Irisin Prevents High-Fat Diet-Induced Metabolic Disorders via Brown Adipose Tissue Activation

doi:10.21203/rs.3.rs-4777539/v1

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Irisin Prevents High-Fat Diet-Induced Metabolic Disorders via Brown Adipose Tissue Activation

https://doi.org/10.21203/rs.3.rs-4777539/v1

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Background

High-fat diet (HFD) induces negative effects on interscapular brown adipose tissue (iBAT) activity and systemic energy metabolism. Irisin, a small hormonal agent known to modulate metabolism has been used for intervening HFD induced obesity. However, its mechanism of actions on iBAT function remains to be fully elucidated. This study sought to investigate whether an intervention with irisin could restore the thermogenic function of iBAT in HFD-induced mice with obesity, thereby regulating systemic metabolism.

Methods

Magnetic resonance imaging (MRI) and positron emission tomography/computed tomography (PET/CT) were used to determine and follow the changes of thermogenic capacity of iBAT and systemic metabolism in mice with obesity and iBAT-deficient mice during intervention with irisin for varying periods of time. Pathological and molecular biology analyses were performed on tissue and blood samples.

Results

Prolonged HFD feeding in mice induced obesity and impaired the thermogenic capacity of iBAT. MRI showed that irisin intervention decreased lipid content in iBAT, coupled with increased uncoupling protein 1 (UCP 1) expression and glucose analogue uptake capacity. This restoration of iBAT activity was accompanied by an improvement in systemic metabolism. The beneficial effects of irisin appears to be dependent on the length of intervention time. When iBAT was removed, the positive effects of irisin were partially suppressed, suggesting that irisin regulates metabolism through the restoration of the thermogenic function of iBAT.

Conclusions

HFD results in reduced thermogenic capacity of iBAT, while irisin intervention can effectively restore iBAT function, leading to improvement in overall glucose and lipid metabolism.

Irisin

Interscapular brown adipose tissue

High-fat diet

UCP 1

Magnetic resonance imaging

Position emission tomography/computerized tomography

High-fat diet (HFD), characterized by an elevated proportion of fat intake as the primary energy source, has the potential to result in obesity and various associated metabolic disorders when sustained over a prolonged period(1, 2). Brown adipose tissue (BAT), which expends energy through thermogenesis, is closely associated with systemic homeostasis in terms of its metabolic state(3–5). In a passive thermoneutral state BAT is associated with the increased risk of metabolic disorders (5). Conversely, the activation of BAT leads to a thermogenic state that elevates tissue uptake of glucose and lipids, thereby facilitating systemic metabolic homeostasis (6, 7). The efficient thermogenic capacity of BAT is primarily dependent on the expression level of uncoupling protein 1 (UCP 1), which is abundantly located in the mitochondrial inner membrane(8). Prolonged HFD has been demonstrated to blunt the thermogenic capacity of BAT, potentially contributing to obesity(9). However, the knowledge and understanding on the relationship between HFD and BAT as well as the contribution of increased BAT activity to the metabolic improvement remain limited, but important to further development of therapies for treating and managing metabolic disorders.

Previous studies have demonstrated that BAT thermogenesis can be stimulated by cold exposure or administration of β3-adrenergic agonists; however, due to the feasibility and safety, clinical applications have been limited(10–12). One promising alternative agent is hormone irisin, a myokine known to fight against metabolic disorders by promoting browning of white adipose tissue (13–15). Therefore, an unresolved question is whether irisin, as an inducer known for its ability to promote thermogenesis in white adipose tissue, can also effectively restore or further enhance the inherent thermogenic capacity of BAT, which already possesses higher thermogenic potential, thereby increasing energy expenditure and improving systemic metabolism.

In this study, we validated the use of continuous magnetic resonance imaging (MRI) and positron emission tomography/computed tomography (PET/CT) to assess the impact of irisin on dysfunctional interscapular brown adipose tissue (iBAT) in animal models of obesity. We also investigated the impact of irisin on dysfunctional iBAT and altering metabolism of reactivated iBAT in animal models of obesity.

