Il ruolo dell'adiponectina e della leptina nel cancro colorettale e nell'adenoma: una revisione sistematica e metanalisi

Introduction

Colorectal cancer (CRC) ranks as the third most frequent and the second deadliest globally, accounting for more than 930,000 fatalities [ ]. Based on the 2020 global cancer statistics, the count of newly diagnosed CRC cases had nearly doubled over the past three decades, and in 2020, nearly 2 million new cases of CRC were reported [ ]. Although the advancements in understanding the pathophysiology of CRC have doubled the overall survival rate for advanced cases to three years, patients with non-metastatic disease continue to have the best survival outcomes [ , ]. Since symptoms typically appear only in later stages, global screening programs are being implemented to enhance early detection and decrease the number of CRC cases and related mortalities [ ]. CRC is influenced by a combination of environmental and genetic factors, which can be broadly categorized into modifiable and non-modifiable risk factors [ ]. Estimates suggest that 25–30% of CRC cases are linked to unchangeable risk factors, including genetics, a personal history of adenomas or polyps, predisposition, and a family history of CRC or inherited genetic risks. Conversely, 70–75% of cases are thought to be affected by changeable risk factors, including alcohol intake, psychological stress, smoking, obesity, physical inactivity, and unhealthy eating habits (characterized by high intake of red and processed meats and fats) [ – ].

Obesity has been linked to cancer development and cancer-related deaths [ ]. Research indicates that excess body weight is related to roughly 8% of all cancer diagnoses in the USA and approximately 7% of all fatalities caused by cancer [ ]. Furthermore, overweight adolescents diagnosed with colon cancer (CC) have double the risk of mortality in adulthood [ ]. Visceral adipose tissue has been linked to colorectal neoplasm due primarily to the involvement in the chronic inflammatory and insulin resistant conditions [ , ]. Some studies have shown increased visceral adipose tissue correlating with change in the secretion profile of adipokines and inflammatory cytokines such as interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) [ , ]. Such molecules are able to set a microenvironment suitable for tumorigenesis by promoting increased cell proliferation and reducing apoptosis, thus facilitating adenoma establishment and its further advancement to cancer [ ]. Specifically, elevated levels of IL-6 are involved in development and progression of the cancer, mediating inflammatory pathway for carcinogenesis [ ]. One suggested explanation for the connection between CRC and obesity is the dysfunction of adipose tissue, which involves the secretion of various hormones classified as adipokines, with adiponectin and leptin being the most notable [ , ]. Leptin is a hormone produced solely by adipocytes within fat tissue. It has an important role in controlling appetite and managing energy balance. Concentrations of leptin are directly connected with BMI, meaning they are higher in individuals who are obese [ ]. It has been shown that leptin affects angiogenesis, the immune system, reproduction, and the metabolism of fats and carbohydrates [ ]. Adipocytes are the main source of the insulin-sensitive hormone adiponectin, which has anti-atherosclerotic, anti-tumor, and anti-inflammatory effects [ ]. Current research indicates that adiponectin takes part in many physiological processes—ranging from lipid metabolism and energy balance to immune-inflammatory regulation and the promotion of insulin sensitivity—through its molecular and cellular actions [ ]. These two adipokines affect different diseases in distinct ways. Cardiovascular disorders and metabolic disorders, including type 2 diabetes, are associated with reduced adiponectin concentrations [ ]. Additionally, an elevated risk condition such as metabolic disorders, obesity, and hypertension might result from higher leptin concentrations [ ]. Furthermore, the development and spread of several cancer types are influenced by these two adipokines. For instance, research has associated the risk of some cancers, including prostate, breast, endometrial, and pancreatic cancers, with higher leptin and lower adiponectin concentrations [ ]. Studies have revealed that reduced total adiponectin concentrations are significantly linked to an elevated risk of CRC. Nonetheless, some studies have indicated elevated total adiponectin concentrations in CRC patients compared to the group of controls [ , ]. The present systematic review seeks to specifically explore the relationship between adipokine concentrations (leptin and adiponectin) and CRC risk.

Material and methods

This study was carried out in alignment with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 checklist standards [ ]. Its protocol was registered in the International Prospective Register of Systematic Reviews (PROSPERO) with a registration ID of CRD42024606249.

