose metabolism, and reduce liver gluconeogenesis [
5]. There aren’t enough studies assessing the cellular or molecular mechanisms behind the effects of bariatric surgery on weight and energy expenditure status. Fat accumulation in obese people could cause inflammation and mitochondrial dysfunction which could in turn decrease mitochondrial biogenesis [
6]. Downregulation of mitochondrial biogenesis and dysfunction in mitochondrial oxidation caused by adipocyte dysfunction and also macrophage infiltration could induce insulin resistance, metabolic syndrome, and liver steatosis [
7]. One of the proteins involved in the regulation of mitochondrial biogenesis is Peroxisome proliferator-activated receptor coactivator-1α (PGC-1α) [
8]. This protein could induce energy production in the electron transport chain in the mitochondria [
9]. Changes in the PGC-1α were not assessed in the previous studies of post-bariatric surgery. Moreover, another mitochondrial protein called uncoupling protein-2 (UCP-2) plays a pivotal role in the optimal mitochondrial function and thermogenesis, and this way it can affect body weight and insulin resistance as well [
10]. Any increase in the level of PGC-1α and UCP-2 in the white adipose tissue could demonstrate the characteristics of increasing fat oxidation and thermogenesis by upregulation of mitochondrial biogenesis and function [
11]. However, few studies assess the changes in PGC-1α and UCP-2 post-operatively, and due to the important role of mitochondrial dysfunction in obesity pathogenesis or lack of success in non-surgical weight loss programs, the aim of this study was to evaluate the changes in serum PGC-1α and UCP-2 simultaneously with the changes in weight and body composition, insulin resistance, blood lipids, insulin, and glycemic control, liver enzymes, and their relationships.
Discussion
Bariatric surgery is considered an effective way for accomplishing appropriate weight loss, both in the short-term and long-term in those with severe obesity. Further, it can facilitate the control and prevention of obesity-related co-morbidities [
1,
2]. One of the main mechanisms concerning obesity or lack of success in weight reduction in patients with morbid obesity is mitochondrial dysfunction [
6].
In the present study, significant decreases were found regarding weight, BMI, body fat, muscle mass, trunk muscle mass, visceral fat, and trunk fat, and an increase was seen in body water in the patients undergoing bariatric surgery overtime after 3, and 6 months post-operatively. These findings confirm the results of a previous study done by Maïmoun et al. [
14], that assessed the changes in body weight and composition after bariatric surgery in 1 and 12 months post-surgery. They also reported significant decreases in body weight, fat, lean body mass, and visceral fat, especially in the long term after the surgery [
14]. This was also in line with the results of the study by Sivakumar and colleagues that showed a decreasing trend in body weight, BMI, body fat, and muscle mass 12 months after the surgery [
15]
.
As another finding of the present study, assessment of biochemical glycolipid profile at three time points before and after the surgery, showed significant increasing trends in the serum levels of PGC-1α and UCP-2 over the time, post-operatively (3 and 6 months) in comparison to the baseline. No study assessed the changes in PGC-1α or UCP-2 post-operatively and only one animal study emphasized the increase in the levels of AMPK [
16] as an important inducer of PGC-1α [
9] which could indirectly confirm the increasing trend in the PGC-1α after the surgery.
Moreover, significant time trend decreases for HOMA-IR, serum Insulin, FBS, and percentage of HbA1c were observed at 3 and 6 months post-operatively. In addition, improvements in lipid profiles and liver function tests were seen at 3 and 6 months after the surgery. This finding was also observed in a previous study by Liu and colleagues who observed reduced levels of insulin, HbA1c, and blood glucose post-operatively in those undergoing bariatric surgery [
17]. Moreover, the decreases in the liver enzymes were in accordance with a previous study showing post-operative reduction of AST and ALT, 2 years after the surgery. It was asserted that the increased level of ALT is related to high serum glucose, low insulin sensitivity, and diabetes risk [
18]. Hence, the decrease in ALT and AST levels post-operatively can be a possible mechanism describing the simultaneous decrease of liver enzymes, FBS, and HOMA-IR.
Several mechanisms are responsible for the decrease in biochemical parameters after bariatric surgery. One of the main mechanisms, independent of weight loss effects, is pertinent to the changes in the gut microbiome. The level of circulating bile acids is increased after the bariatric surgery and this can change the gut microbiome and this can affect the decrease in the liver enzymes independent of the weight-loss effects of the bariatric surgery [
19‐
21]. Moreover, any increase in the activity of the PPAR pathway could definitely decrease the level of liver enzymes [
22] and this was seen in the present study regarding the increase in PGC-1α which probably affected the levels of liver enzymes post-operatively.
According to further analysis, it was observed that FBS, insulin, uric acid, HOMA-IR, fat (kg), and trunk fat (kg) have independent prognostic values for PGC-1α level which means that their decrease was accompanied by and related to the increase in the PGC-1α level post-operatively.