1.1 Animals and treatment

All animal experiments were performed with protocols approved by the Institutional Animal Care and Use Committee of the Medical School of Southeast University (approval ID: 20220301040). C57BL/6J mice (male, seven-eight weeks of age, 20-24g) were purchased from the Charles River Laboratory (Beijing, China) for this study. Mice in the blank control group were fed with a control diet (CD) for 16 weeks (1010001, Xietong, China) followed by daily intraperitoneal injection of phosphate buffer solution (PBS) for four weeks (CD_PBS group). To induce obesity, mice were fed with HFD (60% kcal fat, XTHF60, Xietong, China) and randomly divided into three groups, i.e., 1) HFD_PBS group with daily intraperitoneal injection of PBS for four weeks; 2) HFD_Irisin−2w group with daily intraperitoneal injection of PBS for the first two weeks and then daily injection of the irisin solution (0.8 ng/g/d; HY-P70664, MedChemExpress, USA) for two weeks (16), and 3) HFD_Irisin−4w group with daily intraperitoneal injection of irisin solution at the same concentration for four weeks (Fig. 2a). To investigate whether and how iBAT is involved in the modulation of the systemic metabolism under irisin intervention, we generated the iBAT-deficient mouse model by surgically removing iBAT in HFD mice using the previously reported procedure with slight modifications (17). Animals with iBAT removed (REM) were then randomly divided them into two groups: i.e., 1) REM_PBS group with daily intraperitoneal injection of PBS for four weeks and 2) REM_Irisin group with daily intraperitoneal injection of irisin solution (0.8 ng/g/d) daily for four weeks (Fig. 5a).

1.2 MRI for tissue structure and fat contents

Scanning procedures as previously described(18, 19). Briefly, mice were anesthetized with 1–3% isoflurane and positioned in a prone position in a 7.0 T Micro MRI scanner (ParaVision 4.0, Bruker PharmaScan, Germany). The images were acquired in the transverse direction using a 3.5 cm inner diameter transmit/receive quadrature volume coil (Bruker PharmaScan, Germany). Acquisition parameters of T₁-weighted imaging (T₁WI) included field of view of 4 cm × 4 cm, matrix size of 256 × 256, repetition time of 500.0 ms, echo time of 15.0 ms, number of excitations of 2, slice thickness of 1 mm. For CSSI, the center frequency was set at 0 Hz for imaging of water and at -1000 Hz for imaging of fat, and we used field of view of 4 cm × 4 cm, matrix size of 256 × 256, repetition time of 1000.0 ms, echo time of 9.9 ms with flip angle of 180°, number of excitations of 2 and slice thickness of 1 mm.

3D Slicer 5.1.0 was used to label the voxels of iBAT, visceral and subcutaneous adipose tissues (VAT, SAT) slice by slice. MicroDicom DICOM Viewer 2022.2 was used to define regions of interest with the same positions and sizes on the fat and water selective images and calculated the fat fraction using the following formula(18):

$$\:FF=100\times\:\frac{{Signal\:Intensity}_{fat}}{{Signal\:Intensity}_{fat}+{Signal\:Intensity}_{water}\times\:0.9}$$

1.3 FDG PET-CT imaging

Fluoro-2-deoxy-D-glucose (FDG) PET/CT data were gathered using the Inveon micro-PET/CT system (Siemens Medical Solutions, USA) on anesthetized mice with 1–3% isoflurane. PET/CT was performed three hours after injection 7.4 MBq of FDG(20). The images were analyzed using Inveon Research Workplace 4.2 (Siemens Medical Solutions, USA). The spherical volume of interest is delineated on both sides of the iBAT and averaged, with subsequent analysis utilizing the maximum uptake value(21).

1.4 Immunohistology and histology

Animals were sacrificed for H&E staining and Oil red O-staining. Microscopic images taken from the stained tissue slices were analyzed using Image J 1.48 software (National Institutes of Health, USA) including the lipid droplet size and the percent area of lipid. For immunohistochemical staining of UCP 1 protein, sections were treated with the primary antibody (1:300, GB1121174, Servicebio, China) and HRP-conjugated secondary antibody (1:300, GB23303, Servicebio, China). Image Pro plus 6.0.0.260 software (Media Cybernetics, USA) was used to calculate the optical density value of immunohistochemical sections.

1.5 Statistical analyses

Statistical analysis was conducted using SPSS 11.0 software (IBM, USA). All data were represented as mean ± SEM. We used unpaired Student’s t tests to compare differences between two groups and one-way ANOVA to compare differences among three groups. Pairwise comparisons between groups were conducted using the Bonferroni tests. The MRI data for the mice before and after intervention were analyzed using paired Student’s t tests. The results of the IGTT and ITT experiments were analyzed by calculating the relative area under the curve of the blood glucose level at different time points for each mouse, which can be used to report the level of glucose or insulin tolerance. For analyzing data from the measurements of the area of lipid droplet, the median value was used for the subsequent statistical analysis due to the non-normal distribution of the data obtained from each mouse. A statistically significant difference is defined as P < 0.05.

