CIDeRplusGeneral Information:
| Id: | 6,894 |
| Diseases: |
Diabetes mellitus, type II
- [OMIM]
Insulin resistance |
| Mammalia | |
| review | |
| Reference: | Salameh TS et al.(2016) Insulin resistance, dyslipidemia, and apolipoprotein E interactions as mechanisms in cognitive impairment and Alzheimers disease Exp. Biol. Med. (Maywood) 241: 1676-1683 [PMID: 27470930] |
Interaction Information:
| Comment | In the peripheral circulation, APOE aids in shuttling lipids between various lipoproteins. In the brain, APOE is the most abundant lipoprotein and a crucial regulator of lipid metabolism. |
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Formal Description Interaction-ID: 67327 |
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| Drugbank entries | Show/Hide entries for APOE |
| Comment | APOE mediates transport of lipoprotein particles between various cell types in the brain via carriers such as the low-density lipoprotein receptor related protein-1 (LRP-1). |
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Formal Description Interaction-ID: 67339 |
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| Drugbank entries | Show/Hide entries for APOE |
| Comment | APOE mediates transport of lipoprotein particles between various cell types in the brain via carriers such as the low-density lipoprotein receptor related protein-1 (LRP-1). |
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Formal Description Interaction-ID: 67340 |
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| Drugbank entries | Show/Hide entries for LRP1 |
| Comment | At the blood‚Äďbrain barrier (BBB), LRP-1 is involved in amyloid beta (Abeta) clearance from brain and the decrease in BBB LRP-1 levels that occurs in Alzheimer disease has been postulated as one reason why Abeta builds up in the brain. |
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Formal Description Interaction-ID: 67341 |
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| Drugbank entries | Show/Hide entries for LRP1 |
| Comment | APOE is important in repairing the blood‚Äďbrain barrier (BBB) after injury, and dysfunction of the BBB has been considered to be both a cause and a consequence of Alzheimer disease. |
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Formal Description Interaction-ID: 67342 |
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| Drugbank entries | Show/Hide entries for APOE |
| Comment | In humans, there are three alleles of APOE: E2, E3, and E4. The APOE4 protein is folded into a more compact structure compared to the other APOE isoforms, leading to a decreased ability to bind lipids and a higher likelihood of cleavage into neurotoxic fragments. Perivascular removal of amyloid beta (Abeta) is hindered with the expression of E4, which was shown in many in vitro studies as well as in mice expressing human E4. This decreased drainage, in turn, leads to decreased clearance of Abeta peptides and increased amyloid plaques, as well as other pathophysiologic features such as alterations in the neurovascular unit and blood‚Äďbrain barrier (BBB) function. |
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Formal Description Interaction-ID: 67343 |
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| Comment | In humans, there are three alleles of APOE: E2, E3, and E4. The APOE4 protein is folded into a more compact structure compared to the other APOE isoforms, leading to a decreased ability to bind lipids and a higher likelihood of cleavage into neurotoxic fragments. Perivascular removal of amyloid beta (Abeta) is hindered with the expression of E4, which was shown in many in vitro studies as well as in mice expressing human E4. This decreased drainage, in turn, leads to decreased clearance of Abeta peptides and increased amyloid plaques, as well as other pathophysiologic features such as alterations in the neurovascular unit and blood‚Äďbrain barrier (BBB) function. |
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Formal Description Interaction-ID: 67344 |
gene/protein mutant decreases_activity of |
| Comment | In humans, there are three alleles of APOE: E2, E3, and E4. The APOE4 protein is folded into a more compact structure compared to the other APOE isoforms, leading to a decreased ability to bind lipids and a higher likelihood of cleavage into neurotoxic fragments. Perivascular removal of amyloid beta (Abeta) is hindered with the expression of E4, which was shown in many in vitro studies as well as in mice expressing human E4. This decreased drainage, in turn, leads to decreased clearance of Abeta peptides and increased amyloid plaques, as well as other pathophysiologic features such as alterations in the neurovascular unit and blood‚Äďbrain barrier (BBB) function. |
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Formal Description Interaction-ID: 67345 |
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| Comment | APOE4 knock-in mice had higher levels of blood‚Äďbrain barrier (BBB) breakdown in response to injury, via upregulation of the proinflammatory cyclophilin A pathway in pericytes. |
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Formal Description Interaction-ID: 67346 |
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| Drugbank entries | Show/Hide entries for PPIA |
