In a recent study published in Science, researchers report that diet-induced obesity can trigger epigenetic changes, which alter the regulation of the innate immune system long-term. This “reprogramming” may predispose individuals to damaging neuroinflammation, which can lead to loss of vision later in life, as seen in diseases like age-related macular degeneration (AMD).
Age-related macular degeneration
AMD is a neuroinflammatory condition and a leading cause of irreversible blindness globally. AMD is classified into two forms, neovascular AMD (nAMD) and non-neovascular AMD (geographic atrophy), with nAMD causing over 80% of vision loss in patients with AMD. AMD is a multifactorial disease and is driven by both genetic and environmental factors, such as obesity – previous studies such as the Age-Related Eye Disease Study (AREDS) have shown that obesity is the major risk factor for AMD. However, the mechanisms through which obesity predisposes individuals to AMD, and the long-term impact of prior obesity on the immune system remain poorly understood.
What we do know, is that like other neurodegenerative diseases, AMD is triggered by chronic inflammation that spirals out of control. In nAMD this leads to choroidal neovascularization (CNV); the growth of abnormal blood vessels from the choroid (under the retina) under the macula (part of the retina). This growth can lead to retinal oedema or haemorrhage, damaging and killing photoreceptors, as well as fibrovascular scarring – causing the irreversible blindness seen in nAMD. In this study, researchers used mouse models to investigate the long-term consequences of obesity on neuroinflammation in the retina, how that may lead to CNV and retinal degeneration, as well as whether weight loss can restore healthy neuroinflammation in the ageing eye.
Epigenetic reprogramming of innate immune cells
Until fairly recently, the concept of immune memory has been reserved for adaptive immune cells. However, epigenetic and metabolic regulation of macrophages, monocytes, neutrophils – and so on – mean that the innate immune system can be altered by the environment. In this study, researchers found that a history of obesity in mice leads to long-term changes in innate immune cells.
So how does obesity affect the immune system? During obesity, and in a high-fat diet, several effectors (such as fatty acids) are thought to activate innate immune cells. The researchers of this study identified stearic acid as a potential fatty acid that might drive epigenetic changes in innate immune cells. ATAC-seq analysis revealed that stearic acid, acting through Toll-like receptor 4 (TLR4), caused remodelling of the chromatin landscapes of innate immune cells such as adipose tissue macrophages. These changes enhanced the accessibility of binding sites for activator protein-1 (AP-1), a transcription factor that targets many genes involved in the immune response, such as nuclear factor of kappa light polypeptide gene enhancer in B cells 1 (Nfkb1), interleukin 1-beta (IL1b), and more. The researchers then showed that these obesity-driven epigenetic changes in myeloid cells (such as macrophages) lead to proinflammatory cytokine transcription, which causes an exacerbated inflammatory response. This can then lead to the development of CNV, and consequently retinal degeneration and loss of sight.
One significant finding in this study was that the obesity-induced epigenetic changes persisted after the mice returned to normal weight and regained metabolic homeostasis. If these findings translate to humans, this may suggest that a past history of obesity predisposes individuals to neuroinflammation and AMD.