Obesity is the “home” of chronic low-grade inflammation, which is the “super culprit” of many metabolic diseases such as type 2 diabetes (insulin receptor defects), hypertension, and atherosclerosis. Although it is still controversial whether obesity itself is a disease or not, it has been generally recognized as a risk factor for many diseases. However, the causes of obesity are not yet fully understood, and there are many problems to be solved regarding the mechanism of obesity-induced diseases. The definition of obesity is being challenged, the current body mass index (BMI) only consider the weight per unit area, but did not take into account the proportion of adipose tissue, not to mention the share of visceral fat, the result is a high BMI “healthy” and normal BMI “unhealthy” and other anomalies. As a result, high BMI is “healthy” and normal BMI is “unhealthy” and other anomalies. Obesity research is the key to the treatment of various chronic diseases, and thus has become the focus of current attention. At the same time, obesity-induced metabolic syndromes are diverse and all-encompassing, and thus are also difficult to study in molecular pathology. The following is a list of the latest literature and combined with our findings, one by one inventory and specific analysis of obesity and its complications of the top ten “unanswered questions”. First, is obesity an evolutionary trait? Fat is the body’s most important energy storage, can guarantee the body’s ability to resist hunger and cold. Some hibernating animals in the long winter months do not eat or drink, rely on the body of stored fat to provide energy. From this point of view, obesity obviously gives hibernating animals a certain survival advantage, not enough fat reserves of animals certainly can not survive the long winter. Similarly, other non-hibernating animals and humans in the overwintering season also need a lot of fat to dissipate heat for warmth. Accordingly, obesity seems to be a conservative evolutionary trait that is prevalent in humans and animals. However, hibernation is a species-specific trait rather than an inherent human trait, as the hibernation-inducing trigger (HIT), prolyl endorphins, which are isolated from the blood of hibernating animals, are not present in humans. However, archaeological evidence suggests that humans may have originated in the tropics and gradually spread to temperate, subtropical, and boreal regions, and that obesity traits are more akin to the body’s adaptation to environmental temperatures. This makes it easy to understand why Africans are generally thin, Europeans are predominantly fat, and Asians are moderately built. However, modern people to indoor activities, environmental temperature on the body fat and thin regulation is weakened, people’s body should be more and more close. However, the actual situation is not so. According to the “Thrifty Gene Hypothesis, in the course of human evolution, due to food scarcity and difficulty in finding food, the human body is inclined to be obese, because obese people have a better chance of surviving famine. With today’s abundant food supply, the thrifty gene is still at work, making people fatter and fatter. However, the hypothesis has not been generally recognized, and even encountered criticism. Second, can obesity be inherited? In fact, the human body varies greatly, but the obese family offspring of obese people in a significantly higher proportion. Studies show that if both parents are obese, 80% of children will also be obese; parents normal weight, the proportion of obese children is less than 10%. Obesity or some hereditary obesity syndrome and non-syndromic obesity is the main feature. In patients with early-onset obesity, 7% carry genes such as FTO with point mutations. Apparently, obesity is controlled by polymorphisms in appetite- and metabolism-related genes. According to 2006 statistics, 41 obesity-related polymorphic gene loci have been identified. For example, carriers of two FTO genes weigh an average of 3-4 kilograms more than non-carriers, increasing the risk of obesity by 1.67 times. However, the contribution of genetic factors to obesity is highly variable across populations, ranging from 6-85%. This indicates that obesity is a complex quantitative genetic trait, involving a large number of genes, how to screen out the key target genes will be the main direction of obesity genomics research in the next period of time. Third, obesity is eaten out? In the crowd can be observed, and not eat a lot of people must be obese, also not eat the less on the more thin. However, eating and obesity obviously has an inseparable link, especially high-fat, high-sugar diet is more likely to lead to obesity. Therefore, it is accurate to say that obesity should be family obesity genetics plus high-fat, high-sugar diet combined effect. From the metabolic regulation, the body originally exists a set of perfect hunger and satiety signaling system, so as to flexibly regulate appetite. For example, leptin (leptin) is responsible for conveying satiety signals, which can make eaters lose their appetite. Obese people usually have a high appetite, is the leptin signaling pathway in their body impaired? Overnutrition can act on IKKβ by stimulating Toll-like receptor (TLR) signaling and endoplasmic reticulum (ER) stress, which activates NF-κB, initiates macrophage function, and produces pro-inflammatory cytokines that promote adipocyte death. In turn, adipocyte death stimulates pro-inflammatory cytokine synthesis, which in turn further activates macrophages. In this process, the activation of NF-κB and the synthesis of pro-inflammatory cytokines can block the secretion of leptin, the “obesity inhibitor”, and the inhibition of the leptin signaling pathway can lead to obesity. Saturated fatty acids may be immune system activators, and spontaneous inflammation in obese people is the result of saturated fatty acids. Saturated fatty acids have been found to act through the hepatic secretion of the protein FetA, which binds to Toll-like receptor 4 (TLR4). However, recent clinical trial evidence suggests that saturated fatty acids do not increase the risk of cardiovascular disease. Further research is needed. Fourth, obesity or inflammation first? In general, diet-induced obesity will at least activate the leptin pathway, which conveys satiety signals to the hypothalamus, thereby reducing appetite and reducing intake. So, is it possible that obese people binge on food because the leptin pathway is blocked? This brings us to a key question about obesity: does obesity or inflammation come first? It is an indisputable fact that obesity induces inflammation, but it is not conclusive that inflammation causes obesity. High-fat diet-induced obesity is strongly associated with systemic low-grade inflammation and insulin resistance. Recent evidence