CN113956334A - Application of brown adipocyte secretory peptide and derivative thereof in prevention and treatment of obesity - Google Patents

Application of brown adipocyte secretory peptide and derivative thereof in prevention and treatment of obesity Download PDF

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CN113956334A
CN113956334A CN202111581987.7A CN202111581987A CN113956334A CN 113956334 A CN113956334 A CN 113956334A CN 202111581987 A CN202111581987 A CN 202111581987A CN 113956334 A CN113956334 A CN 113956334A
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brown adipocyte
obesity
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CN113956334B (en
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季晨博
崔县伟
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Nanjing Maternity and Child Healthcare Hospital
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    • C07K2319/01—Fusion polypeptide containing a localisation/targetting motif
    • C07K2319/10—Fusion polypeptide containing a localisation/targetting motif containing a tag for extracellular membrane crossing, e.g. TAT or VP22

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Abstract

The invention provides an application of human brown adipocyte secretory peptide FAQPEILIGTIPGAGGTQR in prevention and treatment of obesity; the brown adipocyte secretes peptide FAQPEILIGTIPGAGGTQR and can realize the weight loss effect in an obese model mouse, improve the insulin sensitivity and the glucose tolerance and play a role in treating obesity; FAQPEILIGTIPGAGGTQR also can slow down weight increase caused by high fat diet under mild cold exposure, reduce abnormal metabolic indexes related to obesity such as blood sugar and blood lipid, and prevent obesity; therefore, the brown adipocyte secretory peptide and the derivative or the drug combination thereof have the potential of preparing polypeptide drugs for treating and preventing obesity and complications thereof.

Description

Application of brown adipocyte secretory peptide and derivative thereof in prevention and treatment of obesity
Technical Field
The invention belongs to the technical field of biological medicines, relates to a polypeptide and a derivative thereof, and particularly relates to application of brown adipocyte secretory peptide FAQPEILIGTIPGAGGTQR and the derivative thereof in medicines, health-care products and food additives for preventing and treating obesity and metabolic complications thereof.
Background
Obesity is a chronic disease caused by abnormal accumulation of white fat due to disorder of energy metabolism of the body. Obese patients are often accompanied by related complications such as hyperglycemia, hypertension, cardiovascular diseases and the like, and the obesity patients become serious public health problems facing the world at present. With the change of economic development and life style, the obesity population in China is increased sharply and gradually becomes a low-age development trend, the overweight obesity rate of the Chinese adults is over 50 percent at present, and the overweight obesity rate of school-age children is about to 20 percent. Although obesity is theoretically caused by energy intake exceeding energy expenditure, and weight can be reduced by dietary restriction to reduce energy intake and exercise to increase energy expenditure, long-term practice of both methods is often based on the strong willingness of obese patients and is not suitable for all obese people. With the rapid development of medical technology, weight-loss surgery becomes the first choice for treating severely obese people, but weight-loss surgery often brings about certain sequelae and can negatively affect the long-term life quality of the people. Therefore, it is urgent to find a new weight reduction method with high efficiency.
Because the polypeptide has low molecular weight, strong targeting property, easy modification and reconstruction and the like as good basis of the medicine, the research of the polypeptide medicine becomes the focus of preventing and treating obesity and complications. A large number of researches find that the polypeptide YY and the neuropeptide Y can suppress appetite and reduce weight by regulating the gastrointestinal axis; the polypeptide pNaKtide derived from the Na/K-ATPase alpha subunit can inhibit adipocyte differentiation through inhibiting a Reactive Oxygen Species (ROS) generation channel regulated by Na/K-ATPase, and can effectively reduce the body weight of an obese mouse and improve insulin sensitivity; glucagon-like peptide-1 (GLP-1) stimulates insulin secretion, inhibits glucagon secretion, inhibits gastric emptying, reduces appetite to reduce food intake, and reduces body weight while treating diabetes, and GLP-1 receptor agonists (liraglutide), an analog thereof, have been successfully marketed as polypeptide drugs for the treatment of diabetes and obesity. These studies indicate that the polypeptides have good therapeutic application prospects in obesity and related metabolic diseases.
