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Table of Contents
ORIGINAL ARTICLE
Year : 2022  |  Volume : 65  |  Issue : 3  |  Page : 117-124

Combined effects of voluntary running and liraglutide on glucose homeostasis, fatty acid composition of brown adipose tissue phospholipids, and white adipose tissue browning in db/db mice


Beijing Key Laboratory of Diabetes Prevention and Research, Center for Endocrine Metabolic and Immune Disease, Beijing Luhe Hospital, Capital Medical University, Beijing, China

Date of Submission16-Oct-2021
Date of Decision04-Mar-2022
Date of Acceptance26-Apr-2022
Date of Web Publication27-Jun-2022

Correspondence Address:
Prof. Dong Zhao
Beijing Key Laboratory of Diabetes Prevention and Research, Center for Endocrine Metabolic and Immune Disease, Beijing Luhe Hospital, Capital Medical University, Beijing 101149
China
Dr. Longyan Yang
Beijing Key Laboratory of Diabetes Prevention and Research, Center for Endocrine Metabolic and Immune Disease, Beijing Luhe Hospital, Capital Medical University, Beijing 101149
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/cjp.cjp_87_21

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  Abstract 


There is a potential therapeutic application targeting brown adipose tissue (BAT). Either voluntary running or liraglutide increases the thermogenesis of BAT in type 2 diabetes mellitus, but their combined effect is not yet clarified. Male leptin receptor-deficient db/db diabetic mice (n = 24) were randomly divided into voluntary running, liraglutide, voluntary running + liraglutide, and control groups (n = 6/group). Normal male C57 mice were the negative control (n = 6). Fasting blood glucose was monitored every week, plasma insulin and lipid profiles were analyzed, and thermogenic protein expression in BAT and white adipose tissue (WAT) were analyzed by the western blot. A total of 128 metabolites associated with phosphatidylcholines, phosphatidylethanolamines, sphingomyelins, and ceramides were targeted in BAT. Compared to the control group, voluntary running or liraglutide treatment significantly lowered the blood glucose and increased the insulin level; the combined group showed a better effect than liraglutide alone. Hence, the combined treatment showed an enhanced hypoglycemic effect. Uncoupling protein 1 (UCP1) and OXPHOS protein expression in BAT and UCP1 in WAT were significantly increased after exercise training and liraglutide treatment. However, BAT metabolomics showed that compared to the control mice, nine fatty acids increased in the exercise group, six increased in the liraglutide group, and only three increased in the combined group. These results may suggest a higher hypoglycemic effect and the activation of BAT and WAT browning in the combined group.

Keywords: Brown adipose tissue, lipidomic, liraglutide, voluntary running


How to cite this article:
Yin R, Ma Y, Zhang N, Yang L, Zhao D. Combined effects of voluntary running and liraglutide on glucose homeostasis, fatty acid composition of brown adipose tissue phospholipids, and white adipose tissue browning in db/db mice. Chin J Physiol 2022;65:117-24

How to cite this URL:
Yin R, Ma Y, Zhang N, Yang L, Zhao D. Combined effects of voluntary running and liraglutide on glucose homeostasis, fatty acid composition of brown adipose tissue phospholipids, and white adipose tissue browning in db/db mice. Chin J Physiol [serial online] 2022 [cited 2022 Aug 17];65:117-24. Available from: https://www.cjphysiology.org/text.asp?2022/65/3/117/348362

Ruili Yin and Yan Ma contributed equally to this work.