### Literature search

A systematic literature search was performed across different databases, such as Scopus, PubMed, Web of Science, and Google Scholar, in November 2024. The search was conducted by using the subsequent Medical Subject Headings (MeSH) keywords and terms in the databases: (Adiponectin OR Adipocyte Complement-Related Protein 30-kDa OR ACRP30 Protein OR Adipocyte Complement Related Protein 30 kDa OR Adipocyte, C1q OR Collagen Domain Containing Protein OR apM 1 Protein OR apM-1 Protein OR Adipose Most Abundant Gene Transcript 1 OR Leptin OR Ob Gene Product OR Gene Product, Ob OR Ob Protein OR Obese Gene Product OR Gene Product, Obese OR Obese Protein) AND (Colorectal Neoplasms OR colorectal cancer OR Neoplasm, Colorectal OR Colorectal Neoplasm OR Neoplasms, Colorectal OR Colorectal Tumors OR Tumor, Colorectal OR Colorectal Tumor OR Tumors, Colorectal Cancers OR Colorectal OR Cancer, Colorectal OR Colorectal Cancer OR Cancers, Colorectal OR Carcinoma, Colorectal OR Colorectal Carcinoma OR Colorectal Carcinomas OR Carcinomas, Colorectal). Furthermore, forward and backward citation searching was systematically conducted. A backward citation search was systematically performed to ensure the inclusion of pivotal and foundational prior studies. We searched through the reference lists of included articles to find other pertinent works that might have been overlooked at first. Newer studies that have cited the included studies since they were published were evaluated through forward citation searching.

### Study selection and data collection

The eligibility evaluation was conducted by M.M. and M.K., who independently evaluated the titles, abstracts, and full texts of the studies. In case of disagreement, an interactive discussion panel was used to reach a settlement. Any unresolved conflicts were referred to a third reviewer (M.R.). The inclusion criteria were based on how relevant the study was to our research question, explicitly assessing circulating levels of adiponectin or leptin in CRC or adenoma patients. The exclusion criteria included editorials, reviews, in vitro, and animal studies. We used the PECO framework as follows: The population (P) consisted of patients with CRC or adenoma, and comparison groups included healthy individuals or patients with other diseases. The exposure (E) focused on the body’s adiponectin or leptin circulating levels. The comparison (C) included the comparison of concentrations of adiponectin and leptin between patients with CRC or adenoma of the colorectal and healthy individuals or those with other diseases. The outcome (O) assessed the association between serum concentrations of leptin and adiponectin and CRC and adenoma development risk.

### Data extraction

M.A. and F.E. designed a standardized data extraction form. Data were systematically retrieved from the included articles by the mentioned reviewers. Any discrepancies were resolved through consensus. The subsequent data were collected: the first author’s name, study design, country, publication date, leptin level, type of disease (CRC or adenoma), gender, age, and BMI.

### Risk of bias evaluation

A. A. and M.M. utilized the Joanna Briggs Institute (JBI) critical assessment tools [ ] to assess the standard of the selected articles. A third reviewer (M.R.) was consulted in cases of disagreement.

### Statistical analysis

We conducted random-effects meta-analyses to calculate the pooled odds ratios (ORs) and corresponding 95% confidence intervals (CIs) for the association between serum leptin and adiponectin levels and the risk of colorectal cancer and adenoma. The restricted maximum likelihood (REML) method was applied. To explore sources of heterogeneity, we performed subgroup analyses based on gender, cancer type, geographic region, and the method of risk estimation. Additionally, meta-regression analyses were conducted to assess the influence of study-level covariates, including mean age, sex distribution, and body mass index (BMI), on the pooled estimates. Heterogeneity was assessed using Cochran’s Q test and quantified using the I 2 statistic. Egger’s regression test was used to evaluate potential publication bias. A p-value < 0.05 was considered statistically significant.

All statistical analyses were performed using R software (version 4.4.1, 2024–06–14), utilizing the “meta” and “metafor” packages.

Results

### Study selection

A total of 2,589 studies were identified following a comprehensive search. After the elimination of duplicates, 1,669 articles remained. In total, 1,491 articles were excluded based on their titles and abstracts, and 178 articles remained for evaluation of full text. Finally, 148 articles were excluded, and 30 articles were included in this study. Figure illustrates the study selection process.