Disclosure of Invention
In order to solve the problems, the invention discloses a brown adipocyte secretory peptide and a derivative thereof, and an application of the brown adipocyte secretory peptide and the derivative thereof in prevention and treatment of obesity and complications thereof.
In order to achieve the purpose, the technical scheme of the invention is as follows:
the invention aims to provide a brown adipocyte secretion peptide FAQPEILIGTIPGAGGTQR, wherein the sequence of the brown adipocyte secretion peptide is shown as SEQ ID NO:1 is shown.
The invention also aims to provide a brown adipocyte secretory peptide derivative, which is a chimeric peptide containing an active amino acid sequence shown as SEQ ID NO.1, wherein the chimeric peptide is formed by connecting a polypeptide and a cell-penetrating peptide, or the brown adipocyte secretory peptide is formed by substituting, deleting or adding one or more amino acid residues to form the polypeptide derivative which retains the activity of the peptide.
Further, the sequence of the brown adipocyte secretory peptide derivative is shown as SEQ ID NO:2, respectively.
The invention also aims to provide an application of the brown adipocyte secretory peptide FAQPEILIGTIPGAGGTQR in preparing a medicament for preventing and treating obesity and metabolic complications thereof, wherein the medicament for preventing and treating obesity and metabolic complications thereof comprises a peptide sequence shown as SEQ ID NO:1, which can exert an obesity preventing effect by reducing body fat content.
Further, the content of the brown adipocyte secretory peptide in the medicine for preventing and treating obesity and metabolic complications thereof is 5-10 mg/kg.
The invention also aims to provide an application of the brown adipocyte secretory peptide derivative in preparing medicines for preventing and treating obesity and complications thereof, wherein the brown adipocyte secretory peptide derivative is a polypeptide chimeric peptide with a sequence shown as SEQ ID NO:2, respectively.
Further, the medicine for preventing and treating obesity and complications thereof comprises the brown adipocyte secretory peptide and/or the brown adipocyte secretory peptide derivative, and the content of the brown adipocyte secretory peptide and/or the brown adipocyte secretory peptide derivative is 1-10 mg/kg.
Further, the medicament for preventing and treating obesity and metabolic complications thereof also comprises other pharmaceutically acceptable carriers or excipients, wherein the other pharmaceutically acceptable carriers comprise nano materials, liposomes, hydrogels and extracellular vesicles, and the other pharmaceutically acceptable excipients comprise mannitol, lactose and sodium chloride.
Further, the metabolic complications of obesity include hyperlipidemia, hyperglycemia, and insulin resistance.
As another application of the invention, the brown adipocyte secretory peptide and the derivative thereof are applied to health care products or food additives for preventing and treating obesity and metabolic complications thereof.
The sequence of brown adipocyte secretory peptide FAQPEILIGTIPGAGGTQR is represented by SEQ ID NO:1 as follows:
Phe-Ala-Gln-Pro-Glu-Ile-Leu-Ile-Gly-Thr-Ile-Pro-Gly-Ala-Gly-Gly-Thr-Gln-Arg。
SEQ ID NO. 2 is as follows:
GRKKRRQRRRPPQQFAQPEILIGTIPGAGGTQR。
the invention has the beneficial effects that:
the invention provides a brown adipocyte secretory peptide FAQPEILIGTIPGAGGTQR and a derivative thereof, which can reduce the body weight and the body fat content of an obese model mouse and a mouse in a high-fat diet state, reduce blood sugar and blood fat, and improve insulin sensitivity and glucose tolerance by activating energy metabolism of adipose tissues. Therefore, the brown adipocyte secretory peptide and the derivative thereof have the potential of preparing medicaments for treating and preventing obesity and complications thereof.
