Why is it easy for fat people to "eat more and stare"? The Wang Liming/Huang Rui collaboration reveals the neural mechanisms in which a high-fat diet promotes foraging behavior.

In the post industrial world, a wide range of junk food, uncontrolled diet and widespread obesity are major health problems that perplex hundreds of millions of people.studies have shown that, without strong intervention, more than half of Americans will suffer from obesity before 2030.in China, although the relative proportion of obese population is still low, it shows a strong momentum of rapid growth.from the perspective of evolution, metabolic diseases such as excessive energy intake and obesity can be regarded as "mismatch" diseases, that is, the products of "mismatch" between long evolutionary history and modern lifestyle.on the one hand, the long history of evolution, especially the collection and hunting history of human ancestors, has made our bodies accustomed to the life of starvation, cold and lack of food, and have a natural love and impulse to eat high-energy food; on the other hand, since the industrial revolution, the grain production capacity of human beings has been rapidly improved, and the developed food industry has been developed A variety of tempting (which generally means super high calorie) cuisine.there is a "mismatch" between evolutionary instinct and modern life, and all these changes have taken place in a short period of one or two hundred years. Our human body has no time to respond, so metabolic diseases such as obesity break out in this way.however, in the development of metabolic diseases, an important balance mechanism needs to be broken.we know that the nervous system of animals has the ability to balance energy intake and output. In a period of time, if the energy intake exceeds the consumption, the nerve cells responsible for foraging and feeding in the brain will reduce energy intake and restore energy homeostasis under the action of relevant nerve and hormone signals (such as leptin, insulin, etc.).however, in the early stage of the development of metabolic diseases such as obesity, this negative feedback regulation mechanism was destroyed, and a positive feedback enhancement mechanism of "eating more and more hungry" appeared, which provided a hotbed for the development of the disease [1].how does this phenomenon of "eating more and more hungry" appear? Recently, Wang Liming's research group of Zhejiang University and Huang Rui of Chongqing University jointly published an article in eLife magazine, high fat diet enhancement cultivation induced hyperactivity via sensing hunger sensing nerves in drophila, which has made an in-depth explanation on the mechanism of this phenomenon.specifically, in this study, the researchers found a slight but significant increase in fat accumulation after a short period of high-fat diet (about 5 days) in Drosophila, although there was no abnormality in the overall physiological indicators and metabolism of fruit flies.however, in the context of excess energy reserves, once these flies are hungry, their foraging behavior will be significantly enhanced.this counter intuitive phenomenon suggests that these Drosophila with excessive intake of high-fat food and slightly fat body do not have a stronger resistance to hunger, but their nervous system may become more sensitive to hunger signals.Wang Liming Laboratory of Zhejiang University has long been engaged in behavioral research related to "eating".in the past few years, they have established a highly quantitative paradigm of foraging behavior and feeding behavior in fruit flies [2, 3] These behavioral paradigms were used to screen out the starvation signal, AKH hormone (similar to mammalian glucagon), and the specific neurons (AKH receptor neurons) that received the hunger signal and output foraging behavior were identified in Drosophila brain [4].subsequently, we focused on the effects of nutrition in food on these behaviors, and found that protein deficiency induced foraging behavior through akhr neurons [5].therefore, when researchers found that high-fat diet could make Drosophila's foraging behavior more intense, they naturally suspected that the foraging neural circuits found in previous studies, especially akhr neurons, might become more sensitive to starvation signals when stimulated by high-fat food. later studies also demonstrated this - the researchers found that under high-fat diet, the sensitivity of specific akhr neurons in the brain of Drosophila melanogaster to the starvation signal AKH was greatly increased, and the response of calcium signal was significantly improved, resulting in a stronger foraging behavior output. what factors lead to this neurobiological change? The researchers found that under the condition of high-fat diet, the synthesis and secretion of AKH hormone were basically normal, the expression of akhr gene in akhr neurons was not significantly affected, but the accumulation level of akhr protein was significantly increased. this suggests that the degradation pathway of akhr protein may be disturbed by the influence of high-fat food. sure enough, using single-cell RNA sequencing, haemolymph mass spectrometry and other technical means, the researchers further found that after excessive intake of high-fat food, LTP in the circulatory system of Drosophila can transport the absorbed excessive lipid molecules to the central nervous system, and then LTP binds with the receptor lpr1 on the surface of akhr neurons to deliver the lipid into the cells. after these lipid molecules enter the cells, they can inhibit the autophagy level of neurons by regulating the activity of ampk-tor pathway, and eventually lead to the accumulation of akhr protein on the surface of neurons. As a result, high concentration of akhr protein enhanced the response of cells to AKH, and completed the activation of neurons and the output of foraging behavior when the starvation signal was not strong. in conclusion, this study elucidates the underlying molecular mechanism of "eating more and starving" caused by junk food in the Drosophila system. excessive fat intake can directly act on specific brain neurons with the help of apolipoproteins, affecting the protein degradation mechanism within nerve cells, and eventually lead to the abnormal sensitivity of brain to hunger signals and excessive output of foraging behavior. this study helps us better understand the relationship between modern lifestyle, especially high-fat food intake and metabolic diseases. it is particularly noteworthy that in the Drosophila system, the abnormal nervous system and the phenomenon of "eating more and more hungry" caused by high-fat food are even earlier than the appearance of obesity symptoms and other metabolic abnormalities. this indicates that the pathogenesis of metabolic diseases may be more complex than we expected, and the abnormality of nervous system may play a secret and key role in it. it is reported that Huang Rui and song Tingting, two co first authors, have completed the research under the guidance of Professor Wang Liming, School of life sciences, Zhejiang University. Dr Huang Rui and Dr. Song Tingting conducted long-term postdoctoral research in Wang Liming's laboratory. at present, Dr. Huang Rui has been a researcher in the center of neurointelligence, School of medicine, Chongqing University, and a cooperative researcher of Shenzhen Bay laboratory. Dr. Song Tingting is currently an associate researcher of Shenzhen Bay laboratory. for a long time, they have devoted themselves to analyzing the specific instinctive behaviors of Drosophila models by using multi omics techniques including single-cell RNA sequencing and single-cell mass spectrometry, and mapping the neural circuits and single-cell transcriptome maps of these behaviors, striving to fully understand the molecular and cellular basis of these behaviors, and to seek potential targets for disease treatment [4, 6]. Hariri, N. and L. Thibault, high fat diet induced obsity in animal models. Nutr res rev, 2010.23 (2): P. 270-99.2. Qi, W., et al., a quantitative feeding assessment in adult Drosophila Reeves rapid modulation of food intake by its nutritional value. Mol brain, 2015 8: p. 87.3.Yang, Z., et al., Octopamine mediates starvation-induced hyperactivity in adult Drosophila. Proc Natl Acad Sci U S A, 2015. 112(16): p. 5219-24.4. Yu, Y., et al., Regulation of starvation-induced hyperactivity by insulin and glucagon signaling in adult Drosophila. Elife, 2016. 5.5. Tian, Y. and L. Wang, Octopamine mediates protein-seeking behavior in mated female Drosophila. Cell Discov, 2018. 4: p. 66.6. Yang, Z., et al., A post-ingestive amino acid sensor promotes food consumption in Drosophila. Cell Res, 2018. 28(10): p. 1013-1025.