Insulin resistance induced by chronic inflammation enhances metabolic dysfunction in obesity. The aim of this study was to investigate the effects of Bangle (Zingiber purpureum) extract (Ba) on insulin resistance and inflammation in the gastrocnemius muscle (GM) of high-fat diet (HFD)-fed SAMP8 mice. Male mice were divided into three groups: HFD, HFD + 1%Ba, and + 2%Ba. The SAMP8 control (Con) and SAMR1 control (Rcon) were fed a low-fat diet. At week 26, plasma blood parameters, macrophage infiltration, levels of expression and phosphorylation of Akt, mTOR, and AMPK were examined. The levels of plasma glucose and insulin in the HFD group were significantly higher than those in the Con group. Conversely, these levels in the HFD + 2%Ba group were significantly lower than those in the HFD group. Treatment with 2% Ba suppressed the degree of macrophage infiltration induced by HFD in the GMs. The levels of phosphorylated Akt and mTOR were decreased and the levels of phosphorylated AMPK in the HFD + 2%Ba group were increased compared with those in the HFD group. Ba may attenuate HFD-induced insulin resistance and inflammation by modulating the AMPK/Akt/mTOR pathway in the GMs of HFD-fed young SAMP8 mice.
A high-fat diet (HFD) intake increases the circulation of non-esterified fatty acids, resulting in insulin resistance in the liver, adipose tissues, and skeletal muscle 1. Chronic inflammation in metabolic tissues is involved in the onset and/or progression of insulin resistance 2. In addition, insulin resistance induced by chronic inflammation may enhance metabolic dysfunction in the skeletal muscle in type 2 diabetes mellitus 3. In animal models, chronic inflammation and macrophage markers in the skeletal muscle are increased and associated with insulin resistance 4. Moreover, chronic inflammation is associated with apoptosis induction 5. In addition, aging is associated with chronic inflammation concomitant with increased plasma levels of pro-inflammatory mediators such as tumor necrosis factor (TNF)-α and interleukin (IL)-6 in sarcopenic elderly people 6, suggesting that these mediators affect insulin resistance as well as protein metabolism in skeletal muscle with aging. Therefore, chronic inflammation and/or insulin resistance in the skeletal muscle may be potential therapeutic targets for the prevention of age-related wasting of muscles.
Obesity-related insulin resistance is associated with the regulation of insulin signaling pathway by proteins including phosphoinositide 3-kinase (PI3K) and Akt 7. In skeletal muscles, mammalian target of rapamycin (mTOR), which senses various environmental and intracellular changes, including nutrient availability and energy status 8, regulates muscle mass, resulting in the modulation of muscle hypertrophy and muscle wastage 9. The increase in Akt and mTOR activity is associated with the development of insulin resistance in skeletal muscles 10, 11. For instance, Lepidium sativum seed extract attenuates insulin resistance and hepatic inflammation in HFD-fed rats through the regulation of Akt/mTOR signaling 12. AMP-activated protein kinase (AMPK) is known to regulate various physiological events, including cellular growth and proliferation, mitochondrial function, and factors linked to insulin resistance, inflammation, and oxidative stress 13. For instance, AMPK activation improves inflammation and insulin resistance in the skeletal muscle and adipose tissue of women with gestational diabetes mellitus and normal glucose tolerance 14. When HFD-fed mice received dietary red raspberry, the inflammatory responses and sensitizing insulin signaling were alleviated in the skeletal muscle through the activation of AMPK 15. Thus, stimulation of the AMPK/Akt/mTOR pathway is expected to alter inflammation and insulin resistance in the skeletal muscle of obese or elderly people.
Bangle (Zingiber purpureum) is a tropical ginger widely distributed in Southeast Asia. In Indonesia, Bangle is known to be a spice and a traditional medicine to treat fever and headaches. Bangle extract improves spatial learning and reduces deficits in memory in senescence-accelerated mice 16. However, the protective effects of Bangle on chronic inflammation and insulin resistance in skeletal muscles are not fully understood. Therefore, the aim of the present study was to examine whether Bangle extract (Ba) could improve insulin resistance and inflammation, and whether Ba stimulates the AMPK/Akt/mTOR pathway in the gastrocnemius muscle (GM) of HFD-fed senescence-accelerated prone mice (SAMP8).
