Application of BRD7 as a target in the preparation of drugs for obesity-related mental illnesses

Abstract

The present invention discloses an application of a bromodomain structural protein BRD7 as a target in the preparation of a drug for obesity-related psychiatric disorders, wherein the drug is a BRD7 small molecule inhibitor, and the BRD7 small molecule inhibitor BI-7273. The present application experimentally verifies that BRD7 small molecule inhibitors have a good therapeutic effect on obesity-related psychiatric disorders, just like knocking out BRD7 using gRNA. The present invention proves that obesity-induced anxiety and depression-like behaviors can be significantly improved by inhibiting T cell BRD7 gene expression or inhibiting BRD7 protein activity. The present invention reveals a new role of the BRD7 gene in immune cells and obesity-related psychiatric disorders, and designs and prepares drugs or other treatment methods for treating obesity-related psychiatric disorders using the BRD7 gene or protein as a target.

Description

Technical Field

[0001] The present invention relates to the field of medical technology, and in particular to an application of a bromodomain structural protein BRD7 as a target in the preparation of a drug for obesity-related mental illness. Background Art

[0002] The brd7 gene encodes the BRD7 protein, which contains a highly conserved bromodomain that recognizes histone H3 and regulates its acetylation, participating in gene transcriptional regulation. BRD7 has been shown to be a core component of the SWI / SNF chromatin remodeling complex and contributes to disease progression by influencing the transcriptional activity and expression of downstream genes. Our previous studies have shown that complete knockout of BRD7 leads to impaired spermatogenesis and cognitive dysfunction. Studies have reported that BRD7 is closely linked to obesity, glucose homeostasis, and the insulin signaling pathway. For example, BRD7 regulates glucose homeostasis by binding to the PI3K regulatory subunit, regulating XBP1 activity; and treatment with a BRD7 inhibitor can restore β-cell function. BRD7 is ubiquitously expressed in immune cells, but its immune regulatory functions remain largely unexplained. Obesity in both humans and mice leads to altered immune status. A growing body of research reveals a symbiotic relationship between obesity and depression. Studies in some individuals with depression have shown that persistent immune activation associated with obesity may contribute to mood disorders. Therefore, immune responses mediated by lipid metabolism disturbances in obesity are inextricably linked to anxiety and depressive symptoms. Studies have shown that blood lipid and lipoprotein concentrations are inversely correlated with measures of depression and anxiety, and that low cholesterol is associated with both state and trait aggression in depressed individuals who have attempted suicide. Specifically, individuals with low lipoprotein concentrations have significantly increased rates of depression, anxiety, suicide attempts, and violent behavior. Given the crucial role of BRD7 in regulating metabolic homeostasis in obesity, elucidating its role in immune homeostasis and obesity-related mood disorders could be an effective approach for preventing and treating obesity-related psychiatric disorders.

[0003] It should be noted that the above introduction to the technical background is merely intended to provide a clear and complete description of the technical solutions of this application and facilitate understanding by those skilled in the art. Simply because these solutions are described in the background technology section of this application, it should not be assumed that the above technical solutions are well known to those skilled in the art. Summary of the Invention

[0004] The purpose of the present invention is to provide a method for preparing drugs for obesity-related psychiatric disorders using the bromodomain structural protein BRD7 as a target. This application experimentally verifies that small molecule BRD7 inhibitors, like gRNA knockout of BRD7, have a good therapeutic effect on obesity-related psychiatric disorders. The present invention demonstrates that inhibiting T cell BRD7 gene expression or inhibiting BRD7 protein activity can significantly improve obesity-induced anxiety and depression-like behaviors. The present invention reveals a new role for the BRD7 gene in immune cells and obesity-related psychiatric disorders, and designs and prepares drugs or other treatments for obesity-related psychiatric disorders using the BRD7 gene or protein as a target.

[0005] In order to achieve the above object, the present invention provides an application of a bromodomain structural protein BRD7 as a target in the preparation of a drug for obesity-related mental illness, wherein the drug is a BRD7 small molecule inhibitor, the BRD7 small molecule inhibitor BI-7273, molecular weight 353.51, CAS No. 1883429-21-7, molecular formula C 20 H 23 N3O3, its structural formula is shown in Ⅰ:

[0006]

[0007] According to one aspect of the present invention, the targeting of the bromodomain structural protein BRD7 is to use chemical drugs to reduce the protein activity of BRD7 or to silence BRD7.