### Study characteristics

Among the included studies, 29 were case–control [ – ], and one was a cohort study [ ]. In total, 44,271 men between the ages of 40 and 69 with a three-year follow-up duration participated in a cohort study that was performed in Japan. A total of 9,554 cases and 12,789 controls were included in the case–control studies. Eight articles were performed in the United States [ – ], seven in Japan [ – ], four in China [ – ], three in Sweden [ – ], two in Norway [ , ], two in Greece [ , ], two in Europe [ , ], and one in France [ ]. Among the reviewed articles, seven discussed the effect of leptin [ , , , , , , ], 10 examined the impact of adiponectin [ , , , , , , , , , ], and 13 articles [ – , , – , , , , ] investigated the influence of both factors on CRC. Among the analyzed studies, four [ , , , ] exclusively focused on female participants, while six [ , , , , , ] examined only men. The remaining studies included both genders in their analysis. Among these, the lowest female representation was observed in a case–control study [ ] with 31.5%, whereas another case–control study [ ] had the highest female representation, covering 70.3% of the participants (Table ).

### Quality of the included studies

The quality assessment of case–control studies indicated that most of the included articles had a low risk of bias, with the exception of two studies [ , ], which exhibited a moderate risk of bias (Table ). The risk of bias evaluation of cohort studies indicated that the cohort study [ ] included in our analysis had a moderate risk of bias (Table ).

Findings

### Adiponectin and colorectal cancer

For adiponectin and CRC, a total of 28 studies were analyzed using a random-effects model. The pooled OR was 0.85 (95% CI: 0.74–0.96), indicating a statistically significant negative association. Moderate heterogeneity was observed, with I 2 at 48% and τ 2 estimated at 0.0257 (P for heterogeneity > 0.01) (Fig. ). No significant funnel plot asymmetry was observed ( p = 0.98) (Figure ).

### The subgroup analysis for the connection between the levels of adiponectin and the risk of colorectal cancer

In the subgroup of men, the OR was 0.65 (95% CI: 0.50–0.85), indicating a notable decrease in risk. Within the subgroup of women, the OR was 0.85 (95% CI: 0.64–1.12) with a weaker effect. The mixed-gender group showed moderate heterogeneity (I 2 = 55%). A test for subgroup differences ( P = 0.10) suggested no statistically significant variation between genders. These findings indicate a stronger effect in men, while the effect in women remains unclear (Fig. ). In the CRC subgroup, the OR was 0.81 (95% CI: 0.69–0.95) with a moderate level of variability (I 2 = 54%, P < 0.01). For colon cancer (CC) and rectal cancer (RC), the pooled ORs are 1.05 (95% CI: 0.82–1.35, I 2 = 0%) and 0.77 (95% CI: 0.43–1.35, I 2 = 2%), respectively, with no significant heterogeneity. The test for subgroup differences ( P = 0.20) was not statistically significant, indicating no substantial variation in adiponectin’s effect across CRC types (Figure S2).

A subgroup analysis based on the comparison method showed variability in the link between higher adiponectin levels and the risk of CRC, with an OR of 0.87 (95% CI: 0.73–1.03) for quartile-based comparisons, 0.73 (95% CI: 0.54–0.98) for logistic regression, and 3.46 (95% CI: 1.72–6.97) for dichotomous comparisons. The heterogeneity (I 2 ) ranged from 0 to 57%, with the highest heterogeneity observed in per doubling concentration comparisons (I 2 = 57%, P = 0.04). The analysis revealed significant differences among subgroups ( P < 0.01), suggesting that the estimated effect of adiponectin varies depending on the comparison method used in different studies (Figure S3).

In the European studies, the pooled OR for adiponectin and CRC risk was 0.92 (95% CI: 0.84–1.00). The heterogeneity was of 33%. In the Asian studies, a stronger inverse relationship was observed, with an OR of 1.23 (95% CI: 0.68–2.22), though indicating no statistically significant association. The heterogeneity in these studies was higher, with an I 2 of 67%, and the P-value was significant at P < 0.01.

For the studies in the USA, the pooled OR was 0.75 (95% CI: 0.59–0.94), showing an inverse association between adiponectin levels and CRC risk. The heterogeneity for these studies was 34%. The test for subgroup differences was not significant ( P = 0.15) (Figure S4).

Adjusting for BMI in 22 studies strengthened the inverse association, resulting in a pooled OR of 0.78 (95% CI: 0.65–0.95), although heterogeneity increased (I 2 = 48.27%, τ 2 = 0.0649). Adjustments for insulin across three studies, however, yielded a not statistically pooled OR of 1.745 (95% CI: 0.71–4.24), with moderate heterogeneity (I 2 = 57.05%, τ 2 = 0.35).