Drawings
FIG. 1 Effect of FAQPEILIGTIPGAGGTQR peptides of the invention on body weight in obese model mice, wherein a is the body weight change before and after FAQPEILIGTIPGAGGTQR effect, b is the body weight change before and after solvent control injection, c is the percent body fat change, d is the lean body mass level;
FIG. 2 is a graph of the effect of FAQPEILIGTIPGAGGTQR peptides of the invention on insulin sensitivity and glucose tolerance in obese model mice, wherein a is the glucose tolerance test, b is the area under the curve of the glucose tolerance test, c is the insulin sensitivity test, and d is the area under the curve of the insulin sensitivity test;
FIG. 3 is a graph of the effect of FAQPEILIGTIPGAGGTQR peptides of the invention on weight gain in mice on a high fat diet under mild cold exposure, wherein a is weight change before and after FAQPEILIGTIPGAGGTQR effect, b is feeding level, c is percent body fat change, and d is lean body mass level;
FIG. 4 is a graph of the effect of FAQPEILIGTIPGAGGTQR peptides of the invention on insulin sensitivity and glucose tolerance in mice on a high fat diet under mild cold exposure, wherein a is the glucose tolerance test, b is the area under the curve of the glucose tolerance test, c is the insulin sensitivity test, and d is the area under the curve of the insulin sensitivity test;
FIG. 5 is a graph of the effect of FAQPEILIGTIPGAGGTQR peptides of the invention on blood glucose, blood lipid, and insulin levels in mice on a high-fat diet, wherein a is random blood glucose levels, b is blood lipid changes, and c is insulin levels, under mild cold exposure.
Detailed Description
The present invention will be further illustrated with reference to the accompanying drawings and specific embodiments, which are to be understood as merely illustrative of the invention and not as limiting the scope of the invention.
Example 1
FAQPEILIGTIPGAGGTQR Effect of peptides on body weight in obese model mice
Experimental methods
Male C57BL/6J mice, 6-week old, of cleaning grade, were purchased from the model animal research center of Nanjing university and were housed in the SPF laboratory animal center of Nanjing university of medicine, maintaining them at a 12h light/dark cycle, 24 ℃ at room temperature and 50% humidity. After 1 week of acclimation (free food and water intake) in SPF laboratory animal center, high fat diet alone(s) ((60% fat) continuously feeding the mice for 6 months, and successfully inducing the obese mouse animal model; thereafter, the obese mice were intraperitoneally injected with FAQPEILIGTIPGAGGTQR peptide (5 mg/kg), which was used as a control group, and intraperitoneally injected with dissolved physiological saline (Vehicle) 1 time per day for 8 weeks. Weighing and obtaining the weight change of the mice before and after 8 weeks of intraperitoneal injection, weighing the white abdominal fat (iWAT) and the white epididymis adipose tissue (eWAT) after the mice are killed, respectively obtaining the fat content of a control group and a peptide intervention group after the intraperitoneal injection, and calculating to obtain the lean body weight of the mice. Data analysis was performed using GraphPad Prism8, and differences were calculated using a t-test comparison whenP<A difference of 0.05 was considered significant. DenotesP<0.05; denotesP<0.01; denotesP<0.001。
Results of the experiment
As can be seen from fig. 1, the intraperitoneal injection of the peptide FAQPEILIGTIPGAGGTQR at the concentration of 5mg/kg into the mice for 8 weeks reduced the body weight of the mice in the constructed high fat diet-induced obesity model, and the body weight of the mice in the control group (Vehicle) did not have a significant difference, indicating that the reduction in body weight in the intervention group was caused by the peptide FAQPEILIGTIPGAGGTQR at the concentration of 5mg/kg, but not by the intraperitoneal injection. Meanwhile, compared with the control group (Vehicle), the fat content of the mice in the FAQPEILIGTIPGAGGTQR peptide intervention group with the concentration of 5mg/kg is obviously lower than that of the mice in the control group (Vehicle), and no obvious difference is found in the lean body mass of the mice, which indicates that the weight reduction of the FAQPEILIGTIPGAGGTQR peptide intervention group is caused by the reduction of body fat. FAQPEILIGTIPGAGGTQR the peptide can reduce obesity degree of obese mice induced by high fat diet.
Example 2
FAQPEILIGTIPGAGGTQR effects of peptides on insulin sensitivity and glucose tolerance in obese model mice.
