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

Abstract

Objective 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. New hypothesis 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. Major challenges for the hypothesis 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. Linkage to other major theories 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.

Path analysis reveals the direct effect of PCB28 on cognitive dysfunction in older Chinese females

“…In addition to genetics and aging, environment pollutants have recently been considered as a risk factor that affects elder adults' cognition functions [6]. Toxicological studies have found that the exposure of persistent organic pollutants (POPs) can result in severe issues in the central nervous system, including the MCI [7]. As the typical POPs, polychlorinated biphenyls (PCBs) are a group of organochlorine compounds synthesized by biphenyl chlorination, with a total of 209 homologs [8].…”

Comment on: Obesity is Associated with Improved Postoperative Overall Survival, Independent of Skeletal Muscle Mass in Lung Adenocarcinoma by Lee et al.

“… 29 , 30 This unanticipated consequence can be attributed to the POP dynamics observed during intentional weight loss. 31 , 32 It is important to note that weight fluctuation, a common result of intentional weight loss, can lead to redistribution of POPs from adipose tissue to critical organs, as observed in animal experimental studies. 33 …”

“…29,30 This unanticipated consequence can be attributed to the POP dynamics observed during intentional weight loss. 31,32 It is important to note that weight fluctuation, a common result of intentional weight loss, can lead to redistribution of POPs from adipose tissue to critical organs, as observed in animal experimental studies. 33 The role of adipose tissue in storing POPs and other environmental pollutants may not be trivial and can explain many puzzling findings on obesity observed in epidemiological studies.…”

Plasma exchange: An effective method to eliminate neurotoxic lipophilic chemicals from blood

“…3 Importantly, PE can effectively remove persistent organic pollutants (POPs) that have recently emerged as a novel risk factor for dementia. 4,5 Human adipose tissue is contaminated by a large number of environmental pollutants, yet this is often ignored by researchers and clinicians. 6 The most problematic chemicals in terms of neurodegenerative disease risk would be POPs as many of them are well-known neurotoxins.…”

“… 3 Importantly, PE can effectively remove persistent organic pollutants (POPs) that have recently emerged as a novel risk factor for dementia. 4 , 5 …”