[0008] Beneficial effects of the present invention:

[0009] The T cell knockout of BRD7 gene expression in the present application can significantly improve obesity-induced anxiety and depression-like behaviors.

[0010] The present invention experiments have shown that conditional knockout of T cell BRD7 can significantly improve anxiety-depression-like behaviors induced by a high-fat diet. The present invention also proves that by inhibiting the expression of the T cell BRD7 gene, the concentration of low-density lipoprotein cholesterol in the blood of mice fed a high-fat diet is increased, while having no effect on blood sugar, total cholesterol, and high-density lipoprotein cholesterol concentrations, indicating that BRD7 may maintain metabolic homeostasis through T cell immune regulation, thereby playing a role in treating obesity-related anxiety and depression. Based on this, a new treatment method for mental illness has been developed: BRD7 gene-specific siRNA knocks down the expression of BRD7, and small molecule inhibitors inhibit BRD7 protein activity. The present application designs drugs for the treatment and / or prevention of obesity-related mental illnesses with BRD7 as the target. It reveals the new role of BRD7 in immune cells and the immune system, and provides new therapeutic targets and effective new drugs for the prevention and treatment of obesity-related mental illnesses. BRIEF DESCRIPTION OF THE DRAWINGS

[0011] Figure 1This is a process flow chart for constructing BRD7-CKO mice as described in Example 1 of the present invention;

[0012] Figure 2 The WT mice (4 weeks old) of Example 2 of the present invention were fed a high-fat diet (65% fat) for 8 months and then orally administered with drinking water and the BI-7273 inhibitor as described in Example 3. The control group was fed a normal diet for 8 months and then orally administered with drinking water and the BI-7273 inhibitor as described in Example 3. The weight of the mice was analyzed.

[0013] Figure 3 (a) WT mice (4 weeks old) of Example 2 of the present invention were fed a high-fat diet (65% fat) for 8 months and then orally administered with drinking water and the BI-7273 inhibitor according to Example 3. A control group was fed a normal diet for 8 months and then orally administered with drinking water and the BI-7273 inhibitor according to Example 3. After feeding, an open field test was performed to measure the total distance traveled. Figure 3 (b) WT mice (4 weeks old) of Example 2 of the present invention were fed a high-fat diet (65% fat) for 8 months. The control group was fed a normal diet for 8 months and grouped as in Example 3 and given oral drinking water and the BI-7273 inhibitor. After feeding, an open field test was performed, and the percentage of time spent in the central grid was observed.

[0014] Figure 4 (a) WT mice (4 weeks old) according to Example 2 of the present invention were fed a high-fat diet (65% fat) for 8 months and then administered oral drinking water and the BI-7273 inhibitor according to the grouping method of Example 3. A control group was fed a normal diet for 8 months and then administered oral drinking water and the BI-7273 inhibitor according to the grouping method of Example 3. After feeding, an elevated plus maze test was performed to analyze the total distance traveled. Figure 4 (b) WT mice (4 weeks old) of Example 2 of the present invention were fed a high-fat diet (65% fat) for 8 months and then grouped as in Example 3 to receive oral drinking water and the BI-7273 inhibitor. A control group was fed a normal diet for 8 months and then grouped as in Example 3 to receive oral drinking water and the BI-7273 inhibitor. After feeding, they were subjected to an elevated plus maze test, and the percentage of time spent in the open arms was analyzed.

[0015] Figure 5 (a) WT mice (4 weeks old) were fed a high-fat diet (65% fat) for 8 months and then orally administered drinking water and the BI-7273 inhibitor as described in Example 2 of the present invention. A control group was fed a normal diet for 8 months and then orally administered drinking water and the BI-7273 inhibitor as described in Example 3. The latency of the mice to ingest food in their home cages was analyzed. Figure 5(b) WT mice (4 weeks old) of Example 2 of the present invention were fed a high-fat diet (65% fat) for 8 months and then orally administered with drinking water and the BI-7273 inhibitor according to the grouping method of Example 3. A control group was fed a normal diet for 8 months and then orally administered with drinking water and the BI-7273 inhibitor according to the grouping method of Example 3. The latency period of the mice in ingesting food in a novel environment was analyzed.

