The role of NAFLD in the development of insulin resistance remains controversial, even when comparing studies in which body weight gain has been ruled out as a confounding factor. In general, we believe that NAFLD cannot be considered to be one of the main drivers of insulin resistance in mice, but there is more likely to be a dangerous liaison between the two. Whether this is also the case in human NAFLD remains to be determined.
As alterations in body weight or fat mass appear to be a driving factor in the intricate relationship between NAFLD and systemic as well hepatic insulin resistance in many studies, this supports the idea that adiposity is more important than NAFLD in the etiology of insulin resistance. On the one hand steatosis, inflammation and insulin resistance may simply be correlated via the common driver of obesity, suggesting that there is no causal relationship in either direction, while, on the other hand, it is possible that NAFLD only causes insulin resistance under certain circumstances. These circumstances are likely to include environmental factors, such as gut microbiota and dietary composition. In addition, the intracellular localization of lipids, fatty acid composition in the liver, and the amount and duration of inflammation may determine if NAFLD causes insulin resistance.
Moreover, it may also depend on whether adipose tissue inflammation is affected.
To further investigate the circumstances under which NAFLD causes insulin resistance, we recommend taking lipid species and their localization into account as markers of steatosis in future studies. We further consider it important to measure inflammatory endpoints (such as cytokines, chemokines, and markers for macrophages
and Kupffer cells) to determine whether modulations in the pathways involved in inflammation actually alter the levels of inflammation. Since inflammation is tightly controlled, the many negative-feedback pathways that regulate it could interfere with the outcome and detailed measurements might lead to surprising results. In this respect, it is also important to measure if inflammation in adipose tissue is affected. Moreover, discrepancies between the various reports offer an opportunity to investigate the underlying differences and to learn more about the role of environmental factors in the disease process. For example, NAFLD is associated with insulin resistance in some models of the disease, but not in all. It would be interesting to investigate what underlies the differences between these NAFLD models. Finally, by studying more liver-specific models and gain-of-function models, greater insight into the role of NAFLD in insulin resistance will be obtained. We are certain that, with the techniques now available, many factors that play a role in the etiology of insulin can be elucidated in the near future.
Acknowledgements
The authors would like to thank Jackie Senior for editing the manuscript.
Financial support: This study was performed within the framework of CTMM, the Dutch Center for Translational Molecular Medicine (www.ctmm.nl), project PREDICCt (grant 104), and it was also supported by the Dutch Heart Foundation (grant 01C-104) the Dutch Kidney Foundation (grant 01C-01C-104) and the Dutch Diabetes Research Foundation (grant 2009.80.016; 2004.00.018). The funders had no role in the study design, the collection, analysis and interpretation of the data, the writing of the manuscript and the decision to submit the article for publication.
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