Meta-regression analyses for adiponectin and CRC examined similar moderators. Age did not show a significant effect (estimate = −0.006, P = 0.75), nor did sex (estimate = −0.25, P = 0.25) or BMI (estimate = −0.027, P = 0.705). These findings suggest that the observed associations were not significantly influenced by these covariates.

### Leptin and colorectal cancer

The systematic review for leptin and CRC included 23 studies, analyzed utilizing a random-effects model. The pooled odds ratio (OR) was 1.12 (95% CI: 0.96–1.31), suggesting no significant statistical relationship between elevated leptin levels and CRC. Moderate heterogeneity was observed, with I 2 at 49% and τ 2 estimated at 0.0389 (P for heterogeneity < 0.01) (Fig. ).

Funnel plot asymmetry tests were conducted to assess potential publication bias. For leptin, no significant asymmetry was detected for CRC ( p = 0.49) (Figure S5).

### The subgroup analyses

Subgroup analyses showed ORs of 1.06 (95% CI: 0.88–1.27, I 2 = 50%) for mixed-gender studies, 1.40 (95% CI: 0.83–2.36, I 2 = 54%) for men, and 1.10 (95% CI: 0.91–1.33, I 2 = 26%) for women. No notable variations were observed ( P = 0.61) (Fig. ).

The subgroup analysis by cancer type for the connection between levels of leptin and CRC risk showed a pooled OR of 1.11 (95% CI: 0.94–1.32, I 2 = 43%) for CRC, 1.30 (95% CI: 0.63–2.68, I 2 = 80%) for CC, and 0.83 (95% CI: 0.52–1.35, I 2 = 0%) for RC. The analysis showed no statistically significant differences among subgroups ( P = 0.47), suggesting no significant difference in the relationship among various types of cancer (Figure S6).

The subgroup analysis based on comparison methods presented a pooled OR of 1.25 (95% CI: 0.90–1.73, I 2 = 37%) for quartile comparisons, 1.07 (95% CI: 0.52–2.22, I 2 = 0%) for logistic regression, 1.21 (95% CI: 0.51–2.89, I 2 = 65%) for dichotomous comparisons, and 1.18 (95% CI: 0.96–1.46) for per doubling concentration, 0.33 (95% CI: 0.08–1.28, I 2 = 31%) for tertile comparisons, 1.23 (95% CI: 0.62–2.43, I 2 = 68%) for quintile comparisons, 0.92 (95% CI: 0.82–1.04) for per 1 SD increase, and 1.35 (95% CI: 0.72–2.54) for per 1 unit increment. The overall random effects model showed an OR of 1.12 (95% CI: 0.96–1.31, I 2 = 49%), with no significant subgroup differences ( P = 0.19) (Figure S7).

In European studies, the pooled OR was 1.06 (95% CI: 0.85–1.31), indicating a marginal positive association between higher leptin levels and CRC risk. The heterogeneity in these studies was low, with an I 2 of 47%. In the Asian studies, leptin showed a stronger association, with an OR of 1.20 (95% CI: 0.70–2.07), although the confidence intervals suggest variability in the results. The heterogeneity for Asian studies was moderate, with an I 2 of 58%, and the P-value for heterogeneity was significant ( P = 0.02). In the USA, the pooled OR for leptin and CRC was 1.15 (95% CI: 0.92–1.43), demonstrating a modest positive association, with very low heterogeneity (I 2 = 1%). The subgroup differences did not reach statistical significance (P = 0.83) (Figure S8).

When adjusted for BMI using 17 studies, the pooled OR was slightly reduced to 1.02 (95% CI: 0.86–1.21), accompanied by a decrease in heterogeneity (I 2 = 24.47%, τ 2 = 0.02). Further sensitivity analysis adjusting for insulin levels across four studies demonstrated a meaningful relationship, with a pooled OR of 1.58 (95% CI: 1.07–2.32), and no observed heterogeneity (I 2 = 0%, τ 2 = 0).

Meta-regression analyses for leptin and CRC assessed potential moderators, including age, sex, and BMI. Age was not found to significantly influence the association (estimate = −0.016, P = 0.23). Similarly, sex (estimate = −0.008, P = 0.11) and BMI (estimate = −0.01, P = 0.75) did not significantly moderate the relationship between leptin levels and CRC.