[0016] Figure 6 WT mice (4 weeks old) of Example 2 of the present invention were fed a high-fat diet (65% fat) for 8 months and then grouped as in Example 3 to receive oral drinking water and the BI-7273 inhibitor. A control group was fed a normal diet for 8 months and then grouped as in Example 3 to receive oral drinking water and the BI-7273 inhibitor. After feeding, a tail suspension test was performed to determine the percentage of immobility time.

[0017] Figure 7 The weight of WT mice and BRD7-CKO mice in Example 2 of the present invention were fed a high-fat diet (65% fat) for 8 months, while the control group was fed a normal diet.

[0018] Figure 8 (a) Total movement distance of WT mice and BRD7-CKO mice from Example 2 of the present invention after being fed a high-fat diet (65% fat) for 8 months and a control group fed a normal diet in an open field test; Figure 8 (b) WT mice and BRD7-CKO mice from Example 2 of the present invention were fed a high-fat diet (65% fat) for 8 months, while the control group was fed a normal diet. The open field test shows the percentage of time spent in the central grid.

[0019] Figure 9 (a) WT mice and BRD7-CKO mice from Example 2 of the present invention were fed a high-fat diet (65% fat) for 8 months, while the control group was fed a normal diet. They were then subjected to an elevated plus maze test, and their total distance traveled. Figure 9 (b) WT mice and BRD7-CKO mice from Example 2 of the present invention were fed a high-fat diet (65% fat) for 8 months, while the control group was fed a normal diet. They were then subjected to an elevated plus maze test, and the percentage of time spent in the open arms was plotted.

[0020] Figure 10 (a) WT mice (4 weeks old) and BRD7-CKO mice according to Example 2 of the present invention were fed a high-fat diet (65% fat) for 8 months, and a control group was fed a normal diet for 8 months. The latency of the mice to ingest food in their home cages was analyzed; Figure 10(b) WT mice (4 weeks old) and BRD7-CKO mice from Example 2 of the present invention were fed a high-fat diet (65% fat) for 8 months, while the control group was fed a normal diet for 8 months. The latency of the mice in the novel environment was analyzed;

[0021] Figure 11 WT mice (4 weeks old) and BRD7-CKO mice of Example 2 of the present invention were fed a high-fat diet (65% fat) for 8 months, and a control group was fed a normal diet for 8 months. After feeding, a tail suspension test was performed to measure the percentage of immobility time.

[0022] Figure 12 A shows the peripheral blood glucose levels of WT mice (4 weeks old) and BRD7-CKO mice fed with a high-fat diet (65% fat) for 8 months, and a control group fed with a normal diet for 8 months; Figure 12 B shows the total cholesterol levels in peripheral blood of WT mice (4 weeks old) and BRD7-CKO mice fed with a high-fat diet (65% fat) for 8 months, and a control group fed with a normal diet for 8 months; Figure 12 C shows the peripheral blood high-density lipoprotein-cholesterol levels of WT mice (4 weeks old) and BRD7-CKO mice fed with a high-fat diet (65% fat) for 8 months, and a control group fed with a normal diet for 8 months; Figure 12 D is the low-density lipoprotein cholesterol levels in peripheral blood of WT mice (4 weeks old) and BRD7-CKO mice fed with a high-fat diet (65% fat) for 8 months, and a control group fed with a normal diet for 8 months; Figure 12 E is the ratio of high-density lipoprotein cholesterol to total cholesterol in peripheral blood of WT mice (4 weeks old) and BRD7-CKO mice fed with a high-fat diet (65% fat) for 8 months, and a control group fed with a normal diet for 8 months; Figure 12 F shows the concentration of non-HDL cholesterol in peripheral blood of WT mice (4 weeks old) and BRD7-CKO mice fed with a high-fat diet (65% fat) for 8 months and a control group fed with a normal diet for 8 months in Example 2 of the present invention. DETAILED DESCRIPTION

[0023] To make the present invention easier to understand, the present invention is further described below with reference to specific examples. It should be understood that these examples are only used to illustrate the present invention and are not used to limit the scope of the present invention. Obviously, the embodiments described are only part of the embodiments of the present invention, rather than all of the embodiments. Based on the embodiments in the present invention, all other embodiments obtained by ordinary technicians in this field without making creative work are within the scope of protection of the present invention. Unless otherwise defined, the professional terms used below are consistent with the meanings understood by professional and technical personnel in this field; unless otherwise specified, the raw materials and reagents involved in this article can be purchased from the market or prepared by known methods.

