Intensive weight loss and cognition: The dynamics of persistent organic pollutants in adipose tissue can explain the unexpected results from the Action for Health in Diabetes (Look AHEAD) study.

The aim of this paper is to propose a new hypothesis for the role of lipophilic chemical mixtures stored in adipose tissue in the development of dementia. Specifically, we present how the dynamics of these chemicals can explain the unexpected findings from the Action for Health in Diabetes (Look AHEAD) study, which failed to show long-term benefits of intentional weight loss on cognition, despite substantial improvements in many known risk factors for dementia. Moreover, we discuss how the role of obesity in the risk of dementia can change depending on the dynamics of these chemicals in adipose tissue.Human adipose tissue is widely contaminated with various neurotoxic chemicals. Typical examples are persistent organic pollutants (POPs), strong lipophilic chemicals with long half-lives. Both unintentional and intentional weight loss increases the release of POPs from adipocytes into the circulation. As POPs in the blood can easily reach the brain, the intentional weight-loss group of the Look AHEAD study may have experienced an unappreciated and long-term disadvantage on their cognition. Additionally, POPs may be involved in the link between obesity and dementia, as dysfunctional hypertrophic adipocytes enhance the release of POPs from adipocytes to the circulation through uncontrolled lipolysis. In contrast, metabolically healthy obese people may have a low risk of dementia because the safe storage of POPs in adipose tissue would decrease the amount of POPs reaching the brain.In human studies, there are practical difficulties involved with measuring POPs in the blood, including high costs and complex assays. As the serum concentrations of POPs are continuously affected by weight loss and gain, prospective studies may require serial measurements of POPs. In in-vitro and in-vivo experimental studies, how to simulate the exposure dose, duration, and mixture patterns in humans would be critical.Even though POPs are direct neurotoxins at a high dosage, low-dose POPs are mitochondrial toxins. Therefore, chronic exposure to low-dose POPs is linked to known key interrelated mechanisms in the pathogenesis of dementia, such as mitochondrial dysfunction and neuroinflammation.