| Comment | The role that APOE plays in transport and clearance of molecules depends on the APOE isoform, and these transport differences may be related to differences in receptor utilization for the isoforms, with APOE4-Abeta complexes using the very low-density lipoprotein (VLDL) receptor and the other isoforms using LRP-1. These isoform specific differences may also affect how the blood-brain barrier (BBB) transports insulin, free fatty acids (FFAs), and other metabolites involved in cognitive processes. |
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Formal Description Interaction-ID: 67347 |
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| Comment | The role that APOE plays in transport and clearance of molecules depends on the APOE isoform, and these transport differences may be related to differences in receptor utilization for the isoforms, with APOE4-Abeta complexes using the very low-density lipoprotein (VLDL) receptor and the other isoforms using LRP-1. These isoform specific differences may also affect how the blood-brain barrier (BBB) transports insulin, free fatty acids (FFAs), and other metabolites involved in cognitive processes. |
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Formal Description Interaction-ID: 67348 |
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| Drugbank entries | Show/Hide entries for LRP1 |
| Comment | The role that APOE plays in transport and clearance of molecules depends on the APOE isoform, and these transport differences may be related to differences in receptor utilization for the isoforms, with APOE4-Abeta complexes using the very low-density lipoprotein (VLDL) receptor and the other isoforms using LRP-1. These isoform specific differences may also affect how the blood-brain barrier (BBB) transports insulin, free fatty acids (FFAs), and other metabolites involved in cognitive processes. |
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Formal Description Interaction-ID: 67349 |
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| Drugbank entries | Show/Hide entries for LRP1 |
| Comment | APOE4 carrier status is correlated with increased LDL and triglyceride levels, and an increased risk of heart disease. |
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Formal Description Interaction-ID: 67350 |
gene/protein mutant increases_activity of |
| Comment | APOE4 carrier status is correlated with increased LDL and triglyceride levels, and an increased risk of heart disease. |
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Formal Description Interaction-ID: 67351 |
gene/protein mutant increases_activity of phenotype |
| Comment | APOE4 carrier status is correlated with increased LDL and triglyceride levels, and an increased risk of heart disease. |
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Formal Description Interaction-ID: 67352 |
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| Comment | Human and experimental animal studies have confirmed a link between peripheral insulin resistance and cognitive impairment. |
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Formal Description Interaction-ID: 67353 |
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| Comment | There is a close association between lipid homeostasis and glucose regulation. |
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Formal Description Interaction-ID: 67354 |
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| Comment | Elevated lipid levels can chronically impact insulin secretion by the beta-cell in the pancreas. |
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Formal Description Interaction-ID: 67355 |
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| Comment | Chronic peripheral hyperinsulinemia serves to reduce transport of insulin into the brain. |
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Formal Description Interaction-ID: 67356 |
phenotype decreases transport of complex/PPI Insulin |
| Comment | Intranasal insulin improves cognition. |
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Formal Description Interaction-ID: 67357 |
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| Comment | APOE4 carriers showed poorer responses to intranasal insulin treatment compared to patients who were E4 noncarriers. |
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Formal Description Interaction-ID: 67358 |
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| Comment | Studies investigating the role of lipids in the brain have revealed abnormal lipid metabolism as an important pathophysiological process in the development of Alzheimer disease (AD). Diets consisting of an increased consumption of saturated and trans-fats incur an increased incidence of AD, while diets rich in healthy fats are protective. |
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Formal Description Interaction-ID: 67359 |
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| Comment | Studies investigating the role of lipids in the brain have revealed abnormal lipid metabolism as an important pathophysiological process in the development of Alzheimer disease (AD). Diets consisting of an increased consumption of saturated and trans-fats incur an increased incidence of AD, while diets rich in healthy fats are protective. |