  Introduction Top


Brown adipose tissue (BAT) is composed of multilocular brown adipocytes and regulates the body temperature via non-shivering thermogenesis.[1] While white adipose tissue (WAT) is specialized for energy storage, BAT has a high concentration of mitochondria and uniquely expresses uncoupling protein 1 (UCP1), enabling it to be specialized for energy expenditure and thermogenesis.[2] BAT is mainly distributed in the neck and the supraclavicular region in humans, and the amount of BAT is altered based on age, gender, body mass index, and cold exposure.[3] Unlike white adipocytes, brown adipocytes contain a large number of mitochondria, which carry UCP1 protein and function on the inner mitochondrial membrane.[4] Mitochondria are ubiquitous organelles within eukaryotic cells owing to their essential function of supplying cellular energy in the form of adenosine triphosphate (ATP) via oxidative phosphorylation (OXPHOS) carried out by the electron transport chain and ATP synthase.[5] Human and animal studies have addressed the importance of BAT metabolism with respect to efficient adaptive thermogenesis.[6],[7],[8],[9] Owing to energy expenditure and glucose consumption properties, BAT becomes an attractive target for treating obesity and diabetes.[10] However, the mechanisms of BAT in decreasing hyperglycemia are not yet investigated.

Several studies have already reported that exercise prevents the onset of type 2 diabetes mellitus (T2DM), obesity, and metabolic disease;[11],[12],[13] moderate-intensity treadmill running of rodents for 6–8 weeks also increases BAT activity and upregulates the expression of BAT-specific gene markers, including Ucp1, Dio2, Prdm16, and Pgc1α.[14],[15] Physical exercise increases the thermogenic activity and decreases the triglycerides in BAT.[16] Regular exercise also improves BAT insulin sensitivity and glucose uptake.[17] A randomized clinical trial reported that intensive lifestyle intervention in T2DM affects glycemic control.[18] Liraglutide is an analog of human glucagon-like peptide 1 with 97% structural homology to endogenous human glucagon-like peptide-1 (GLP-1).[19] Animal and human studies have found that GLP-1 agonist analogs cause thermogenesis and browning of BAT, and brown adipocyte-like cells can be dispersed in WAT.[20],[21],[22] However, few studies have focused on the combined effects of exercise and liraglutide on BAT.

Considering that activating BAT accelerates the intake of glycolipids and reduces the insulin secretion requirement, which may be a new strategy to improve glycolipids metabolism and insulin resistance of obese and T2DM patients. Lipid plays a significant structural and functional role in regulating cellular homeostasis; lipid metabolism or disruption of signaling is associated with the onset and progression of metabolic disorders.[23] Lipidomics can comprehensively identify and structurally characterize various lipid species in samples of interest and quantitatively monitor their abundance under different physiological or pathological conditions. Thus, mass spectrometry (MS) has become a technological platform for lipidomics research.[24] The present study applied an improved quantitative and high-throughput MS to target 128 fatty acids in BAT, which obtaining from exercise or/and liraglutide-treated mice and db/db mice; then, specific markers of BAT genes or proteins were analyzed in the study, and the browning process of WAT was also accessed for further explored the effect of exercise or/and liraglutide treatment on BAT.


  Materials and Methods Top


Animals

Six male C57BL/6J mice and 24 male db/db (BKS.Cgm+/+ Leprdb/J) mice were purchased from the Institute for Animal Center in Nanjing Medical College (Nanjing, China) and housed in standard cages under a 12/12 h light/dark cycle at 22°C ± 1°C; drinking water and standard animal chow were available freely. All the animal experiments were approved by the Animal Care and Use Committee of Beijing Luhe Hospital of Capital Medical University (AEEI-2021-158) and conducted in accordance with the NIH Guidelines for the Care and Use of Laboratory Animals. The study was carried out in compliance with the ARRIVE guidelines.

Treatment

At 6-week-old, db/db mice were randomly divided into the following groups: (1) control group treated with saline subcutaneously and sedentary (CS); (2) voluntary running group subjected to daily exercise (1 h/day, 5 days/week for 8 weeks) and injected saline subcutaneously (EC); (3) liraglutide group injected liraglutide subcutaneously (LC); (4) voluntary running + liraglutide group with exercise and injected liraglutide (LE). Six-week-old C57BL/6J mice were no treated (NC). Liraglutide (Selleck, USA) was injected at a dose of 200 μg/kg body weight/day (twice a day for 8 weeks), the solvent for liraglutide was saline, the volume of test solution injected into mice was according to the weight of per mice.[25] In the first week, exercising mice began wheel running at 4 m/min, which was increased daily by 0.2 m/min and reached 5.2 m/min by the end of the first week on a mouse walking wheel system (SANS, China). In subsequent weeks, the mice were run at 5.2 m/min for 1 h/day.