2.1 Prolonged HFD induced the dysfunction of iBAT and systemic metabolism disruption

As expected, mice in the HFD group exhibited a significant state of obesity, with notable increases in both body weight and the volume of WAT (Fig. 1a, d; S1a, b). It is noteworthy that the MRI results indicated an increase in the volume of iBAT in the HFD group mice (P < 0.001), accompanied by a significant elevation in fat fraction (P = 0.04) (Fig. 1b, c). The iBAT in the HFD mice exhibited lighter color and larger volume as illustrated in the ex vivo images (Fig. 1d). As showed in Fig. 1e, the lipid droplets size (P = 0.04) and the lipid area proportion (P = 0.02) in the iBAT of HFD_PBS group were both higher compared to CD_PBS group (Figure S1c). Additionally, the HFD_PBS group exhibited a reduction in UCP 1 protein expression in iBAT (P = 0.02) (Figure S1c).

The glucose tolerance in HFD-induced mice with obesity was considerably impaired (P < 0.001) (Fig. 1f), even though insulin tolerance was not significantly altered (P = 0.11) (Fig. 1g). Furthermore, HFD increased the level of total cholesterol in serum (P < 0.001), but not the level of triglycerides (P = 0.08) (Fig. 1h).

2.2 Irisin reactivates the dysfunctioning iBAT due to HFD

To investigate the continuous changes in iBAT following irisin intervention, CSSI was performed on the mouse iBAT region weekly. As the duration of irisin intervention extends, there was a clear reduction in the fat fraction of iBAT (P = 0.01), along with a tendency for volume reduction (P = 0.24) (Fig. 2b-d). As shown in Fig. 2e, the SUV of iBAT measured from the uptake of FDG in HFD_Irisin−4w group was significantly higher than HFD_PBS group (P = 0.03) (Fig. 2f), suggesting a significant enhancement in the metabolic capacity of iBAT following irisin intervention, despite the smaller volume of iBAT. It is worth noting that the notable decrease in FDG uptake observed in various tissues of the HFD_Irisin group, including liver, muscle, kidney, eWAT and iWAT, in comparison to those in the HFD_PBS group, could be attributed to the substantial flow of FDG directed towards iBAT (Figure S2a). Ex vivo iBAT exhibited darker color and reduced volume after irisin intervention (Fig. 2g). As illustrated in Fig. 2h, the size of the lipid droplets (P = 0.02) and the lipid area proportion (P < 0.001) markedly shrank in the HFD_Irisin−4w group compared to the HFD_Irisin−2w group (Figure S2b, c). Furthermore, irisin intervention also led to the gradual increase of the UCP 1 protein expression level (P = 0.006) (Figure S2d). The results from western blot (Fig. 2i) also demonstrated that irisin intervention for four weeks changed the expression level of UCP 1 protein in iBAT.

2.3 Irisin ameliorates the glucose and lipid metabolism

Mice receiving irisin intervention exhibited a marked decrease in the body weight from 49.65 ± 0.74 to 45.61 ± 1.43 g (P = 0.03) with no difference observed in food intake between the two groups of mice (Fig. 3a-c). Additionally, irisin intervention has shown an amelioration in glucose tolerance (P = 0.002) and insulin sensitivity (P < 0.001), with a more noticeable enhancement observed as the duration of irisin intervention extends (Fig. 3d, e). The total cholesterol level of mice with HFD was gradually reduced after the irisin intervention of (P < 0.001), while no significant difference was observed in the serum triglycerides levels (P = 0.08) among the three groups (Fig. 3f).

2.4 Irisin reduces lipid deposition in white adipose tissue and liver

We manually segmented SAT, VAT, and non-adipose tissue volumes in T₁WI images and assessed their fat fractions in CSSI images (Fig. 4a, b). The volumes of SAT (P = 0.049) and VAT (P = 0.02) gradually decreased with the extended duration of irisin intervention, and there were no significant changes in the volumes of non-adipose tissues (P = 0.51) (Fig. 4c). However, their fat fractions did not show significant changes (SAT, P = 0.49; VAT, P = 0.82) (Fig. 4d). The isolated tissues of eWAT, iWAT are depicted in Fig. 4e. The irisin intervention also led to a significant reduction in the size of lipid droplet in both iWAT (P < 0.001) and eWAT (P < 0.001) (Fig. 4f, g).