Experimental methods
Male C57BL/6J mice, 6-week old, of cleaning grade, were purchased from the model animal research center of Nanjing university and were housed in the SPF laboratory animal center of Nanjing university of medicine, maintaining them at a 12h light/dark cycle, 24 ℃ at room temperature and 50% humidity. In SPF experimentsAfter adaptation (free food intake and water drinking) in the animal center for 1 week, the mice are continuously fed with high fat feed (60% fat) for 6 months, and the induction of the animal model of the obese mice is successful; thereafter, the obese mice were intraperitoneally injected with FAQPEILIGTIPGAGGTQR peptide (5 mg/kg), which was a control group, and intraperitoneally injected with dissolved physiological saline (Vehicle) 1 time a day for 8 weeks, after which the insulin sensitivity and glucose tolerance of 2 groups of obese mice were measured after 8 weeks. Insulin sensitivity measurement protocol: after fasting for 12h, the mice are subjected to intraperitoneal injection for 1 time by insulin with the concentration of 0.5U/kg, tail vein blood is taken at 0min, 15min, 30min, 60min, 90min and 120min respectively, and the blood glucose value of the mice is detected by using blood glucose test paper and a glucometer so as to evaluate the insulin sensitivity of the mice. Glucose tolerance experimental measurement protocol: after fasting for 6h, the mice are subjected to intraperitoneal injection of 1g/kg glucose for 1 time, tail vein blood is taken at 0min, 15min, 30min, 60min, 90min and 120min respectively, and blood glucose change of the mice is detected by using blood glucose test paper and a glucometer so as to evaluate the glucose tolerance of the mice. Data analysis was performed using GraphPad Prism8 expressed as mean (average). + -. Standard Deviation (SD) and differences were calculated using a t-test comparison whenP<A difference of 0.05 was considered significant. DenotesP<0.05; denotesP<0.01; denotesP<0.001。
Results of the experiment
As can be seen from fig. 2, intraperitoneal injection of the mouse with FAQPEILIGTIPGAGGTQR peptide at a concentration of 5mg/kg for 8 weeks significantly increased insulin sensitivity and glucose tolerance of obese mice that had been successfully induced by high fat diet, and improved insulin and glucose metabolism levels of the obese mice, compared to the control group (Vehicle).
Example 3
Effect of FAQPEILIGTIPGAGGTQR peptides of the invention on weight gain in mice on a high fat diet under mild cold exposure.
Experimental methods
Male C57BL/6J mice of 6-8 weeks old of clean grade were purchased from Nanjing university model animal research center and maintained in Nanjing university of medicine SPF laboratory animal centerAfter 12h light/dark cycle, humidity is 50%. After adapting (free food intake and water intake) in a refrigerator at 16-18 ℃ of the center of SPF experimental animals for 1 week, the mice are fed with high-fat feed (60% fat) in the refrigerator at 16-18 ℃, the mice are continuously raised for 10 weeks to induce the C57BL/6J mice to have an obesity phenotype, meanwhile, the mice are injected with FAQPEILIGTIPGAGGTQR peptide (5 mg/kg) in the abdominal cavity, namely a dry pre-treatment group, and are injected with dissolved normal saline (Vehicle) in the abdominal cavity as a control group for 1 time every day. After 10 weeks, the weight of two groups of mice was weighed, the daily food intake of the mice was calculated, the subcutaneous white fat (iWAT) and epididymal white adipose tissue (eWAT) were taken from the sacrificed mice and weighed, and the lean body mass and fat content of 2 groups of mice after intraperitoneal injection were calculated. Data analysis was performed using GraphPad Prism8, and differences were calculated using a t-test comparison whenP<A difference of 0.05 was considered significant. DenotesP<0.05; denotesP<0.01; denotesP<0.001。
Results of the experiment
As can be seen from fig. 3, FAQPEILIGTIPGAGGTQR peptide (5 mg/kg) significantly slowed the weight gain of obese mice caused by a high-fat diet under high-mild cold exposure compared to the control group (Vehicle), with no significant difference in food intake between the two groups, indicating that the slowing of weight gain was not caused by decreasing food intake; meanwhile, the fat content of FAQPEILIGTIPGAGGTQR peptide (5 mg/kg) in the intervention group is significantly lower than that of the control group (Vehicle), and the lean body mass of the mice has no significant change, which indicates that FAQPEILIGTIPGAGGTQR peptide (5 mg/kg) is used for reducing the weight increase of the intervention group due to the reduction of the fat content in the body.