Blood samples, according to the University of Minnesota guidelines (Blood Collection Guidelines, AHC Research Services, University of Minnesota [umn.edu]), collecting blood by lacerating tail vessels requires review and approval by the IACUC. Meantime, no infection, hemorrhage, and other complications were observed in all groups. Following treatment for 8 weeks, all mice were euthanized by an intraperitoneal injection of 150 mg/kg pentobarbital, 1 mL blood samples were collected from the inferior vena cava after euthanasia, and plasma was obtained by centrifugation at 3500 rpm for 10 min at 4°C and stored at −80°C. Intrascapular BAT and epididymal white fat were snap-frozen in liquid nitrogen and stored at −80°C for further analyses after death, confirmed by the absence of heart rate, no breathing, and no reflexes.

Intraperitoneal glucose tolerance test

At the 8th week of treatment, mice were weighed after fasting 8 h, and 0 min plasma samples were collected from the tail and reading by Accu-check Performa glucometer (Roche Diagnostic, Mannheim, Germany). Then, intraperitoneally injected with 2 g/kg glucose and blood samples were collected from the tail and glucometer readings at 15, 30, 60, 90, and 120 min.

Enzyme-linked immunosorbent assay

According to the manufacturer's instructions, the insulin level in plasma was evaluated using an ELISA kit (American Laboratory Products Company, Keewaydin Drive, Salem, NH, USA).

Lipid measurement

According to the manufacturer's instructions, the plasma levels of triglyceride and cholesterol were measured by commercial kits (Biosino, Beijing, China).

Western blotting

Western blotting was performed as described previously.[26] Primary antibodies used in this study were anti-mouse UCP1 (ab10983, Abcam, Cambridge, MA, USA), anti-mouse OXPHOS (ab110413, Abcam, MA, USA), and anti-human GAPDH (5174S, Cell Signaling Technology, Beverly, MA, USA). Tissues were homogenized in cold RIPA lysis buffer (APPLYGEN, Beijing, China) containing phenylmethylsulfonyl fluoride (PMSF, APPLYGEN, Beijing, China). The total amount of protein was determined using a BCA protein assay kit (Thermo Fisher, USA). The protein samples (40 μg) were separated by 10% SDS-polyacrylamide gel (PPLYGEN, Beijing, China) electrophoresis and transferred to PVDF membranes. Following the transfer, the membranes were blocked in TBST containing 5% skim milk for 1 h at room temperature. Then, the blots were incubated with the primary antibodies overnight at 4°C. After the membranes had been washed with TBST, the secondary antibodies (goat anti-rabbit, 1:3000; goat anti-mouse, 1:3000; APPLYGEN, China) were applied and incubated for 1 h at RT. After the secondary antibody reaction, the bands were visualized with enhanced chemiluminescence, and the positive pixel area was detected by an image analysis system (Fusion, Germany). The band sensitivities were normalized against the corresponding GAPDH loading controls. Image J software was used for the band analysis.

High-performance liquid chromatography conditions

HPLC is necessary for analyzing low-abundance and isomeric metabolites.[27] This method was performed by Beijing Mingde Zhengkang Technologies Co., Ltd (Beijing, China). Lipidomic data were mean-centered and pareto-scaled using Simca 14.1 (Umetrics, Umeå, Sweden) to reduce the noise and artifacts. Shinazu LC-20AXR Rapid Separation LC system from Agilent series 1290 UHPLC instrument (Agilent, Waldbronn, Germany) was used for reverse-phase liquid chromatography column based on the gradient conditions. Multiple reaction monitoring analysis was performed using a 5500 Qtrap MS (AB Sciex, Framingham, MA, USA). All experiments were performed in positive electrospray ionization mode.

The quality of each OPLS-DA model was evaluated using the R2Y (cum) value, identifying changes in all the components in the model. An additional 7-fold cross-validation was performed in the OPLS-DA model. In this process, Q2 (cum) is calculated to represent the predictability of the model. An R package termed Mfuzz, which implemented SoftClustering tools, was utilized for microarray data analysis.