### Adiponectin and colorectal adenoma

For adiponectin levels and colorectal adenoma, seven studies were evaluated by using random-effect models. The pooled OR was 0.79 (95% CI: 0.46–1.36), showing no meaningful statistical association. However, high heterogeneity was present, with I 2 at 80% and τ 2 estimated at 0.4509 (P for heterogeneity < 0.01) (Fig. ). The funnel plot was almost asymmetric with the p -value of 0.05 in Egger’s test (Figure S9).

### The subgroup analysis for the linkage between the levels of adiponectin and the risk of colorectal adenoma

In studies involving both genders, the pooled OR was 0.90 [95% CI: 0.16–5.25] with high heterogeneity (I 2 = 92%). In men, the OR was 0.79 [95% CI: 0.60–1.03] with low heterogeneity (I 2 = 2%), while in women, a single study indicated an OR of 0.88 [95% CI: 0.54–1.42]. No meaningful differences were identified among the subgroups ( p = 0.92) (Fig. ).

The pooled OR across the studies in Asia was 0.79 (95% CI: 0.46–1.36), though the confidence intervals overlap with 1, indicating no significant association. The heterogeneity was high (I 2 = 80%) with a P-value for heterogeneity less than 0.01 (Figure S10).

Meta-regression analyses for adenoma did not identify significant effects of moderators such as age, sex, or BMI.

### Leptin and colorectal adenoma

Regarding leptin levels and colorectal adenoma, we included five studies, and the analysis conducted with a random-effects model revealed a pooled OR of 1.39 (95% CI: 1.06–1.84). This indicates a meaningful positive relationship between the level of leptin and adenoma of the colorectal. No heterogeneity was observed, as I 2 was 0% and τ 2 was estimated at 0 (P for heterogeneity = 0.80) (Fig. ). Funnel plot asymmetry tests for leptin detected no significant asymmetry for adenoma ( P = 0.59) (Figure S11).

### The subgroup analyses

In the study involving both genders, the OR was 1.77 [95% CI: 0.67–4.67]. In men, the pooled OR was 1.50 [95% CI: 1.05–2.14], while in women, it was 1.14 [95% CI: 0.70–1.86], with no meaningful heterogeneity in either subgroup (I 2 = 0%). The test for subgroup differences showed no statistically significant variation between men and women ( p = 0.60) (Fig. ).

The pooled OR for studies in Asia was 1.36 (95% CI: 1.02–1.82), indicating a positive association. The heterogeneity was low (I 2 = 0%), suggesting minimal variability across studies. In the USA, the pooled OR was 1.70 (95% CI: 0.75–3.86), which also indicated a positive association, but with a wider confidence interval, indicating greater uncertainty (Figure S12).

Discussion

CRC is one of the leading causes of cancer-related morbidity and mortality worldwide. Obesity has been suggested to greatly raise the risk of developing CRC [ ]. Obesity is characterized by altered adipokine levels, including leptin and adiponectin [ ]. Adiponectin is a hormone with anti-inflammatory and anti-tumor properties, whereas leptin is involved in regulating energy balance and promoting cellular processes like proliferation and angiogenesis [ , ]. Despite substantial research, the role of these adipokines in CRC and adenoma risk remains controversial. This study aimed to clarify the association between serum adiponectin and leptin concentrations with CRC and adenoma risk, considering factors such as gender, BMI, and insulin levels. In this study, a statistically significant inverse relationship was observed between adiponectin levels and CRC, particularly in men. In addition, significant positive association was found between leptin levels and colorectal adenoma.

For adiponectin and CRC, a statistically meaningful inverse relationship was identified, which was strengthened after adjusting for BMI. Analyzing similar moderators, including age, gender, and BMI, indicated that these covariates did not significantly influence the observed associations. Touvier et al. [ ] identified a negative association between adiponectin levels and CRC, similar to our findings, which remained unaffected by other established risk factors. Aleksandrova et al. [ ] also determined that both total adiponectin and non-HMW adiponectin showed an inverse relationship with colorectal risk, independent of lifestyle and dietary factors. Similarly, Yamaji et al. [ ] identified a meaningful negative association between the levels of adiponectin and CRC. They suggested that adiponectin might reduce colorectal neoplasia risk through mechanisms that operate independently of the indirect pathway involving insulin resistance. However, their study had certain limitations, including the comparatively small size of the study population, as the mean BMI for women and men in the control group was 21.8 and 23.4 kg/m 2 , respectively. These results might not be exactly relevant to populations with severe obesity, which are more common in North America and Europe, where over 50% of adults fall into the overweight or obese category. However, different results were reported by Michael T. Marrone et al. [ ], who found no meaningful linkage between the levels of adiponectin and CRC. These findings revealed that the level of adiponectin does not seem to mediate the connection between obesity and CRC. The difference may arise from the varying proportions of adiponectin isoforms, each potentially having distinct relationships with CRC.