[0024] It should be noted that "Brd7-201" means that the Brd7 gene has 7 transcripts, and the transcript used in this application is transcript 201.

[0025] It should be noted that the BRD7 gene knockout mice of the present application are based on C57BL / 6 mice with their BRD7 gene knocked out, referred to as BRD7-CKO mice; the C57BL / 6 mice of the present application are referred to as WT mice.

[0026] It should be noted that the BRD7 gene-specific siRNA of the present application is a gRNA, specifically including gRNA1 and gRNA2. The 5'-3' sequence number of gRNA1 is: 5'-AGTGTGACCGTGAGACAGCG-3', as shown in SEQ ID NO.6; the 5'-3' sequence number of gRNA2 is: 5'-ATGTGCAAGGGCCAACCGAC-3', as shown in SEQ ID NO.7.

[0027] Example 1

[0028] CRISPR / Cas9 technology was used to construct T cell knockout BRD7 mice (BRD7-CKO mice). The flow chart is as follows Figure 1 shown.

[0029] The Brd7 gene has seven transcripts. The sense strand of the Brd7 gene DNA sequence is shown in SEQ ID NO. 1. Based on the structure of the Brd7 gene, exons 3 to 4 of the Brd7-201 (ENSMUST00000034085.7) transcript are the knockout region. The sequence numbers for exon 3 are shown in SEQ ID NO. 2, and the sequence numbers for exon 4 are shown in SEQ ID NO. 3. This region contains 188 base pairs of coding sequence, and knocking out this region will result in protein disruption. We used CRISPR / Cas9 technology to edit the Brd7 gene. The brief procedure is as follows: CRISPR / Cas9 system gRNA was microinjected into fertilized eggs of C57BL / 6JGpt mice. The resulting F0 mice were positive and confirmed by PCR and sequencing. Positive F0 mice were mated with C57BL / 6JGpt mice to generate a stable F1 mouse model. Stable F1 mice (flox-carrying mice) were mated with mice expressing Cre recombinase (a universal tool mouse) to knock out exons 3-4 of the BRD7 gene, resulting in loss of BRD7 function in T cells. The gRNA was designed as follows: the target sequence was edited with the BRD7Brd7-201 (ENSMUST00000034085.7) transcript, which is the positive strand of the DNA sequence of the Brd7 gene as shown in SEQ ID NO.1. The loxp insertion sites are shown in SEQ ID NO.4 and SEQ ID NO.5, respectively. Among them, the gRNA of the CRISPR / Cas9 system includes gRNA1 and gRNA2, which are used to cut exon 3 and exon 4, respectively. The 5'-3' sequence number of gRNA1 is: 5'-AGTGTGACCGTGAGACAGCG-3', as shown in SEQ ID NO.6; the 5'-3' sequence number of gRNA2 is: 5'-ATGTGCAAGGGCCAACCGAC-3', as shown in SEQ ID NO.7.

[0030] It should be noted that Loxp tags are inserted on both sides of exons 3-4. Cre recognizes the Loxp tags inserted on both sides and knocks out the exon 3-exon 4 region within the tags, thereby achieving the purpose of gene editing.

[0031] It should be noted that due to the limited equipment of the applicant, we provided the above-mentioned plan for knocking out exons 3-4 of the BRD7 gene to Jiangsu Jicui Yaokang Biotechnology Co., Ltd. for processing, and prepared mice with knockout of exons 3-4 of the BRD7 gene (BRD7-CKO mice) for the experiments of this application, which are specifically shown in Evidence 1.

[0032] It should be noted that the above-mentioned mice in this application are only used for laboratory purposes and not for commercial use, and the gRNA of their CRISPR / Cas9 system has not been disclosed before this application.

[0033] It should be noted that the synthesis of gRNA in the CRISPR / Cas9 system of the present application is base synthesis, which is a common method for sequence synthesis and will not be described in detail here.