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Formal Description Interaction-ID: 67360 |
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| Comment | Studies investigating the role of lipids in the brain have revealed abnormal lipid metabolism as an important pathophysiological process in the development of Alzheimer disease (AD). Diets consisting of an increased consumption of saturated and trans-fats incur an increased incidence of AD, while diets rich in healthy fats are protective. |
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Formal Description Interaction-ID: 67363 |
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| Comment | Lipid metabolism is closely associated with the processing of APP, which results in increased production of Abeta. |
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Formal Description Interaction-ID: 67364 |
process affects_activity of |
| Comment | APOE4 positive individuals have more exaggerated plasma lipid changes after high-fat diet intake. |
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Formal Description Interaction-ID: 67365 |
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| Comment | Animal studies have shown diets high in saturated fats or cholesterol increase levels of Abeta and decrease brain insulin levels. |
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Formal Description Interaction-ID: 67366 |
environment high-saturated-fat diet decreases_quantity of complex/PPI Insulin |
| Comment | Animal studies have shown diets high in saturated fats or cholesterol increase levels of Abeta and decrease brain insulin levels. |
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Formal Description Interaction-ID: 67367 |
environment high-saturated-fat diet increases_quantity of gene/protein |
| Comment | Insulin showed decreased transport across the blood-brain barier (BBB) in diet-induced obese mice and increased transport in a state of starvation. The transport of insulin is influenced by the level of triglycerides. |
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Formal Description Interaction-ID: 67368 |
phenotype affects transport of complex/PPI Insulin |
| Comment | Insulin in the brain acts as a satiety factor. It does this through a number of mechanisms including reducing appetite and decreasing body mass. |
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Formal Description Interaction-ID: 67369 |
complex/PPI Insulin increases_activity of phenotype increased sense of satiety |
| Comment | Insulin in the brain acts as a satiety factor. It does this through a number of mechanisms including reducing appetite and decreasing body mass. |
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Formal Description Interaction-ID: 67370 |
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| Comment | Insulin in the brain acts as a satiety factor. It does this through a number of mechanisms including reducing appetite and decreasing body mass. |
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Formal Description Interaction-ID: 67371 |
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| Comment | Similar results have been observed with ghrelin, where its transport across the blood-brain barrier (BBB) was decreased with obesity and increased with triglycerides. Ghrelin is known to have an effect on cognition. |
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Formal Description Interaction-ID: 67372 |
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| Comment | Similar results have been observed with ghrelin, where its transport across the blood-brain barrier (BBB) was decreased with obesity and increased with triglycerides. Ghrelin is known to have an effect on cognition. |
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Formal Description Interaction-ID: 67373 |
phenotype increases_transport of gene/protein |
| Comment | Similar results have been observed with ghrelin, where its transport across the blood-brain barrier (BBB) was decreased with obesity and increased with triglycerides. Ghrelin is known to have an effect on cognition. |
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Formal Description Interaction-ID: 67374 |
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| Comment | Triglycerides do not enhance all peptide transport across the blood-brain barrier (BBB). In a study examining leptin transport during starvation and diet-induced obesity, it was observed that leptin transport was decreased in both conditions. A commonality between these two states is the increased levels of triglycerides in circulation. The findings of this study identified triglycerides as a factor inhibiting leptin transport during starvation. Also, the authors showed that increasing triglyceride levels with diet or fasting in normal or obese mice had an inverse effect on leptin transport; and that lowering triglycerides using gemfibrozil reversed the impairment in leptin transport. These results demonstrate that triglycerides are involved in peripheral leptin resistance observed during starvation and obesity. |
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Formal Description Interaction-ID: 67375 |
phenotype decreases transport of gene/protein |