Statistical analysis

The data were expressed as means ± standard deviation. The differences between pairwise comparisons were evaluated using t-test using SPSS 18.0 software (SPSS Inc., Chicago, IL, USA). Differences between the groups were analyzed using two-way ANOVA (with post hoc analyses). A P < 0.05 was considered statistically significant.


  Results Top


Effects of exercise or liraglutide on blood glucose levels and glucose tolerance

db/db mice showed significantly high fasting blood glucose levels and impaired glucose tolerance at the end of the study. Compared to the control group, exercise or liraglutide alone and their combination groups showed significantly decreased blood glucose levels [Figure 1]a, and also significantly improved glucose tolerance [Figure 1]b. The quantification of the area under the curve from the glucose tolerance was significantly decreased in the exercise alone, liraglutide alone, and their combination group. Moreover, their combination showed significant decrease than exercise alone or liraglutide alone [Figure 1]c. Moreover, compared with liraglutide group alone, their combination showed a distinct effect in regulating fast blood glucose. Moreover, the insulin level in plasma was significantly downregulated in the exercise alone, liraglutide alone and their combination group. Moreover, their combination showed lower insulin levels than the exercise alone or liraglutide alone (P < 0.01) [Figure 1]d. Hence, these findings suggested that liraglutide and exercise combination showed more improved hypoglycemic effects.
Figure 1: Exercise training and liraglutide treatment improved glucose homeostasis and lipid metabolism. (a) Blood glucose levels in control and treated db mice subjected to exercise, liraglutide, and a combination of exercise and liraglutide for 8 weeks. (b) IPGTT. The mice fasted for 8 h, and then the blood glucose was tested on 0, 15, 30, 60, 90, and 120 min following intraperitoneal glucose injection. (c) Quantification of the AUC from the IPGTT. (d) Plasma insulin levels were determined using insulin ELISA kits. (e) Plasma cholesterol levels in control and treated db mice. (f) Plasma triglyceride levels in db mice and treated db mice. *P < 0.05, **P < 0.01, ***P < 0.001, and ****P < 0.0001 compared to the control group. #P < 0.05, ##P < 0.01, ####P < 0.0001, LE compared with LC or EC. Data were expressed as mean ± SD. CS: Control group, EC: Exercise group, LC: Liraglutide group, LE: Liraglutide and exercise group, IPGTT: Intraperitoneal glucose tolerance test, AUC: Area under the curve, SD: Standard deviation.

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Effect of exercise or liraglutide on blood lipid levels

As shown in [Figure 1]e and [Figure 1]f, cholesterol and triglyceride levels were significantly decreased in liraglutide alone and their combination groups, but not the exercise alone [Figure 1]e and [Figure 1]f. However, only in the 8th week, a significant difference was observed in weight levels between treated and non-treated db/db mice during the 8-week treatment [Figure 2]a. All mice were weighed before sacrifice, and the result showed that compared to the control group, the combination showed a significantly decreased body weight [Figure 2]b. Thus, these results showed that exercise combined with liraglutide decreases blood lipid levels.
Figure 2: The effect of exercise training and liraglutide treatment on body weight. (a) Body weight in db mice and treated db mice subjected to exercise, liraglutide, and a combination of exercise and liraglutide for 8 weeks. (b) Body weight levels on 8th week. *P < 0.05, compared to the control group. Data were expressed as mean ± SD. CS: Control group, EC: Exercise group, LC: Liraglutide group, LE: Liraglutide and exercise group, SD: Standard deviation.