The Bangle extract (Ba) powder contained trans- and cis-3-(3',4'-dimethoxyphenyl)-4-[(E)-3”,4”-dimethoxystyryl]cyclohex-1-ene (phenylbutenoid dimers; 5.0%) (Figure 1) and composed of Ba 20.2%, emulsifier 8.5%, and dextrin 71.3%. The Ba powder was kindly supplied by Hosoda SHC Co. (Fukui, Japan).
All procedures were performed in accordance with the regulations of the Guidelines for Animal Experimentation, Aomori University of Health and Welfare (Permission number: 17004). The animal experiments described in the article have been carried out in accordance with EU directive for animal experiments and the relevant national guides on the care and use of laboratory animals (“Act on Welfare and Management of Animals” in Japan). Four-week-old male SAMP8 and R1 (Japan SLC, Inc., Shizuoka, Japan), weighing 21.6–23.3 g and 19.7–25.0 g, were used, respectively. After 4 weeks of adaptation maintenance, SAMP8 received diets providing 45% of energy from fat (HFD; n = 22) and 13% of energy from fat (LFD; n = 8, SAMP8 control (Con) group) for 8 weeks. To confirm the effect of HFD intake on body weight gain, all mice received LFD for 2 weeks. SAMR1 control (Rcon; n = 6) was fed a diet that provided 13% of energy from fat. Thereafter, the mice that received a HFD were randomly divided into three groups, where n indicates the number of animals in each group: 0% Bangle extract (Ba) (HFD + 0% Ba; n = 8), 1% Ba (HFD + 1% Ba; n = 6), and 2% Ba (HFD + 2% Ba; n = 8). The rest of SAMP8 (Con; n = 8) was fed a diet providing 13% of energy from fat during the treatments. All mice were maintained at a constant temperature of 23 ± 1 °C under a 12 h light/dark cycle and were fed the corresponding diets and distilled water ad libitum. Before the mice were euthanized at week 26, all animals were fasted overnight (15–16 h), weighed, and blood samples were collected from the abdominal aorta under anesthesia. The GMs and epididymal fat tissue were quickly removed, and fixed in 4% paraformaldehyde phosphate buffer solution for immunohistochemistry. Portions of the GMs were immediately frozen in liquid nitrogen and stored at -80°C until use.
2.3. Plasma Biochemical ParametersPlasma samples were separated by centrifugation, and tested for glucose (Glc), triacylglycerol (Tg), and non-esterified fatty acid (NEFA) levels using a commercially available kit. Plasma insulin levels were measured using the LBIS Mouse Insulin ELISA Kit (AKRIN-011RU, FUJIFILM Wako Shibayagi Corporation, Gunma, Japan). Homeostatic model assessment insulin resistance (HOMA-IR), a biomarker of insulin sensitivity, was determined using the following equation 17:
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Paraformaldehyde-fixed GMs and epididymal fat tissues were embedded in paraffin, and were stained with collagen fibrils using a Sirius red/Fast green collagen staining kit (Chondrex, Inc., Redmond, WA, USA). After 10 randomly selected fields per animal were chosen, the Sirius red-stained area was measured, and normalized to the total cross-sectional area and expressed as a percentage. The GM sections were stained for macrophages as described in a previous study 18. Briefly, deparaffinized sections were pre-treated with pepsin solution and hydrogen peroxide (H2O2) and subsequently pre-incubated with skimmed milk in PBS and incubated with F4/80 antibody (1:60, Bio-Rad Laboratories, Inc., Hercules, CA, USA). The sections were incubated with Histofine Simple Stain Mouse MAX PO (Nichirei Biosciences Inc., Tokyo, Japan), and positive reactions were visualized using 3,3'-diaminobenzidine tetrahydrochloride in 50 mM Tris-HCl buffer containing H2O2. For the measurement of F4/80-immunopositive cells in the GM and epididymal fat tissue, 10 randomly selected fields were chosen. Quantification was performed using CellSensDimension software (Olympus Corporation, Tokyo, Japan).