[0034] Example 2

[0035] Establish a high-fat diet (HFD) model: Four-week-old weaned C57BL / 6 (WT) or BRD7 knockout (BRD7-CKO) mice were fed a HFD (60% fat, #12492, Research Diets) for 32 weeks with free access to water. Changes in mouse body weight and related indicators such as blood lipids and blood glucose were measured.

[0036] Example 3

[0037] After the HFD model was established, mice were randomly divided into two groups of 10 mice each, designated as the control group (saline group) and the BI-727 group, starting on Day 0. Each mouse in the BI-727 group was orally administered 180 mg / kg of the BI-7273 inhibitor daily, while each mouse in the control group received the same volume of drinking water. Both groups of mice were tested for anxiety- and depression-like behaviors.

[0038] Example 4

[0039] After the HFD model was established, the open field test (OFT) was performed to assess the mice's activity and anxiety-like behavior. The testing apparatus consisted of a 40 cm × 40 cm × 40 cm open field, divided evenly into 25 grids, with the central 9 grids representing the central area. Mice were acclimated to the behavioral chamber for one hour before the experiment. Behavioral testing began after acclimation. At the start of the experiment, mice were placed in the central area of ​​the open field and allowed to freely explore the field for 5 minutes. Using a camera system and Smart 3.0 software, the distance traveled within the open field and the percentage of time spent in the central area were recorded over the 5-minute period. After each mouse was tested, the open field was disinfected with 75% medical alcohol to reduce mouse odor and prevent residual odor from contaminating the test results of the next mouse. The total distance traveled by the mouse served as an indicator of activity. The amount of time a mouse spent in the central area reflected its level of anxiety-like behavior. The shorter the time a mouse spent in the central area, the higher its level of anxiety-like behavior.

[0040] Example 5

[0041] After the HFD model was established, the elevated plus maze (EPM) was performed to assess anxiety-like behaviors in mice. The elevated plus maze consists of two open arms (30 cm × 8 cm), two closed arms (30 cm × 8 cm), and a central platform (8 cm × 8 cm). The elevated plus maze is 50 cm above the ground. Mice were acclimated to the behavioral chamber for 1 hour before the experiment. Behavioral testing began after acclimation. At the beginning of the experiment, mice were placed on the central platform facing the open arms. Using a camera system and Smart 3.0 software, the distance traveled, time spent entering an open arm, time spent entering a closed arm, number of entries into an open arm, and number of entries into a closed arm were recorded over a 5-minute period. Between tests, the elevated plus maze was cleaned with 75% alcohol. The length of time a mouse spent in an open arm reflects its anxiety-like behavior. The longer a mouse spent in an open arm, the higher its anxiety-like behavior.

[0042] Example 6

[0043] After the HFD model was established, novel environment suppressed feeding (NSFT) was performed: the depressive-like behavior of mice was assessed by NSFT. The mice were fasted for 24 hours before the behavioral test, but free access to water was guaranteed. Before the experiment, the mice were placed in the behavioral room for 1 hour to adapt, and behavioral testing began after the adaptation was completed. A piece of food was placed in the middle of the new environment (detection device: 40cm×40cm×40cm), and then the mouse was placed in the corner of the detection device, and the mouse's feeding latency within 600s (defined as the time it takes for the mouse to bite the first bite of food) was recorded. In addition, the mouse's feeding latency in the home cage was immediately tested to evaluate the effects of HFD feeding and T cell knockout of BRD7 on feeding motivation. The longer the mouse's feeding latency in the experiment, the higher the mouse's depression-like level.

[0044] Example 7

[0045] After the HFD model was established, the tail suspension test (TST) was performed: the TST was used to assess the depressive-like behavior of mice. Before the experiment, the mice were placed in the behavior room for 1 hour to adapt, and behavioral testing began after the adaptation was completed. A tape was tied at the tip of the mouse's tail (1 cm) and it was hung 20 cm from the ground for a 6-minute experimental test. The data was recorded using the Smart 3.0 behavioral video acquisition and analysis system, of which the first 2 minutes were the adaptation time of the mouse, and the last 4 minutes were used to record the percentage of the mouse's immobility time. The immobility time is defined as the time when the mouse stops struggling while hanging and shows behavioral despair. The longer the mouse is immobile in the experiment, the higher the level of depression in the mouse.