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Exercise- or liraglutide-induced activation of brown adipose tissue and browning of white adipose tissue

To explore the mechanisms of exercise and/or liraglutide on lipid, UCP1 and thermogenic expression of BAT and WAT were explored. As a marker of BAT activation and WAT browning, western blot showed the expression of UCP1 was significantly elevated in exercise alone, liraglutide-treated alone, and their combination. For mitochondrial OXPHOS, the level of ATP synthase subunit alpha (ATP5A) was significantly elevated in exercise alone, liraglutide-treated alone, and their combination. Level of NADH dehydrogenase (ubiquinone) 1b subcomplex (NDUFB8) was significantly elevated in liraglutide-treated alone, and their combination [Figure 3]a and [Figure 3]b. Meanwhile, the expression of UCP1 was increased in WAT from exercise alone, liraglutide-treated alone, and their combination [Figure 3]c and [Figure 3]d.
Figure 3: Thermogenic protein expression in BAT and WAT of db mice and treated db mice. (a) The protein expression of UCP1, ATP5A, UQCRC2, SDHB, and NDUFB8 in different treated BAT. GAPDH was used as the loading control. (b) Quantification of protein expression normalized to GAPDH. (c) The protein expression of UCP1 in different treated WAT. GAPDH was used as the loading control. (d) Quantification of UCP1 protein expression normalized to that of GAPDH.*P < 0.05, **P < 0.01, ***P < 0.001, compared to the CS. Data are expressed as the mean ± SD on a logarithmic scale. CS: Control group, EC: Exercise group, LC: Liraglutide group, LE: Liraglutide, and exercise group, SD: Standard deviation, BAT: Brown adipose tissue, WAT: White adipose tissue.

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Lipidome results of brown adipose tissue under exercise or liraglutide treatment

To investigate the metabolism of BAT during low hyperglycemia, targeted metabolomics method was used by LC and MS. Phosphatidylcholines (PC), phosphatidylethanolamines (PE), and sphingomyelins (SM) are the most dominant phospholipids that account for 80% of the cell membranes.[28] A total of 128 fatty acids, consisting of 18 PEs, 7 lyso-PEs (LPEs), 11 ceramides (Cers), 23 SMs, 50 PCs, and 19 lyso-PCs (LPCs), were identified and quantified [Supplementary Table 1]. The PCA score plot of each group was constructed in the positive and negative modes. Finally, four groups of PCA models of BAT samples were established in the positive and negative modes [Supplementary Figure 1]a. Hierarchical clustering heatmap analysis identified lipids and suggested the variation of each fatty acid among the groups [Supplementary Figure 1]b.



As shown in [Figure 4], the levels of 9 fatty acids were significantly higher in exercise alone than in the control group, which included PE 34:1, PE 38:6, PC 36:4-1, LPE 16:0, LPE 18:1, Cer 40:1-1, Cer 40:2-3, Cer 44:2-3, and SM 42:5. The levels of 6 fatty acids were significantly increased in liraglutide alone, which contained PE 38:6, PC 36:4-1, Cer 40:1-1, Cer 40:2-3, Cer 44:2-3, and SM 42:5. Interestingly, compared to the control mice, exercise combined with liraglutide significantly elevated the levels of LPE 18:1, PE 38:6, and SM 42:5 in BAT.
Figure 4: Bar plots showing 128 fatty acid levels in BAT. Levels of (a) Cer, (b) LPE, (c) PC, (d) PE, (e) SM in non-treated db/db mice (CS), treated with exercise (EC), liraglutide (LC), and both exercise and liraglutide (LE) groups. Data are expressed as the mean ± SD on a logarithmic scale. Difference between the groups were analyzed by two-way ANOVA (with post hoc analyses). *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001, compared to the CS or EC. Data are expressed as the mean ± SD on a logarithmic scale. LPE: Lyso PE, Cer: Ceramide, PC: Phosphatidylcholine, PE: Phosphatidylethanolamine, SM: Sphingomyelin, SD: Standard deviation, CS: Control group, EC: Exercise group, LC: Liraglutide group, LE: Liraglutide, and exercise group, BAT: Brown adipose tissue.

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Soft clustering applied for the classification of 128 fatty acids

Next, to study the effects of these two ways of reducing blood glucose on BAT fatty acids and find the two optimal clustering parameters, all the 128 fatty acids levels were analyzed by Mfuzz (a package based on the open-source statistical language R). [Supplementary Figure 2] shows that different fatty acids treated with exercise and/or liraglutide were inconsistent. Furthermore, many fatty acids do not change significantly after exercise and/or liraglutide treatment. Metabolites with values of VIP >1 and P < 0.05 were included, and 24 fatty acids were screened for the metabolite biomarkers in db/db models.