Mingyang Song et al. [ ] assessed plasma levels of adiponectin in both genders and found that elevated levels of plasma adiponectin were linked to a lower CRC risk in men. However, they found no meaningful connection between total adiponectin level and the CRC incidence in women. While the exact mechanism underlying this sex-based heterogeneity remains unclear, higher adiponectin levels in women might explain the lack of a significant association. Studies have represented that sex differences in adiponectin levels are not related to fat mass or distribution and could be influenced by sex steroid hormones. Therefore, the heterogeneity that existed in the relationship between adiponectin, obesity, and CRC risk based on sex may also reflect the specific impact of changes in estrogen and testosterone concentrations associated with obesity. Additionally, they found that the association between adiponectin levels and CRC risk varied based on the concentrations of CRP. The inverse association is stronger in patients with high CRP concentrations than in those with lower CRP levels. Given that circulating CRP levels indicate systemic inflammation and adiponectin has anti-inflammatory properties, these findings suggest that adiponectin may offer protection against CRC development in individuals with chronic inflammatory conditions but not in those with normal or low inflammation. However, no interaction was identified between adiponectin levels and other inflammatory markers beyond CRP. Another limitation of the study was the assessment of only total adiponectin levels, without examining specific adiponectin isoforms.

Esther K. Wei et al. [ ] also confirmed a significant negative association between plasma adiponectin levels and CRC in men. Contrasting these findings, Lukanova et al. [ ] claimed no significant relationship between circulating adiponectin concentrations and the risk of CRC, rectal, or colon cancers in men. Ultimately, it is possible that the insulin-sensitizing and anti-inflammatory effects of adipokines are more relevant during tumor progression rather than in the initial stages of clinically detectable disease. However, Paulette Dh et al. [ ] conducted their research exclusively in women and reported no statistically significant link between circulating adiponectin concentrations and the incidence of CRC . A possible mechanism underlying these sex-based differences may be associated with body fat. More specifically, it has been indicated that body fat percentage is inversely connected with the concentrations of adiponectin in men, while no such correlation has been found in women, indicating an independent relationship between body fat and adiponectin levels in women. Moreover, the study assessed only total levels of adiponectin, which may not correctly represent the true relationship with CRC risk.

One known risk factor for CRC is obesity, especially central obesity. A negative association exists between circulating adiponectin levels and obesity. Decreased circulating adiponectin in obese people may be caused by underlying factors such as an aberrant hormonal milieu, elevated oxidative stress, and a pro-inflammatory state that is frequently associated with obesity. Furthermore, adiponectin has strong anti-inflammatory and insulin-sensitizing properties. Insulin resistance and inflammation have been proposed as potential mechanisms correlating obesity to CRC. Adiponectin also exerts direct anti-cancer impacts by inhibiting cell proliferation and inducing apoptosis [ ].

In this meta-analysis, no statistically meaningful relationship was found between the concentrations of leptin and CRC. Meta-regression analysis assessed potential moderating factors, including age, gender, and BMI, in the relationship between the levels of leptin and CRC. Age did not significantly influence this association. Similarly, neither BMI nor gender significantly moderated the relationship between the concentrations of leptin and CRC.

Consistent with our results, numerous studies have claimed no significant relationship between leptin concentrations and CRC [ , , ]. Nevertheless, contrasting findings have been reported by Masataka Taguri et al. [ ], who identified an inverse relationship between the concentrations of leptin and CRC. However, their findings also revealed a negative association between leptin levels and BMI. Serum leptin levels increase in correlation with rising BMI, resulting in an elevated CRC risk. Conversely, adiponectin levels decrease, further contributing to an elevated CRC risk. Ho et al. [ ] performed a study on postmenopausal women and discovered that leptin was the only adipokine related to CRC after adjusting for insulin and pro-inflammatory factors. Nevertheless, these findings may not necessarily be generalizable to premenopausal women or men. Another study by Tamakoshi et al. [ ], conducted on Japanese women, reported that higher leptin levels were significantly connected to CRC, independent of potential risk factors. However, since the study population exclusively consisted of Japanese women, these findings may not be applicable to Western women with higher BMI. Stattin et al. [ ] found that leptin may represent a significant relationship between obesity and CRC risk in men.