Example 4
Effect of FAQPEILIGTIPGAGGTQR peptides of the invention on insulin sensitivity and glucose tolerance in mice on a high-fat diet under mild cold exposure.
Experimental methods
Male C57BL/6J mice, 6-8 weeks old, of clean grade, were purchased from the model animal research center of Nanjing university and housed in the SPF laboratory animal center of Nanjing university of medicine, maintaining them at 12h light/dark cycle and 50% humidity. Acclimation (free food intake) in the 16-18 ℃ refrigerator in SPF laboratory animal centerAnd drinking water), after 1 week, feeding the mice with high-fat feed (60% fat) in a refrigerator at 16-18 ℃, continuously feeding for 10 weeks to induce the C57BL/6J mice to have an obese phenotype, meanwhile, injecting FAQPEILIGTIPGAGGTQR peptide (5 mg/kg) into the abdominal cavity of the mice to obtain a dry pre-group, injecting dissolved normal saline (Vehicle) into the abdominal cavity as a control group, injecting for 1 time every day, and measuring the insulin sensitivity and glucose tolerance of the obese mice caused by high-fat diet under mild cold exposure of 2 groups after 10 weeks. Insulin sensitivity measurement protocol: the mice are fasted for 12h, the obese mice are injected with insulin with the concentration of 0.5U/kg in the abdominal cavity the next day, tail vein blood is taken at 0min, 15min, 30min, 60min, 90min and 120min respectively, and the blood glucose change of the mice is detected by a glucometer to evaluate the insulin sensitivity of the mice. Glucose tolerance experimental measurement protocol: after fasting the mice for 6 hours, 1g/kg glucose is injected into the abdominal cavity of the obese mice; tail vein blood was taken at 0min, 15min, 30min, 60min, 90min and 120min, respectively, and blood glucose changes of mice were measured using a glucometer to evaluate glucose tolerance of mice. Data analysis was performed using GraphPad Prism8, and differences were calculated using a t-test comparison whenP<A difference of 0.05 was considered significant. DenotesP<0.05; denotesP<0.01; denotesP<0.001。
Results of the experiment
As can be seen from fig. 4, intraperitoneal injection of FAQPEILIGTIPGAGGTQR peptide at a concentration of 5mg/kg significantly increased insulin sensitivity and glucose tolerance in obese mice on a high fat diet under mild cold exposure and improved insulin and glucose metabolism levels in obese mice under mild cold exposure compared to the control group (Vehicle).
Example 5
Effect of FAQPEILIGTIPGAGGTQR peptides of the invention on blood glucose, blood lipids and insulin levels in mice on a high-fat diet under mild cold exposure.
Experimental methods
Male C57BL/6J mice of 6-8 weeks old of clean grade were purchased from Nanjing university model animal research center and were housed in the SPF laboratory animal center of Nanjing medical university, and kept for 12h of lightDark cycle, humidity 50%. Adapting (freely taking food and drinking water) in a refrigerator at 16-18 ℃ of the center of SPF experimental animals for 1 week, feeding mice with high-fat feed (60% fat) in the refrigerator at 16-18 ℃, continuously feeding for 10 weeks to induce the C57BL/6J mice to have an obesity phenotype, simultaneously injecting FAQPEILIGTIPGAGGTQR peptide (5 mg/kg) into the abdominal cavity of the mice to obtain a dry pre-group, injecting dissolved normal saline (Vehicle) into the abdominal cavity as a control group for 1 time every day, and detecting the tail vein blood sugar change of the obese mice caused by high-fat diet under mild cold exposure of 2 groups after 10 weeks by using blood sugar test paper and a blood sugar meter; meanwhile, 2 groups of mouse eyeball blood are respectively taken after anesthesia, centrifuged for 15min at 1000rpm and 4 ℃, then the upper serum is taken, and a commercialized kit is adopted to detect the blood fat and the insulin level in the mouse serum. Data analysis was performed using GraphPad Prism8, and differences were calculated using a t-test comparison whenP<A difference of 0.05 was considered significant. DenotesP<0.05; denotesP<0.01; denotesP<0.001。
Results of the experiment
As can be seen from fig. 5, compared to the control group (Vehicle), the FAQPEILIGTIPGAGGTQR peptide (5 mg/kg) resulted in a significantly reduced random blood glucose level, and significantly reduced blood lipid and insulin levels in obese mice following a high fat diet in mild cold exposure, and FAQPEILIGTIPGAGGTQR peptide (5 mg/kg) intervention resulted in alleviation of hyperglycemia, hyperlipidemia, and hyperinsulinemia following a high fat diet in mild cold exposure.