| Comment | Triglycerides do not enhance all peptide transport across the blood-brain barrier (BBB). In a study examining leptin transport during starvation and diet-induced obesity, it was observed that leptin transport was decreased in both conditions. A commonality between these two states is the increased levels of triglycerides in circulation. The findings of this study identified triglycerides as a factor inhibiting leptin transport during starvation. Also, the authors showed that increasing triglyceride levels with diet or fasting in normal or obese mice had an inverse effect on leptin transport; and that lowering triglycerides using gemfibrozil reversed the impairment in leptin transport. These results demonstrate that triglycerides are involved in peripheral leptin resistance observed during starvation and obesity. |
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Formal Description Interaction-ID: 67376 |
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| Comment | Leptin has been shown to play an important role in memory and learning by influencing the synaptic plasticity of hippocampal neurons as well as long-term potentiation and depression. Leptin levels have also been shown to be inversely correlated with AD risk and increased leptin appears to be protective against dementia in adults. |
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Formal Description Interaction-ID: 67377 |
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| Comment | Leptin has been shown to play an important role in memory and learning by influencing the synaptic plasticity of hippocampal neurons as well as long-term potentiation and depression. Leptin levels have also been shown to be inversely correlated with AD risk and increased leptin appears to be protective against dementia in adults. |
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Formal Description Interaction-ID: 67378 |
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| Comment | Leptin has been shown to play an important role in memory and learning by influencing the synaptic plasticity of hippocampal neurons as well as long-term potentiation and depression. Leptin levels have also been shown to be inversely correlated with AD risk and increased leptin appears to be protective against dementia in adults. |
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Formal Description Interaction-ID: 67379 |
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| Comment | Leptin has been shown to play an important role in memory and learning by influencing the synaptic plasticity of hippocampal neurons as well as long-term potentiation and depression. Leptin levels have also been shown to be inversely correlated with AD risk and increased leptin appears to be protective against dementia in adults. |
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Formal Description Interaction-ID: 67380 |
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| Comment | Leptin has been shown to play an important role in memory and learning by influencing the synaptic plasticity of hippocampal neurons as well as long-term potentiation and depression. Leptin levels have also been shown to be inversely correlated with AD risk and increased leptin appears to be protective against dementia in adults. |
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Formal Description Interaction-ID: 67381 |
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| Comment | Leptin has been shown to play an important role in memory and learning by influencing the synaptic plasticity of hippocampal neurons as well as long-term potentiation and depression. Leptin levels have also been shown to be inversely correlated with AD risk and increased leptin appears to be protective against dementia in adults. |
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Formal Description Interaction-ID: 67382 |
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| Comment | There are a number of peptides in the brain that have been shown to stimulate ingestive behavior; for example, the over-consumption of food, which leads to the development of obesity. These peptides include galanin (GAL), the opioid peptides enkephalin (ENK) and dynorphin (DYN), and the orexins (ORX). Investigation of these peptides demonstrates that they are highly responsive to changes in diet and nutrients. Studies have shown that endogenous gene and protein expressions for GAL, ENK, DYN, and ORX in the periventricular nucleus and perifornical lateral hypothalamus are closely related to dietary fat, showing a positive correlation with the amount of fat consumed. |
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Formal Description Interaction-ID: 67383 |
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| Comment | There are a number of peptides in the brain that have been shown to stimulate ingestive behavior; for example, the over-consumption of food, which leads to the development of obesity. These peptides include galanin (GAL), the opioid peptides enkephalin (ENK) and dynorphin (DYN), and the orexins (ORX). Investigation of these peptides demonstrates that they are highly responsive to changes in diet and nutrients. Studies have shown that endogenous gene and protein expressions for GAL, ENK, DYN, and ORX in the periventricular nucleus and perifornical lateral hypothalamus are closely related to dietary fat, showing a positive correlation with the amount of fat consumed. |