Additionally, the fat fraction of liver exhibited a declining trend following irisin intervention, although without statistical significance (P = 0.18) (Fig. 4h, i). The isolated tissues of liver are depicted in Fig. 4i. The liver morphology of the animals in the HFD_Irisin−4w group appear normal after irisin intervention, and the amount of lipid deposition in the liver were diminution (P = 0.002) (Fig. 4j-l).

2.5 Irisin is highly likely to normalize metabolism through the activation of iBAT

To investigate whether irisin improves systemic metabolism by inducing brown fat thermogenesis, we established a model of iBAT-deficient mice with obesity via surgical removal (Figure S3a). The averaged weights of mice in the REM_PBS and REM_Irisin groups were similar after the irisin treatment (P = 0.73) (Fig. 5b, c), suggesting the removal of iBAT impaired the effect of irisin in reducing body weight, despite no difference in the food intake of mice (Figure S3b). The T₁-weighted images in Fig. 5d illustrated the absence of iBAT following various interventions. The measurements of the SAT (P = 0.72), VAT (P = 0.27) and non-adipose tissues (P = 0.34) based on T₁-weighted images and liver fat fraction based on CSSI (P = 0.75) also showed no significant difference between two groups (Fig. 5e-h). The isolated tissues of eWAT, iWAT and liver are depicted in Fig. 5i. No differences were observed in the lipid droplet sizes of iWAT (P = 0.19) and eWAT (P = 0.54) between the two groups (Figure S3c), and there was no improvement in hepatic lipid deposition (Fig. 5j). Furthermore, irisin intervention did not change the glucose tolerance (P = 0.47), serum total cholesterol (P = 0.76) and triglycerides (P = 0.57) levels of mice in the REM group, but improved the insulin tolerance (P = 0.01) (Fig. 5k, l; S4d).

In this study, we investigated the role of irisin in the iBAT of HFD mice and its influence on the systemic metabolism. Our results revealed that irisin treatment can reverse HFD induced "whitening" alterations in iBAT, evidenced by increased lipid content, enlarged lipid droplets, and reduced UCP 1 expression. Following a two-week irisin intervention, iBAT exhibited the reduced lipid content and increased UCP 1 protein level, although an abnormal enlargement in the lipid droplet size was observed. When extending irisin intervention to four weeks, significant reduction in the lipid droplet size, further declining in the lipid content, and a pronounced increase in the UCP 1 protein level were evident in iBAT. Irisin intervention also enhanced FDG uptake by iBAT, suggesting that irisin may have a positive effect on restoring the thermogenic capacity of iBAT by improving the systemic glucose and lipid metabolism. This is supported by irisin intervention having no effect on mice with iBAT-“knocked out” via surgical removal. We postulate that irisin exerts normalization of the metabolism through the activation of iBAT, and the removal of iBAT blocks this mechanism.

Stimulating the BAT thermogenesis has long been regarded as a promising approach for combating obesity. Activation of the BAT thermogenesis induces a shift of the metabolism towards increased energy expenditure (22, 23). Our findings suggest that long-term irisin intervention has the potential to restore the thermogenic capacity of 'whitened' BAT. Similar changes in BAT have been reported in applying other BAT activation agents, such as β3-adrenergic agonists and cold exposure (12, 24, 25). Studies have demonstrated that cold exposure stimulates and increases the secretion of irisin, which, in turn, mediates the crosstalk between muscle and fat metabolic processes, contributing to the cold-activated endocrine axis that lessens metabolic disorder conditions (26). Thus, our results further support the significance role of irisin in promoting the thermogenic process of iBAT.

The lipid droplet within adipocytes participates in various biological processes, including cellular thermogenesis, stress, autophagy, and mitochondrial dynamics (27, 28). The lipid droplets in BAT can release free fatty acids through the action of lipases, which serve as an energy source in the UCP 1-dependent thermogenic process. When BAT is activated, it can take up a significant amount of extracellular lipids. While some of these lipids are subjected to β-oxidation, excess fatty acids are re-esterified into lipids and stored in lipid droplets to alleviate lipotoxicity (29). Furthermore, lipid droplets can attach on mitochondria to form a complex called lipid droplet-anchored mitochondria. This complex facilitates the rapid consumption of fatty acids and heat production in the activated BAT (30, 31). In our experiments, we observed that the size and structures of lipid droplets in iBAT were changed, likely due to these hyperactive processes in BAT's thermogenic function.

