What happens to adipose tissue after obesity surgery.

https://doi.org/10.58974/bjss/azbc027

Based on Dynamics of adipose tissue macrophage populations after gastric bypass surgery.

As stated by the authors of this paper, obesity is an epidemic worldwide and has been implicated as a central factor in the pathophysiology for the metabolic syndrome (MetS) and other chronic medical conditions. For example, obesity is a critical risk factor for the development of type 2 diabetes mellitus (T2DM) with research demonstrating obesity-driven insulin resistance (IR) in white adipose tissue (WAT) as a primary driver.^1,2 This report is significant given that our understanding of adipose tissue has changed and we now know that it is a complex, hormonally active organ. Furthermore, metabolic dysregulation of adipose tissue, as observed in obesity, leads to local inflammation which is a key component in the pathophysiology of MetS and IR.³

The immune cells most central to the development and control of adipose tissue inflammation are macrophages. In obesity, there is a significant shift in macrophage activation from an “M2” or anti-inflammatory state to an “M1” or pro-inflammatory state.⁴ Overproduction of pro-inflammatory cytokines such as TNF-α from M1 macrophages has been linked to IR while IL-10 secretion from M2 macrophages promotes insulin sensitivity.^4,5 However, there is emerging evidence that there are discrete subpopulations and activations states outside the dichotomy of M2 or M1 macrophage phenotypes which may be associated with various diseases including T2DM, cancer, atherosclerosis, etc.⁶ The expanding knowledge of macrophage diversity likely applies to adipose tissue, thus further demonstrating the complexity of adipose inflammation.^7,8

Histologically, the defining feature of adipose tissue inflammation is dead or dying adipocytes surrounded by macrophages which form crown-like structures (CLS) (Figure 1A-C).^9,10 In this study, Palomäki et al. performed a tissue sample analysis on subcutaneous fat from 122 obese subjects undergoing either surgery or conservative treatment. For comparison, they included 39 and 43 subjects with paired adipose tissue samples, respectively. To our knowledge, this is the largest follow-up tissue sample analysis involving obese subjects. Despite advances in medical therapy, bariatric surgery still remains the gold standard for treatment of severe obesity with laparoscopic Roux-en-Y gastric bypass (LRYGB) and vertical sleeve gastrectomy being the most common procedures.¹¹ However, even with its superior effect on weight loss, as pointed out by the authors, 11-35% of patients develop suboptimal weight loss. Importantly, weight loss has been associated with improvement of comorbidities and inflammatory status.^3,12,13 Two aims of this study were addressed: The first was to understand the impact of LRYGB versus conventional obesity treatment on adipose tissue inflammation by measuring macrophage distributions/populations and CLS density before and after each intervention. The second aim was to determine the extent to which inflammation correlated to weight loss.

The methods involved in this study included sampling of periumbilical subcutaneous fat from obese individuals before and at one year following the planned intervention: LRYGB or conventional treatment. Samples were prepared by standard histopathology  and immunohistochemical staining and were analyzed for both adipocyte density, fat cell size and CD68 staining to detect macrophages.¹⁴ Using imaging software, the number of macrophages within a given sample area was determined, as well as manual counting of the number of CLS within the sample.

In the samples collected prior to intervention, there were no major differences seen between the two groups in terms of mean number of CLS per 1000 fat cells. They noted that 16.6% of CD68 macrophage staining was localized to the CLS while the remainder and majority was dispersed throughout the adipose tissue. Using bivariate analysis, they also demonstrated a correlation between CLS density and CD68 staining outside of CLS. Therefore, the greater the number of CLS detected, the greater the number of CD68 staining in the surrounding tissues, correlating to a greater number of macrophages. Interestingly, in patients with obesity who also had T2DM, they observed significantly larger fat cell (FC) size with smaller FC density compared to non-diabetic patients. Prior work by others has demonstrated that FCs are larger in patients with T2DM even among those who are not obese.¹⁵ Some have hypothesized that fat cell hypertrophy may lead to local hypoxia and may serve as a stimulus of inflammation, thus serving as a basis for the white adipose tissue dysregulation.^16,17

As might be expected, at one year follow-up, BMI, weight, and total weight loss (TWL) % had declined in the surgery group, but no change was seen in the conventional treatment group. A shift from larger to smaller FC size adipocyte populations was observed in the LRYGB group but not in the conventional group.

In the surgical group, there was a statistically significant reduction in CLS per 1000 FCs while in contrast, CLS density demonstrated an increased trend in the conventional treatment group (Figure 2A). There was also an increase in CD68 positive staining outside of CLS with the conventional group without a significant change in the surgical group (Figure 2B). Impressively, the surgery group had a greater number of CD68 positive staining within CLS compared to the conservative group at baseline, but had a greater reduction after intervention, indicating reduced inflammation as a result of surgery (Figure 2C). Surgery not only resulted in a greater reduction in CLS-associated macrophages when compared to the conservatively treated group, but also demonstrated a lower overall CLS density. As stated in the manuscript, obese adipocytes are susceptible to a pyroptosis-like programmed cell death which is similar to apoptosis but is characterized by a highly inflammatory state. In pyroptosis, there is release of proinflammatory cellular contents and increased inflammasome stimulation.¹⁸ Therefore, following LRYGB, the reduction in CLS suggests a decrease in adipocyte cell death which in turn, may represent a decrease in macrophage recruitment, activation and inflammation.  

A “within-group” comparison was made in the surgical group; the investigators compared patients who had a good response (TWL >20%) to those with a poor response (TWL <20%) at 12 months. Results indicated no significant associations of the preoperative measurements with eventual weight loss. Interestingly, despite suboptimal weight loss, the TWL <20% groups demonstrated significant decreases in CLS density and CD68 staining within CLS reaching similar values to the TWL >20% group after one year.

This weight-loss independent improvement in CLS density and associated macrophages following surgery emphasizes the positive metabolic response and inflammatory changes that occur with surgery, independent of weight loss alone. Therefore, this study further confirms that there are significant metabolic effects of surgery that appear to occur independent of weight loss. For example, in obese patients with T2DM, metabolic surgery has been shown to improve the incretin effect, increase bile acid circulation and metabolism, alter the gut microbiome, and decrease adipose tissue inflammation. Taken together, there are multiple beneficial effects of surgery that may ultimately lead to improvements in glycaemic control and insulin resistance.^12,13,19,20

Limitations:

Given the lack of difference in CD68 staining outside the CLS, this study was limited in focus as it only quantitatively assessed macrophages without assessing their function qualitatively by examining, for example, their phenotype state (i.e. M1 versus M2). Therefore, whether a functional change in macrophage activity occurred as a result surgery will require further study.

Conclusions and Importance to the field of surgery:

This study represents the largest tissue-based follow-up analysis comparing patients with obesity before and after bariatric surgery versus conservative therapy at one year follow-up. The finding that there were significant decreases in CLS and associated macrophages after bariatric surgery when compared to conservative management, suggests a significant role for surgery to dampen the inflammatory state of the obese patient and perhaps maintain improved metabolic control. This is further strengthened by the observation that regardless of the degree of weight loss following surgery, all surgical patients had improvements in CLS density and associated macrophages. These findings add to the growing body of research demonstrating that weight-loss independent mechanisms after bariatric surgery contribute to the superior improvement in metabolic factors of obese patients versus conventional weight-loss therapy. This study further highlights the role of bariatric surgery in the care of obese patients.