Persistent immunological changes after obesity
An earlier period of obesity caused by a high-fat diet in mice produces persistent changes in innate immunity even after weight loss and normalization of metabolism. Hata et al. found that such diet-induced obesity in mice, even after it was resolved, led to persistent epigenetic changes in chromatin in macrophages associated with increased expression of genes that function in inflammatory responses.
Experiments with adipose tissue or bone marrow transplants implicated alterations of myeloid cells in exacerbating inflammatory responses to experimentally induced ocular lesions. If similar processes occur in humans, the authors propose that such changes could contribute to the predisposition to age-related macular degeneration associated with obesity. —LBR
Summary Age-related macular degeneration is a prevalent neuroinflammatory condition and a leading cause of blindness driven by genetic and environmental factors, such as obesity. In diseases of aging, modifiable factors can combine throughout life. We report that diet-induced obesity earlier in life triggers persistent reprogramming of the innate immune system, lasting long after normalization of metabolic abnormalities. Stearic acid , acting through Toll-like receptor 4 (TLR4), is sufficient to remodel chromatin landscapes and selectively improve accessibility at binding sites for activator protein 1 (AP-1). Myeloid cells show less oxidative phosphorylation and shift to glycolysis, which ultimately leads to the transcription of proinflammatory cytokines, aggravation of pathological retinal angiogenesis, and neuronal degeneration associated with loss of visual function. Thus, a past history of obesity reprograms mononuclear phagocytes and predisposes them to neuroinflammation. |
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A history of obesity triggers persistent epigenetic changes in innate immunity and exacerbates neuroinflammation.
Research at Hôpital Maisonneuve-Rosement in Montreal shows how life stressors, such as obesity, reprogram immune system cells and make them destructive to the eye as you age.
"We wanted to know why some people with a genetic predisposition develop age-related macular degeneration (AMD) while others do not," said University of Montreal ophthalmology professor Przemyslaw (Mike) Sapieha, who led his study. postdoctoral fellow, Dr. Masayuki Hata.
“Although considerable effort has been invested in understanding the genes responsible for age-related macular degeneration (AMD), variations and mutations in susceptibility genes only increase the risk of developing the disease, but do not cause it,” he explained. Sapieha. "This observation suggests that we need to gain a better understanding of how other factors, such as environment and lifestyle, contribute to the development of the disease."
Age-related macular degeneration (AMD) is a leading cause of irreversible blindness worldwide, affecting approximately 196 million people in 2020. It comes in two forms:
- Dry AMD, characterized by the buildup of fatty deposits in the back of the eye and the death of nerve cells in the eye.
- Wet AMD, which is characterized by diseased blood vessels that develop in the most sensitive part of the tissue that generates sight, called the macula.
Contact with pathogens
It is already known that the immune system in the eye of a person with age-related macular degeneration (AMD) becomes dysregulated and aggressive. Normally, immune cells keep the eye healthy, but contact with pathogens such as bacteria and viruses can cause them to go awry.
At the same time, immune cells are also activated when the body is exposed to stressors such as excess fat in obesity, making being overweight the number one non-genetic risk factor for developing age-related macular degeneration. (AMD), after smoking.
In their study, Sapieha and Hata used obesity as a model to accelerate and exaggerate the stressors experienced by the body throughout life.
They found that transient obesity or a history of obesity leads to persistent changes in the DNA architecture within immune cells, making them more susceptible to producing inflammatory molecules.
“Our findings provide important insights into the biology of the immune cells that cause AMD and will enable the development of more personalized treatments in the future,” said Hata, now a professor of ophthalmology at Kyoto University in Japan.
The researchers hope their discovery will lead other scientists to expand their interest beyond obesity-related diseases to other diseases characterized by increased neuroinflammation, including Alzheimer’s disease and multiple sclerosis.
About this study
"The past history of obesity triggers persistent epigenetic changes in innate immunity and exacerbates neuroinflammation," by Mike Sapieha and Masayuki Hata, was published in Science .
Mike Sapieha is director of the Ocular Neurovascular Diseases Research Unit at the Maisonneuve-Rosemont Hospital Research Center associated with CIUSSS de l’Est-de-l’Île-de-Montréal. He also holds the Canada Research Chair in Retinal Cell Biology and the Ophthalmology Research Fund Chair at the Université de Montréal, and the Wolfe Professorial Fellowship in Translational Vision Research.
Masayuki Hata was a postdoctoral fellow in Mike Sapieha’s lab. He is now an associate professor in the Department of Ophthalmology and Visual Sciences at Kyoto University School of Medicine in Japan.