[0046] Result analysis:

[0047] Figure 2The WT mice (4 weeks old) of Example 2 of the present invention were fed with a high-fat diet (65% fat) for 8 months and then orally administered with drinking water and the BI-7273 inhibitor as described in Example 3. The control group was fed with a normal diet for 8 months and then orally administered with drinking water and the BI-7273 inhibitor as described in Example 3. The weight of the mice was measured. Figure 2 It can be seen that a high-fat diet can significantly increase the body weight of mice, but there is no significant difference in the body weight of mice in the saline group and BI-727 group on a high-fat diet;

[0048] Figure 3 The WT mice (4 weeks old) of Example 2 of the present invention were fed with a high-fat diet (65% fat) for 8 months and then divided into groups as in Example 3 for oral administration of drinking water and BI-7273 inhibitor. The control group was fed with a normal diet for 8 months and then divided into groups as in Example 3 for oral administration of drinking water and BI-7273 inhibitor. After feeding, an open field test was performed to measure the total movement distance and the percentage of time spent in the central grid. Figure 3 It can be seen that there is no difference in the total movement distance of the four groups of mice; the percentage of time that mice in the BRD7 inhibitor group (BI-727 group) stayed in the central area increased significantly, indicating that inhibiting BRD7 protein activity does not affect the activity of mice but can alleviate the anxiety-like behavior of HFD mice.

[0049] Figure 4 The WT mice (4 weeks old) of Example 2 of the present invention were fed a high-fat diet (65% fat) for 8 months and then divided into groups as in Example 3 for oral administration of drinking water and the BI-7273 inhibitor. The control group was fed a normal diet for 8 months and then divided into groups as in Example 3 for oral administration of drinking water and the BI-7273 inhibitor. After feeding, they were subjected to an elevated plus maze test to analyze the total distance traveled and the percentage of time spent in the open arms. Figure 4 The total distance traveled by the four groups of mice was similar. The percentage of time spent in the open arms was significantly increased in the BRD7 inhibitor group (BI-727 group), indicating that inhibiting BRD7 protein activity did not affect the mice's mobility but alleviated anxiety-like behaviors in HFD mice.

[0050] Figure 5 The WT mice (4 weeks old) of Example 2 of the present invention were fed a high-fat diet (65% fat) for 8 months and grouped as in Example 3 to receive oral drinking water and BI-7273 inhibitor. The control group was fed a normal diet for 8 months and grouped as in Example 3 to receive oral drinking water and BI-7273 inhibitor. The latency of the mice to eat in their home cage and in a novel environment was analyzed. Figure 5It can be seen that there was no significant difference in the latency of the four groups of mice to eat in the home cage. However, in the novel environment, the latency of the BRD7 inhibitor group (BI-727 group) to eat was significantly reduced compared with the HFD mice in the saline group, indicating that inhibiting BRD7 protein activity can alleviate the depressive-like behavior of HFD mice.

[0051] Figure 6 The WT mice (4 weeks old) of Example 2 of the present invention were fed with a high-fat diet (65% fat) for 8 months and then divided into groups as in Example 3 for oral administration of drinking water and BI-7273 inhibitor. The control group was fed with a normal diet for 8 months and then divided into groups as in Example 3 for oral administration of drinking water and BI-7273 inhibitor. After feeding, the tail suspension test was performed to determine the percentage of immobility time. Figure 6 It can be seen that there was no significant difference in the immobility percentage of mice in the saline and BRD7 inhibitor groups fed with normal feed; after high-fat feeding, the immobility percentage of mice in the saline group increased significantly, while the immobility percentage of mice in the BRD7 inhibitor group (BI-727 group) decreased significantly, indicating that inhibiting BRD7 protein activity can alleviate the depressive-like behavior of HFD mice.

[0052] Figure 7 The weight of the WT mice and BRD7-CKO mice in Example 2 of the present invention were fed with a high-fat diet (65% fat) for 8 months, while the control group was fed with a normal diet. Figure 7 It can be seen that a high-fat diet can significantly increase the body weight of mice, but there is no significant difference in body weight between the WT group and BRD7-CKO mice fed a high-fat diet.