The analysis revealed no statistically significant connection between the levels of adiponectin and colorectal adenoma. Moreover, for adenoma, no significant effects of moderators such as gender, age, or BMI were identified.

Otake et al. [ ] evaluated risk factors associated with early-stage cancer, advanced cancer, and adenoma. The results indicated that reduced adiponectin levels are a significant risk factor for both early-stage cancer and colorectal adenoma. They also established that lower adiponectin concentrations are linked to an elevated risk of early-stage cancer. Nakajima et al. [ ] conducted a study involving Japanese patients, which demonstrated an inverse correlation between adiponectin concentrations and the number of adenomas. Nevertheless, given that the average BMI of the patients in this study was 22.9 and all participants were Japanese, the authors suggest that this may influence the study's results. Furthermore, it is possible that variables not assessed in this study could be associated with impact adipokine levels and obesity.

Our analysis identified a statistically meaningful positive relationship between concentrations of leptin and the risk of colorectal adenoma. Similar to these findings, Chia et al. [ ] indicated that elevated plasma leptin levels were connected to a 2 to threefold greater risk of colorectal adenoma in male participants; however, no significant association was detected in female participants. The observed relationship between circulating levels of leptin and an elevated colorectal adenoma risk in men may be attributed to interindividual variability in leptin concentrations. In contrast, the absence of this relationship in women may be because of differences in endogenous hormonal profiles.

According to laboratory research, leptin promotes angiogenesis, aids in intestinal cell migration, renewal, and proliferation, and functions as a growth factor within the colonic epithelial cells. As a tumor grows, leptin may have a negative cumulative effect. Although women exhibit greater serum leptin levels compared to men, they do not show an increased risk of colorectal adenoma due to several factors. For example, men and women exhibit different body compositions, with men possessing a lower proportion of subcutaneous adipose tissue compared to women, and leptin levels are significantly elevated in subcutaneous adipose tissue compared to those in visceral fat. Moreover, women with overweight or obesity often exhibit elevated levels of hormones, including estrogen, which may provide a protective effect against the harmful impacts of leptin. Moreover, to control fat storage of the body, leptin is implicated in processes including cell proliferation, angiogenesis, and the inhibition of cellular death (the suppression of apoptosis). The relationship between the levels of leptin and the risk of CRC or colorectal adenoma development remains a subject of ongoing debate. Leptin may directly contribute to carcinogenesis, as indicated by the expression of leptin receptors in malignant tissues, adenomas, and normal human colonic mucosa [ ].

The limitations of the current study encompass the demographic characteristics of the examined population, including variations in age, groups, gender, and BMI, which may limit the generalizability to the entire population. Additionally, data on menopausal status among female participants were insufficient in the included studies and therefore could not be incorporated into subgroup or meta-regression analyses. Furthermore, a few studies have explored the impact of different adiponectin isoforms (total and HMW) on early and advanced cancers, while other studies focused only on total adiponectin, which may result in potential bias in the data. Furthermore, differences in the follow-up duration of patients and the frequency of test measurements may increase challenges. Additionally, the examination and elimination of confounding factors were not consistently conducted across all studies, which could have influenced our results.

Conclusion

In conclusion, this study identified a statistically significant inverse association between serum adiponectin levels and CRC, with a stronger protective effect observed in men compared to women. Given adiponectin's role in regulating insulin sensitivity and inhibiting tumorigenesis, these findings support its potential involvement in CRC pathophysiology. Conversely, serum leptin levels did not demonstrate a statistically significant association with CRC risk, even across subgroup analyses by gender and cancer type. However, adjustments for insulin levels hinted at a potential connection, suggesting the need for further research. Regarding colorectal adenoma, adiponectin levels did not show a meaningful relationship, whereas elevated leptin levels exhibited a significant positive association, reinforcing leptin’s proposed role in tumor promotion through mechanisms such as cell proliferation and angiogenesis.

Supplementary Information