2.5. Western Blot AnalysisThe GMs were homogenized in homogenizing buffer (50 mM N-2-hydroxyethylpiperazine-N'-2-ethanesulphonic acid [HEPES], 150 mM NaCl, 1 mM dithiothreitol, and 0.5% (v/v) Tween 20, pH 7.4) supplemented with a protease inhibitor cocktail (Roche Applied Science, Indianapolis, IN, USA). The homogenates were centrifuged. The protein concentrations in the supernatants were determined. Standard western blotting techniques were performed for protein analyses as described in a previous report 18. The proteins were electrophoresed on SDS-PAGE and subsequently electrotransferred onto polyvinylidene difluoride (PVDF) membranes. The membranes were blocked and incubated with a rabbit AMPK antibody, phospho-AMPK-Thr172, Akt, phospho-Akt-Ser473, mTOR, phospho-mTOR-Ser2448, and cleaved caspase 3 (Cell Signaling Technology, Danvers, MA, USA). After washing, the membranes were incubated with the appropriate secondary horseradish peroxidase-conjugated antibodies. Protein bands were visualized using ECL western blotting Detection Reagents (GE Healthcare UK Ltd., Buckinghamshire, UK) on Hyperfilm (GE Healthcare UK Ltd.). The specific band density was quantitatively analysed. Protein levels were normalized using the formula that the band density of the target protein was divided by that of glyceraldehyde-3-phosphate dehydrogenase (GAPDH).
2.6. Statistical AnalysisEach value is expressed as the mean ± SEM. Statistical analyses were performed using one-way analysis of variance, followed by Tukey’s test. In all cases, statistical significance was set at P < 0.05.
The body weights of the HFD-fed groups were significantly higher than those of the Con (LFD-fed SAMP8) group from weeks 21 to 26 (Figure 2). Although no significant difference was found among the body weights of the HFD + 0% Ba, 1% Ba, and 2% Ba groups, the body weights of the 2% Ba group tended to be lower than those of the 0% Ba group at week 26 (P = 0.349). No significant difference was observed in the feed intake of the HFD + 0% Ba, 1% Ba, and 2% Ba groups at weeks 20, 22, and 24 (Table 1). The relative GM weights in the HFD + 0% Ba, 1% Ba, and 2% Ba groups were significantly lower than those of the Rcon (LFD-fed SAMR1) and Con groups, respectively (Table 2). There was no significant difference in the relative GM weights among the HFD + 0% Ba, 1% Ba, and 2% Ba groups. The relative epididymal fat tissue weights in the HFD + 0% Ba, 1% Ba, and 2% Ba groups were significantly higher than those in the Con group. The relative weights of perirenal fat tissue in the HFD + 0% Ba group were significantly higher than those in the Con group. Conversely, the relative weights in the 2% Ba group were significantly lower than those in the 0% Ba group.
The levels of plasma Glc and insulin in the HFD + 0% Ba group were significantly higher than those in the Con group. In contrast, the levels in the HFD + 2% Ba group were significantly lower than those in the 0% Ba group (Figure 3). Likewise, the HOMA-IR levels in the HFD + 0% Ba group increased significantly compared to those in the Con group. Conversely, the HOMA-IR levels in the HFD + 2% Ba group were significantly lower than those in the 0% Ba group, indicating that the 2% Ba treatment may attenuate insulin resistance in HFD-fed mice. The plasma Tg levels in the HFD + 0% Ba group were significantly higher than those in the Con group. Conversely, the levels in the HFD + 2% Ba group were significantly lower than those in the 0% Ba group (Figure 3).