MRI and PET, commonly used in clinical, were applied in our study for continuous and non-invasive assessing of BAT activation process. PET/MR combines the advantages of PET and MRI, offering more comprehensive information for the analysis of metabolic status and compositional components of BAT (32). However, the challenges of PET posed by radioactivity and high costs have limited the widespread clinical application in evaluating BAT metabolic activity. MRI as a relatively cost-effective and safe modality that holds the potential to evaluate iBAT through multiple sequence imaging, thereby providing a potential avenue for its expanded clinical application. For example, water-fat separation techniques, such as the Dixon technique, are commonly employed for BAT detection in lipid and water content (33). Magnetic resonance spectroscopy, which is an in vivo imaging form of in vitro or ex vivo nuclear magnetic resonance used in analytical chemistry and biology can be used to accurately quantify different lipid components and their concentrations (33, 34). Additionally, studies have utilized magnetic resonance T₂* imaging to quantitatively assess iron content in BAT mitochondria, reflecting its blood oxygenation changes (35).

This study has some limitations. Based on our research findings, it becomes evident that PET/MR is a more suitable apparatus for assessing iBAT metabolic activity. However, the availability of such equipment is limited, especially small animal PET/MR. Alternatively, this study conducted joint assessments by combining small animal MRI and PET/CT. Another limitation is that while we have demonstrated the capacity of irisin to activate BAT, the specific molecular mechanisms and targets of this action have yet fully elucidated. Thus, in future studies it is necessary to place a greater emphasis on delving into the molecular mechanisms through which irisin affects iBAT and actively strive to explore the potential of utilizing small animal PET/MR for related studies.

In conclusion, the current study provided experimental evidence demonstrating the effect of irisin on reversing or reactivating iBAT after the HFD induced functional loss. This likely results in improved glucose and lipid metabolism. The beneficial effects of irisin on the systemic metabolism are due in part to the increased energy expenditure from the activated iBAT. These findings provide valuable and mechanistic insights on the action of irisin in mitigating the metabolic disorder conditions, supporting the use of irisin as a potential therapeutic intervention for treating obesity-related metabolic disorders through restoring BAT functions.

BAT, brown adipose tissue

CD, control diet

CSSI, chemical shift-selective imaging

CT, computed tomography

HFD, high-fat diet

iBAT, interscapular brown adipose tissue

PBS, phosphate buffered saline

SAT, subcutaneous adipose tissue

T₁WI, T₁-weighted imaging

UCP 1, uncoupling protein 1

VAT, visceral adipose tissue

FDG, fluoro-2-deoxy-D-glucose

Competing Interests The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Acknowledgements This work is funded by National Natural Science Foundation of China (81871412 and 82272064), Jiangsu Provincial Science and Technique Program (BK20221461), Postgraduate Research & Practice Innovation Program of Jiangsu Province (KYCX21_0159, KYCX22_0297, and KYCX23_0323).

Author Contributions The contributions of all authors are presented as follows. Jingyue Dai: research design and conceptualization, background research, practical performance, data analysis, writing - original draft. Yufei Zhao, Xingzhe Tang, Rui Sun: validation, practical performance. Yue Chen: research design and conceptualization, background research. Yang Jiang, Ying Cui: data collection and analysis. Hui Mao: experimental design, writing - review & editing. Xingui Peng: research design and conceptualization, supervision, project administration, funding acquisition, writing - review & editing. All authors revised and edited the manuscript. The authors extend thanks to Dr. Xiaoxuan Xu, Prof. Yanli An and Prof. Fengchao Zang for their invaluable assistance in methodological support.

Data Availability Statement The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.

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Irisin Prevents High-Fat Diet-Induced Metabolic Disorders via Brown Adipose Tissue Activation

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Abstract

Background

Methods

Results

Conclusions

Figures

Introduction

Materials and methods

1.1 Animals and treatment

1.2 MRI for tissue structure and fat contents

1.3 FDG PET-CT imaging

1.4 Immunohistology and histology

1.5 Statistical analyses

Results

2.1 Prolonged HFD induced the dysfunction of iBAT and systemic metabolism disruption

2.2 Irisin reactivates the dysfunctioning iBAT due to HFD

2.3 Irisin ameliorates the glucose and lipid metabolism

2.4 Irisin reduces lipid deposition in white adipose tissue and liver

2.5 Irisin is highly likely to normalize metabolism through the activation of iBAT

Discussion

Abbreviations

Declarations

References

Additional Declarations

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