a new weight loss idea appeared in nature! helping the brain fight inflammation can help people "control their diet"
2024-09-19
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▎edited by wuxi apptec content team overweight and obesity are health problems faced by many people today. they not only affect body shape and appearance, but also pose hidden dangers to cardiovascular disease, diabetes and other diseases. for people who want to lose weight, reducing calorie intake is the key. for example, the current "star" weight loss drug semaglutide works by mimicking the effects of glucagon-like peptide-1 (glp-1) to reduce an individual's appetite and reduce food intake.but why do obese individuals have difficulty controlling their appetite? imagine that when you have a full meal, the food enters the gastrointestinal tract and is digested, the body immediately responds by secretinginsulinto lower blood sugar levels, this free insulin not only helps cells take up and utilize glucose, but also enters the brain through the circulatory system.as insulin signals accumulate,arcuate nucleus of hypothalamusthe neurons of the arc will sense that the food intake is too much, thus reducing the individual's desire to eat, stopping eating behavior, and insulin levels will also drop. this regulatory process is very important for reasonable eating and energy consumption.in the latest issue of nature magazine, researchers from the university of melbourne found thatin obese individuals, the regulatory role of arc has been lostobese mouse models show that their arc neurons are tightly surrounded by a network of extracellular matrix, which makes it difficult for insulin to reach the neuron's insulin receptors. without this signal, the arc will not issue the command to stop eating. in addition,metabolic disorders can cause local inflammation in the arc, which disrupts the regulation of the extracellular matrix protein network and indirectly aggravates the occurrence of obesity.most previous studies believed that excessive fibrosis caused by abnormal extracellular matrix only occurs in peripheral tissues. however, in recent years, some exploratory findings on the brain are gradually overturning this speculation. for example, more and more papers have shown thata unique extracellular matrix is formed around neurons - the perineuronal matrix network (pnn)。in the new study, the authors created a group of obese mice induced by a high-fat diet and found that as their body weight increased, pnns appeared in the medial lobe of the hypothalamus of the mice, andpnn will be concentrated in the arc area, which are less common in other brain regions. under 12 weeks of high-fat diet, the density of pnns in the arc was already very obvious at week 4, and increased further at weeks 8 and 12. in addition, in obese mice, there was a significant increase in the level of proteins carrying chondroitin sulfate sugar chains, which is a key component of pnns.▲obesity increases extracellular matrix fibers around arc(image source: reference [2])under normal circumstances, pnns in the arc undergo rapid turnover, and metalloproteinases can help digest pnns and prevent their density from being too high. however, obese mice behave differently. their hypothalamus produces persistent neuroinflammation due to excessive inflammatory factors tnf-α and tgf-β. this inflammation destroys the activity of metalloproteinases and prevents pnns from being cleared normally. as pnns accumulate and become fibrotic, it becomes increasingly difficult for insulin to enter the arc and contact neurons, and the insulin signaling pathway disappears, so obese mice also have a harder time controlling their appetite.▲obesity-related inflammation promotes arc neuron “shielding”(image source: reference [1])these findings also bring potential obesity treatment strategies.one way is to reduce inflammatory signals in the bodyfor example, the authors found that expressing some soluble receptors of tnf-α and tgf-β in mice through viral vectors can inhibit neuroinflammation, restore metalloproteinase activity around arc and normalize pnn.another way is to use drugs to lower the level of chondroitin sulfate.for example, the authors have discovered that a compound called fluorosamine can inhibit the synthesis of chondroitin sulfate, restore the state of the extracellular matrix and insulin sensitivity, and mice treated with fluorosamine have a significant reduction in body weight. these methods are expected to become a potential option for obesity treatment after clinical trials.references:
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