[0053] Figure 8 The WT mice and BRD7-CKO mice of Example 2 of the present invention were fed a high-fat diet (65% fat) for 8 months, while the control group was fed a normal diet. Then, an open field test was performed to measure the total movement distance and the percentage of time spent in the central grid. Figure 8 The total distance traveled by the four groups of mice was similar. The percentage of time spent in the central zone by HFD mice with BRD7 knockout in T cells increased significantly, suggesting that BRD7 knockout in T cells did not affect the mice's activity level but alleviated the anxiety-like behavior of HFD mice.

[0054] Figure 9 The WT mice and BRD7-CKO mice of Example 2 of the present invention were fed a high-fat diet (65% fat) for 8 months, while the control group was fed a normal diet. Then, they were subjected to an elevated plus maze test to measure their total movement distance and the percentage of time spent in the open arms. Figure 9The total distance traveled by the four groups of mice was similar. The percentage of time spent in the open arms by HFD mice with BRD7 knockout in T cells increased significantly, suggesting that BRD7 knockout in T cells did not affect the activity of mice but alleviated anxiety-like behaviors in HFD mice.

[0055] Figure 10 The WT mice (4 weeks old) and BRD7-CKO mice of Example 2 of the present invention were fed a high-fat diet (65% fat) for 8 months, and the control group was fed a normal diet for 8 months. The latency of the mice to eat in their home cage and in a novel environment was analyzed. Figure 10 It can be seen that there was no significant difference in the latency of the four groups of mice to eat in the home cage. However, in the novel environment, the latency of HFD mice with T cell BRD7 knockout to eat was significantly reduced compared with the HFD mice in the WT group, indicating that T cell BRD7 knockout can alleviate the depressive-like behavior of HFD mice.

[0056] Figure 11 The WT mice (4 weeks old) and BRD7-CKO mice of Example 2 of the present invention were fed with a high-fat diet (65% fat) for 8 months, and the control group was fed with a normal diet for 8 months. After feeding, the tail suspension test was performed to measure the percentage of immobility time. Figure 11 It can be seen that there was no significant difference in the immobility percentage between WT and BRD7-CKO mice fed with normal diet; after high-fat feeding, the immobility percentage of WT group mice increased significantly, while the immobility percentage of BRD7-CKO mice decreased significantly, indicating that T cell knockout of BRD7 can alleviate the depressive-like behavior of HFD mice.

[0057] Figure 12 The WT mice (4 weeks old) and BRD7-CKO mice of Example 2 of the present invention were fed with a high-fat diet (65% fat) for 8 months, and the control group was fed with a normal diet for 8 months. The peripheral blood glucose, total cholesterol, high-density lipoprotein-cholesterol, low-density lipoprotein-cholesterol, the ratio of high-density lipoprotein-cholesterol to total cholesterol, and the concentration of non-high-density lipoprotein cholesterol were measured after feeding. Figure 12 A shows that fat diet has no significant effect on blood sugar; Figure 12 B shows that compared with normal feed, high-fat diet significantly increased the concentration of total cholesterol, but there was no significant difference between the WT group and the BRD7CKO group; Figure 12 C shows that compared with normal feed, high-fat diet significantly increased the concentration of high-density lipoprotein-cholesterol, but there was no significant difference between the WT group and the BRD7CKO group; Figure 12D shows that compared with normal diet, high-fat diet significantly increased the concentration of low-density lipoprotein-cholesterol in the BRD7CKO group, and the concentration in the BRD7CKO group was significantly higher than that in the WT group. However, there was no significant difference in the concentration of low-density lipoprotein-cholesterol in WT mice between normal diet and high-fat diet. Figure 12 E shows that a high-fat diet has no significant effect on the ratio of high-density lipoprotein cholesterol to total cholesterol; Figure 12 F showed that compared with feeding with ordinary feed, high-fat diet significantly increased the concentration of non-high-density lipoprotein cholesterol, but there was no significant difference between the WT group and the BRD7CKO group.

[0058] The above description is merely a specific embodiment of the present invention, but the scope of protection of the present invention is not limited thereto. Any changes or substitutions that can be easily conceived by a person skilled in the art within the technical scope disclosed in the present invention should be included in the scope of protection of the present invention. Therefore, the scope of protection of the present invention should be based on the scope of protection of the claims.

Claims

1. Use of the BRD7 small molecule inhibitor BI-7273 in the preparation of a drug for treating obesity-induced anxiety and depression-like behaviors, characterized in that: The structural formula of the BRD7 small molecule inhibitor BI-7273 is shown in I:

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