It should be noted that the above-mentioned contents only illustrate the technical idea of the present invention, and the protection scope of the present invention is not limited thereby, and it is obvious to those skilled in the art that several modifications and decorations can be made without departing from the principle of the present invention, and these modifications and decorations fall within the protection scope of the claims of the present invention.
Sequence listing
<110> Nanjing City health care hospital for women and children
<120> application of brown adipocyte secretory peptide and derivative thereof in prevention and treatment of obesity
<160> 2
<170> SIPOSequenceListing 1.0
<210> 1
<211> 19
<212> PRT
<213> Homo sapiens(Homo sapiens)
<400> 1
Phe Ala Gln Pro Glu Ile Leu Ile Gly Thr Ile Pro Gly Ala Gly Gly
1 5 10 15
Thr Gln Arg
<210> 2
<211> 33
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<400> 2
Gly Arg Lys Lys Arg Arg Gln Arg Arg Arg Pro Pro Gln Gln Phe Ala
1 5 10 15
Gln Pro Glu Ile Leu Ile Gly Thr Ile Pro Gly Ala Gly Gly Thr Gln
20 25 30
Arg

Claims (9)

1. A brown adipocyte secretion peptide, wherein the sequence of the brown adipocyte secretion peptide is shown as SEQ ID NO:1 is shown.
2. The application of the brown adipocyte secretory peptide in preparing the medicine for preventing and treating obesity and metabolic complications thereof is characterized in that the medicine for preventing and treating obesity and metabolic complications thereof comprises a peptide sequence shown as SEQ ID NO:1, and the brown adipocytes shown in fig. 1 secrete peptides.
3. The use as claimed in claim 2, wherein the effective concentration of the brown adipocyte secretory peptide for preventing and treating obesity and its metabolic complications is 5-10 mg/kg.
4. The brown adipocyte secretory peptide derivative is a chimeric peptide which comprises an active amino acid sequence shown as SEQ ID NO.1, wherein the chimeric peptide is formed by connecting a polypeptide and a cell-penetrating peptide, or the brown adipocyte secretory peptide is a polypeptide derivative which is formed by substituting, deleting or adding one or more amino acid residues and retains the activity of the peptide.
5. The brown adipocyte secretory peptide derivative of claim 4, wherein the sequence of said brown adipocyte secretory peptide derivative is set forth in SEQ ID NO:2, respectively.
6. Use of a brown adipocyte secretory peptide derivative in the preparation of a medicament for preventing and treating obesity and its complications, wherein the medicament for preventing and treating obesity and its complications comprises the brown adipocyte secretory peptide and/or the brown adipocyte secretory peptide derivative of any of claims 1 to 5.
7. The use according to claim 6, wherein the effective concentration of the brown adipocyte secretory peptide and/or the brown adipocyte secretory peptide derivative in the medicament for preventing and treating obesity and metabolic complications thereof is 1 to 10 mg/kg.
8. The use of claim 2 or 6, wherein the medicament for preventing and treating obesity and its complications further comprises other pharmaceutically acceptable carriers or excipients, the other pharmaceutically acceptable carriers comprise nanomaterials, liposomes, hydrogels, extracellular vesicles, and the other pharmaceutically acceptable excipients comprise mannitol, lactose, and sodium chloride.
9. Use according to claim 2 or 6, characterized in that the obesity complications comprise hyperlipidemia, hyperglycemia, insulin resistance.
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