As another finding, TSH, AST, fat, and FFM had independent predictive effects on the level of UCP-2. This means that higher levels of UCP-2 were accompanied by increased FFM and decreased TSH and body fat. Furthermore, these factors could predict the changes in UCP-2 after bariatric surgery. This finding confirms a previous report in a systematic review that mentioned how changes in the expression of UCP-2 and UCP-3 could affect weight loss after surgery [
23]. Therefore, it emphasizes the relationship between increased levels of UCP-2 and a decrease in fat mass and overall weight.
Regulatory mechanisms of mitochondria are involved in obesity and its pathogenesis and the effects of calorie restriction. In this regard, PGC-1α is definitely related to the metabolic status in the white adipose tissue [
23] and any increase in the PGC-1α and subsequently UCP-2 in the white adipose tissue shows the feature of the brown adipose tissue as they can induce fat oxidation and thermogenesis that all help weight loss and increase insulin sensitivity [
11]. As a fact, PGC-1α can affect the neuro-metabolism, especially the orexinergic system [
24]. As a protein interacting with PPAR-γ, PGC-1α [
25] could bind to some transcription factors such as estrogen-related receptor α (ERRα), nuclear respiratory factor (NRF)-1, and NRF-2, and this way it can activate some genes [
26‐
29]. NRF-1 and NRF-2 could affect some mitochondrial genes, especially those that are active in the respiratory chain [
28]. ERRα can regulate the metabolic pathways related to the tricarboxylic acid cycle and β-oxidation and mitochondrial metabolism [
29‐
31], showing the effects of PGC-1α in the fat metabolism which is necessary in weight management. In addition, UCP-2 is a key regulator of energy expenditure in the mitochondria and they have a pivotal role in the management of obesity, hyperinsulinemia, and metabolic syndrome [
32]. UCP-2, as a protein expressed in the adipose tissue and pancreatic endocrine system [
33], could modulate insulin and glucose metabolism and regulate insulin secretion which could relate it to obesity and diabetes [
34,
35]. Moreover, the effect of PGC-1α on the modulation of the insulin pathway was previously observed [
36]. These effects could possibly justify the simultaneous decrease in body weight and body composition, HOMA-IR, serum insulin, FBS, and percentage of HbA1c with the increase in UCP-2 and PGC-1α in the present study. This increase could show the protective effects of UCP-2 and PGC-1α on energy, fat, and glucose metabolism. However, another hypothesis can also be considered that the increase in energy expenditure serum markers may result from the reversal of comorbidities, thus providing an additional explanation for the results.
On the other hand, it is mentioned previously that the decrease in the adipose tissue following the bariatric surgery could decrease the TSH level subsequently due to the decreased expression of TSH genes or TSH receptor genes [
37]. Hence, it can be hypothesized that the increase in the UCP-2 after the surgery and its effects on decreasing body fat and weight, could indirectly modulate thyroid hormones and decrease TSH and this can in part explain the prognostic significance of TSH for UCP-2 observed in the current study.
Previous studies illustrated that PGC-1α can affect various metabolic pathways or medical conditions including diabetes, neurodegenerative diseases, obesity, and the like [
24]. Hence, the increase shown in the levels of PGC-1α and UCP-2 could possibly correlate to the changes in weight and appetite due to the metabolic effects of PGC-1α and UCP-2, especially in the regulation of fat metabolism and energy expenditure in the mitochondria. This increase could be a possible underling mechanism show the beneficial relationship between weight loss and metabolism through changes in PGC-1α and UCP-2.
This study had some strengths from which the most important one is related to the complete assessment of the patients pre- and post-operatively over various times in six-month periods after surgery, which the most changes in weight, body composition, and metabolic parameters occurred in the first six months postoperatively. Furthermore, the present study evaluates the most important cellular regulator of mitochondrial energy homeostasis, and energy expenditure indicators and their relationship with body composition at three time points pre- and post- bariatric surgery. However, the present study had some limitations as well. Due to the difficulties in following the patients in the long term, only six months of follow-up was possible for the present study compared to other studies with longer follow-ups. Surely, it would be better to follow the patients for longer durations to assess any chance of recurrence of any abnormality. Additionally, due to the design of the study, it was not possible to establish causal relationships. Moreover, due to financial constraints and a limited research budget, we were only able to measure the body composition and blood biochemical parameters at three stages and in larger sample size.
Conclusion
To sum up, patients who undergo bariatric surgeries may experience significant reductions in weight, BMI, body fat, FFM, insulin, FBS, HbA1C, HOMA-IR, blood lipids, and liver enzymes after time, post-operatively. Moreover, increase in UCP-2 and PGC-1α observed post-surgery could be connected to these changes. The effects of UCP-2 on insulin/glucose regulation, fat metabolism, energy expenditure, liver enzyme modulation, and its indirect impact on TSH gene expression (due to fat loss) may explain some of the aforementioned outcomes. Moreover, the effects of PGC-1α on glucose metabolism, fat oxidation, and weight management through the regulation of mitochondrial metabolism may also contribute to these changes. However, additional research is needed to fully comprehend the exact mechanisms and potential cause-and-effect relationship between changes in energy expenditure, factors influencing thermogenesis, and post-surgical metabolic outcomes. It is important for these studies to be conducted over a prolonged period to ensure a thorough understanding.
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