We performed a clinic-based study estimating the association between circulating levels of multimers of adiponectin and the presence of Barrett’s oesophagus. We did not find any association between the total level of adiponectin and the presence of Barrett’s oesophagus, but did find that higher levels of the LMW multimers (trimers) of adiponectin were associated with one-third the risk of Barrett’s oesophagus. These effects may be stronger among women than among men, but we did not find a statistically significant interaction between adiponectin multimers and gender.
If adiponectin levels do influence the risk of Barrett’s oesophagus, what might be the mechanism? Adiponectin can bind to growth factors, thereby inhibiting the growth factors’ interaction with their cell membrane receptors.35
Adiponectin activates the 5′-AMP-activated protein kinase (AMPK) pathway, thereby suppressing cell proliferation, perhaps in part by regulating p21 and p53.18
Adiponectin also suppresses expression of cyclin D1, possibly via regulation of the β-catenin–Wnt pathway.18
Cyclin D1, Wnt and p53 are involved in neoplastic progression in Barrett’s oesophagus.36–38
Indeed, adiponectin induces apoptosis in a cell line of oesophageal adenocarcinoma,19
and inhibits leptin-induced proliferation in cell lines of oesophageal adenocarcinoma.20
However, most of these studies have not attempted to distinguish the effects of the various multimers, and the effect of adiponectin on the metaplastic event has not been directly studied in vitro. Since Barrett’s metaplasia is believed to be an aberrant response in the setting of erosive oesophagitis,39
an attractive hypothesis is that normal levels of circulating LMW adiponectin are sufficient to suppress the inflammatory response to GORD,25
or guide the healing response toward regeneration of squamous mucosa. For instance, LMW adiponectin might suppress the local expression of IL6 in oesophageal mucosa.25
IL6 expression has been shown to be increased in the epithelium of Barrett’s oesophagus.40
In the setting of low levels of LMW adiponectin, the response to GORD might be directed toward a more exuberant oesophagitis and/or metaplasia into intestinal epithelium. Our finding that a low ratio of LMW to total adiponectin may be particularly associated with Barrett’s oesophagus could be explained by the opposing effects of different multimers on inflammation.25
Although high LMW or high LMW to total adiponectin ratio appeared most strongly protective of Barrett’s oesophagus in the current study, a positive but weaker association was observed between high levels of HMW adiponectin and Barrett’s oesophagus. It is not clear whether any effect of adiponectin on Barrett’s oesophagus is mediated by protection by LMW adiponectin, promotion by HMW adiponectin or both.
Adiponectin is one of many circulating factors associated with obesity, and the observed effect of LMW adiponectin may be confounded by any or many of these factors that were not measured in this study. For instance, IL6 downregulates adipocyte expression of adiponectin,41
and circulating IL6 or other cytokines might instead be responsible for Barrett’s metaplasia. Total adiponectin is inversely associated with insulin, and hyperinsulinaemia could instead be the causative factor related to Barrett’s oesophagus.29,30
However, the insulin-sensitising effect of adiponectin appears to be specifically due to the HMW multimer.22
We found no association between serum insulin levels, or between an estimate of insulin resistance, and the presence of Barrett’s oesophagus. Further adjusting for insulin levels or insulin resistance did not appreciably alter the observed association between LMW adiponectin and Barrett’s oesophagus. Menopause is associated with an increase in total adiponectin,29
and studies of the association of adiponectin with breast cancer risk have generally found an inverse association only among post-menopausal women.42–44
The stronger effect of LMW adiponectin on Barrett’s oesophagus that we observed among women might be due to interactions with sex hormones, or an epiphenomenon. Unfortunately, we had too few pre-menopausal women with Barrett’s oesophagus (n = 3) to draw any conclusions regarding an interaction between menopausal status and adiponectin multimers for the risk of Barrett’s oesophagus.
The results of this study differed from our pilot study in a different population finding evidence for an association between Barrett’s oesophagus and low levels of total adiponectin.13
This may have been due to differences in subject populations or the assay used to measure adiponectin. Also, the association in that study with total adiponectin became statistically insignificant after adjusting for waist/hip ratio. Our current null finding is consistent with a small pilot study performed by another group.12
However, unlike the present work, neither of these previous studies measured levels of the specific multimers. Although the present study involved more than 300 subjects, certain stratified analyses were limited by small numbers. The present study is limited by the potential for unmeasured confounders such as dietary habits. A diet high in whole grain cereals is positively correlated with circulating levels of total adiponectin, but to our knowledge dietary habits have not been correlated with circulating levels of the adiponectin multimers.45
Other potential unmeasured confounders include physical activity, Helicobacter pylori
infection, and the use of non-steroidal anti-inflammatory drugs. Despite our attempts to control for multiple factors, there may have also been residual confounding by obesity or GORD. The present study did not have access to adiponectin levels in a control group without GORD; levels of adiponectin and its multimers in our GORD control group were higher than those found in non-obese men without insulin resistance, but these differences may be due to other differences in study populations or assays.25
Comparing adiponectin levels to a non-obese population without GORD and without Barrett’s oesophagus could yield further understanding of the mechanism of the effect of adiponectin on Barrett’s oesophagus. Another limitation is the inclusion of both incident and prevalent cases of Barrett’s oesophagus, and the clinic-based nature of the study. While a population-based design would be preferable, the costs associated with recruiting subjects with GORD, then identifying over 100 Barrett’s oesophagus cases from this population were prohibitive. The strengths of our study include the rigorous data collection by trained research assistants, the prospective nature of our data collection and specimen banking, the low likelihood of misclassification due to the rigorous biopsy protocol, and the measurement of body anthropomorphic measurements on-site by trained study staff.
In summary, we found a strong inverse relationship between circulating levels of LMW adiponectin and the presence of Barrett’s oesophagus among patients with GORD. If noted in other studies, this finding has implications both for models of pathogenesis of Barrett’s oesophagus, as well as for potential use as a biomarker of disease. Further human studies are required to confirm our findings, and in vitro studies are needed to understand if there is a mechanism whereby adiponectin may promote Barrett’s metaplasia.