  Discussion Top


The current study investigated the effect of exercise and/or liraglutide on lipidomic profiles of BAT. After exercise training and treated with liraglutide, db/db mice showed an improvement in the level of glucose control, and combined action mode exhibited an enhanced hypoglycemic effect.

BAT plays a major role in the energy expenditure of mammals.[29] As a result, brown fat activation has become an attractive therapeutic target for the treatment of diabetes and other metabolic syndromes.[30] Yore et al. found that increased adipose tissue lipogenesis has been associated with enhanced insulin sensitivity and glucose tolerance.[30] In the rat model of T2DM, whitening of BAT is accompanied by impaired glucose utilization.[31] BAT activation is related to changes in fatty acid concentration. Some studies have shown that 2–8 weeks of exercise upregulates expression of genes involved in insulin signaling, glucose, and fatty acid oxidation in BAT.[17],[32],[33] These data indicated that BAT metabolism significantly promotes systemic glucose and lipid utilization in a coordinated manner.[34] Liraglutide, as a drug of GLP, activated AMPK in the hypothalamic, which is directly implicated in BAT thermogenesis and browning of WAT.[35] Zhu et al. found liraglutide-induced WAT browning and clarified its mechanism.[21] However, the combination of exercise training and liraglutide has not been investigated.

In the study, among the 128 targeted lipid species in the current study, nine fatty acids increased in the exercise group, six in the liraglutide group, and only three in the combination of exercise and liraglutide group. The exercise combined with liraglutide exerted a significant effect on glucose homeostasis, while for BAT metabolism, the combination of exercise and liraglutide displayed more effect. And for BAT activation and WAT browning, exercise and liraglutide combination showed better effects. Exercise training combined with metformin, rather than exercise training alone, reduces insulin production and increases insulin clearance in adults with prediabetes.[36] In our results, exercise training combined with liraglutide, rather than liraglutide alone, decreased the fasting glucose and the insulin production. With the increase of insulin levels, fasting glucose levels are reduced in mice. Among them, the combined treatment group showed a better hypoglycemic effect. For weight and lipid profiles, exercise training combined with liraglutide showed a significant decrease. However, there was no significant change in body weight during this treatment. Maybe the thermogenic effect caused by BAT is mainly used for lowering blood glucose and has not played a major role in body weight. Considering that the combined treatment of exercise and liraglutide showed a superior hypoglycemic effect, it was speculated that this effect was related to the activation of BAT. The elevated levels of LPE 18:1, PE 38:6, and SM 42:5 in BAT from exercise and liraglutide-treated mice were found by lipidomics. Hence, the elevated levels of LPE 18:1, PE 38:6, and SM 42:5 may be associated with BAT activation. Therefore, the combination effect of lifestyle and hypoglycemic drugs metabolism on BAT needs further investigation.

Nevertheless, the present study has some limitations: one is the number of mice is not enough in the targeted metabolomics, considering the longtime of C57BL/6J mouse model and long treatment time, we only used leptin receptor-deficient db/db diabetic mice as a T2D mouse model; the other is that the mechanism between the selected fatty acids with glucose metabolism is not clear. Further studies should be investigated in the future.


  Conclusion Top


In summary, the current data illustrated a higher hypoglycemic effect, and the activation of BAT and WAT browning in the combined group.

Ethics approval and consent to participate

All the animal experiments were approved by the Animal Care and Use Committee of Beijing Luhe Hospital of Capital Medical University and conducted in accordance with the NIH Guidelines for the Care and Use of Laboratory Animals.

Author's contributions

R. Y. performed the majority experiments and drafted the manuscript. Y. M., N. Z. and L. Y. helped with experiments and analyzed the data. R. Y. and D. Z. conceived the study, supervised the experiments and revised the manuscript. All authors read and approved the final manuscript.

Financial support and sponsorship

This study was funded by the Science and Technology Committee of Tongzhou District (Number: KJ2019CX014-25).

Conflicts of interest

There are no conflicts of interest.



 
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