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Formal Description Interaction-ID: 67384 |
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| Comment | There are a number of peptides in the brain that have been shown to stimulate ingestive behavior; for example, the over-consumption of food, which leads to the development of obesity. These peptides include galanin (GAL), the opioid peptides enkephalin (ENK) and dynorphin (DYN), and the orexins (ORX). Investigation of these peptides demonstrates that they are highly responsive to changes in diet and nutrients. Studies have shown that endogenous gene and protein expressions for GAL, ENK, DYN, and ORX in the periventricular nucleus and perifornical lateral hypothalamus are closely related to dietary fat, showing a positive correlation with the amount of fat consumed. |
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Formal Description Interaction-ID: 67385 |
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| Comment | There are a number of peptides in the brain that have been shown to stimulate ingestive behavior; for example, the over-consumption of food, which leads to the development of obesity. These peptides include galanin (GAL), the opioid peptides enkephalin (ENK) and dynorphin (DYN), and the orexins (ORX). Investigation of these peptides demonstrates that they are highly responsive to changes in diet and nutrients. Studies have shown that endogenous gene and protein expressions for GAL, ENK, DYN, and ORX in the periventricular nucleus and perifornical lateral hypothalamus are closely related to dietary fat, showing a positive correlation with the amount of fat consumed. |
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Formal Description Interaction-ID: 67386 |
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| Comment | There are a number of peptides in the brain that have been shown to stimulate ingestive behavior; for example, the over-consumption of food, which leads to the development of obesity. These peptides include galanin (GAL), the opioid peptides enkephalin (ENK) and dynorphin (DYN), and the orexins (ORX). Investigation of these peptides demonstrates that they are highly responsive to changes in diet and nutrients. Studies have shown that endogenous gene and protein expressions for GAL, ENK, DYN, and ORX in the periventricular nucleus and perifornical lateral hypothalamus are closely related to dietary fat, showing a positive correlation with the amount of fat consumed. |
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Formal Description Interaction-ID: 67387 |
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| Comment | There are a number of peptides in the brain that have been shown to stimulate ingestive behavior; for example, the over-consumption of food, which leads to the development of obesity. These peptides include galanin (GAL), the opioid peptides enkephalin (ENK) and dynorphin (DYN), and the orexins (ORX). Investigation of these peptides demonstrates that they are highly responsive to changes in diet and nutrients. Studies have shown that endogenous gene and protein expressions for GAL, ENK, DYN, and ORX in the periventricular nucleus and perifornical lateral hypothalamus are closely related to dietary fat, showing a positive correlation with the amount of fat consumed. |
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Formal Description Interaction-ID: 67388 |
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| Comment | There are a number of peptides in the brain that have been shown to stimulate ingestive behavior; for example, the over-consumption of food, which leads to the development of obesity. These peptides include galanin (GAL), the opioid peptides enkephalin (ENK) and dynorphin (DYN), and the orexins (ORX). Investigation of these peptides demonstrates that they are highly responsive to changes in diet and nutrients. Studies have shown that endogenous gene and protein expressions for GAL, ENK, DYN, and ORX in the periventricular nucleus and perifornical lateral hypothalamus are closely related to dietary fat, showing a positive correlation with the amount of fat consumed. |
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Formal Description Interaction-ID: 67389 |
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| Comment | There are a number of peptides in the brain that have been shown to stimulate ingestive behavior; for example, the over-consumption of food, which leads to the development of obesity. These peptides include galanin (GAL), the opioid peptides enkephalin (ENK) and dynorphin (DYN), and the orexins (ORX). Investigation of these peptides demonstrates that they are highly responsive to changes in diet and nutrients. Studies have shown that endogenous gene and protein expressions for GAL, ENK, DYN, and ORX in the periventricular nucleus and perifornical lateral hypothalamus are closely related to dietary fat, showing a positive correlation with the amount of fat consumed. |
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Formal Description Interaction-ID: 67390 |
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