suggests that a similar phenomenon exists in the hypothalamus, which promotes weight gain by disrupting leptin and insulin signaling. Therefore, the hypothesis that hypothalamic inflammation is a causative agent of obesity has been proposed. The novelty of this hypothesis lies in its clear distinction between hypothalamic inflammation and obesity-induced inflammation, which may well be induced by other non-obesity factors. Insulin resistance is divided into physiologic and pathologic conditions. When the body encounters a pathogenic infection, the immune system needs to consume a large amount of energy to clear the pathogen, and the body can reduce the efficiency of glucose assimilation into glycogen through insulin resistance, i.e., promote the consumption of energy and cut down on the storage of energy. When insulin receptors are damaged to varying degrees, the body’s sensitivity to insulin is reduced or even lost, leading to type 2 diabetes. Fifth, BMI definition of obesity must be unhealthy? In the United States, 10% of the BMI “obese” is metabolically healthy, they have more subcutaneous fat than visceral fat, a larger share of muscle, a higher degree of physical comfort, hyperinsulinemia and a slight cardiovascular risk, but insulin sensitivity and blood glucose levels are normal. In contrast, 8% of “normal” BMI individuals are metabolically unhealthy, with excess visceral fat, associated muscle loss, reduced body comfort, a variety of chronic diseases including diabetes, insulin resistance, inflammation, and a high risk of cardiovascular disease and cancer. This suggests that obesity defined by BMI is both “healthy” and “unhealthy” obesity, and that it is not possible to equate obesity or normal BMI with either unhealthy or healthy. Although some people have used the “body size index” (ABSI) to identify obesity or overweight, but there is no recognized quantitative indicators to define “unhealthy” obesity. Six, overweight or obesity why can reduce mortality? Early studies have found that obesity and heart disease, coronary vascular disease, kidney disease and other chronic disease mortality rate is inversely correlated. Studies have shown that mild obesity (BMI 30-34.9) has nothing to do with the mortality rate, while the mortality rate of overweight people decreased significantly. Another study also showed that overweight or obese BMI had lower mortality from cardiovascular disease and diabetes than normal BMI. On the one hand, BMI does not reflect the proportion of visceral fat, and excess visceral fat is the real cause of insulin resistance, diabetes, hyperlipidemia and cardiovascular disease. On the other hand, stored body fat may provide older and weaker individuals with the necessary energy to fight off invading pathogens when they become ill. In addition, obese people with diabetes will pay more attention to diet and exercise, the body is likely to return to normal. Seven, the body’s stored fat is how to consume? Body fat storage, whether subcutaneous fat, or visceral fat, need to rely on fat cells in the mitochondria for oxidative decomposition. Brown adipose tissue in the adipocytes contain a large number of mitochondria, and thus the ability to eliminate fat. Adipocytes in white adipose tissue have only a small number of mitochondria and are therefore weak in lipolysis. However, white adipose tissue can be induced by environmental factors (e.g., cold) to turn into light brown adipose tissue, and its capacity for lipolysis increases accordingly. If the volume of fat exceeds the capacity for fat elimination, the body has to use the immune system to remove the extra fat, thus inducing chronic low-grade inflammation. As for how fat induces inflammation, it has been suggested that in addition to fatty acids, bacterial lipopolysaccharides are also one of the synergistic factors, and more evidence is being collected. Eight, why is obesity a high-risk factor for many diseases? Obesity-induced inflammation is one problem, inflammation caused by cardiovascular disease, diabetes, cancer is another problem. On the “sequelae of inflammation” of the molecular pathology of the mechanism, is still unresolved. Apparently, there are “multiple causes and effects” in this process, and elucidating the details is the focus and hotspot of current research. Why can inflammation cause so many diseases? If we link inflammation with oxidative stress and nitrosylative stress, it seems that the above phenomenon of “multiple causes and effects” can be initially explained. For example, genes associated with inflammatory signaling pathways can be mutated by reactive oxygen species-mediated oxidation, and receptor proteins in the pathway can be inactivated by nitrosylation mediated by reactive oxygen species in combination with reactive nitrogen species. Therefore, gene mutation and protein modification inactivation may be the main mechanism of inflammation as a high-risk factor for a variety of diseases, which needs to be further confirmed. IX. Why does the immune system attack its own adipose tissue? When there is an excess of fat that cannot be consumed, the body will mistake fat for pathogens such as bacteria or fungi that are “trespassing” and use the cellular immune system (mainly macrophages) to remove them. During this process, cytokines such as tumor necrosis factor alpha (TNF-alpha), interleukin-6, 8, and 18 are synthesized in large quantities, which leads to systemic inflammation involving a wide range of endothelial cells and other organ systems. Interleukin-6 has been regarded as a pro-inflammatory cytokine in the past, but recently it has been found to inhibit the synthesis of tumor necrosis factor alpha and interleukin-1, which manifests an anti-inflammatory effect. Also, interleukin-6 is produced in large quantities during exercise. Therefore, it has been suggested that interleukin-6 may be a “feedback” cytokine used to inhibit excessive inflammation. X. Can anti-chronic low-grade inflammation treat obesity? The simple way to avoid obesity is to maintain an energy balance, i.e., intake and consumption should be basically equal. Therefore, diet and exercise is to maintain a proportionate figure of the “no two ways”. For those who already have symptoms of obesity, in addition to weight loss, it is also necessary to inhibit chronic low-grade inflammation, otherwise it will cause diabetes, cardiovascular disease, autoimmune disease, neurodegenerative diseases and cancer and other inflammation-induced chronic diseases. In addition, if the hypothesis that hypothalamic inflammation causes obesity is valid, then anti-inflammatory therapy (e.g., aspirin, tamsulosin) will be necessary to prevent and treat obesity. Recent studies have shown that erythropoietin (EPO) has anti-inflammatory effects on white adipose tissue and may be a potential drug against chronic low-grade inflammation.