3.3. Effect of Ba on Macrophages Infiltration and Sirius-red-stained Fibrotic AreasFewer F4/80-positive macrophages were observed in the GM and epididymal fat tissue of the HFD + 2% Ba group, compared with the HFD + 0% Ba group. To examine the effect of Ba treatment on macrophage infiltration in the GM and epididymal fat tissue, F4/80-positive macrophages were counted. The number of macrophages in the GM of the HFD + 0% Ba group was significantly higher than that in the Con group (Figure 4). Conversely, the macrophage numbers in the HFD + 1% Ba and 2% Ba groups were significantly lower than those in the HFD + 0% Ba group. The number of macrophages in the epididymal fat tissue did not differ significantly among the Rcon, Con, and HFD + 0% Ba groups (Figure 4). However, the macrophage numbers in the HFD+2% Ba group were significantly lower than those in the 0% Ba group. These results indicate that Ba treatment attenuated macrophage infiltration into the skeletal muscles and adipose tissues of HFD-fed mice treated with 2% Ba.
Representative Sirius red-stained GM sections from HFD-fed mice treated with Ba are shown in Figure 5. The percentage area of fibrosis per total cross-sectional area in the HFD + 0% Ba group was significantly higher than that in the Con group (Figure 5). Conversely, the fibrotic areas in the GMs of HFD + 1% Ba and 2% Ba groups decreased significantly compared to the levels in the HFD + 0% Ba group, indicating that Ba suppresses the increased fibrotic areas in the GMs of HFD-fed mice.
3.4. Effect of Ba on the Levels of Cleaved Caspase 3Because chronic inflammation is related to the induction of apoptosis, we determined the cleavage levels of caspase 3, which is involved in the apoptotic pathway. The levels of cleaved caspase 3 in the GMs of the Con group tended to be higher than those in the Rcon group (P = 0.246) (Figure 6). This result suggests that apoptosis might be induced in the skeletal muscles, even in young SAMP8 mice. The levels of cleaved caspase 3 in the HFD + 0% Ba group were similar to those in the Con group (Figure 6). Conversely, the expression in the HFD + 2% Ba group was significantly lower than that in the HFD + 0% Ba group, indicating that Ba treatment suppressed obesity-related apoptosis in the GMs of HFD-fed mice.
The levels of phosphorylated Akt in the HFD + 0% Ba group tended to be higher than that in the Con group (P = 0.061) (Figure 7A). Conversely, the levels in the HFD + 2% Ba group were significantly lower than those in the HFD + 0% Ba group. Likewise, the levels of p-Akt/t-Akt ratio in the HFD + 2% Ba group were significantly lower than those in the HFD + 0% Ba group. The levels of phosphorylated mTOR and p-mTOR/t-mTOR ratio in the HFD + 0% Ba group were higher than those in the Con group. Conversely, these levels in the HFD + 2% Ba group were significantly lower than those in the HFD + 0% Ba group (Figure 7B). The levels of phosphorylated AMPK in the HFD + 0% Ba, 1% Ba, and 2% Ba groups were significantly higher than those in the Con group. The levels of p-AMPK/t-AMPK ratio in the HFD + 2% Ba group were significantly higher than those in the HFD + 0% Ba group (Figure 7C), indicating that Ba treatment upregulated AMPK activation in the GMs of HFD-fed mice.
The major findings of the present study in the HFD+Ba-fed young SAMP8 mice were as follows: (i) the plasma levels of glucose and insulin were decreased, (ii) the macrophage number and the fibrotic areas were decreased, (iii) the levels of cleaved caspase 3 were decreased, and (iv) Akt and mTOR phosphorylation were downregulated while AMPK phosphorylation was upregulated in the GMs compared with the HFD-fed SAMP8 mice.
In this study, we found that, in glucose metabolism, significantly higher plasma levels of Glc and insulin were found in the HFD-fed mice than in the control SAMP8 mice. These results are consistent with a previous report that HFD-fed mice showed increased insulin secretion and impaired glucose tolerance 19. Conversely, these levels in the HFD + Ba-fed mice were consistently lower than those in the HFD-fed mice. In addition, we noted that the index of HOMA-IR, which is known to be a valid measure to determine insulin resistance induced by an HFD 17, was reduced in the HFD + Ba-fed mice compared with that in the HFD mice. Furthermore, the relative perirenal fat tissue weights in the HFD-fed mice treated with Ba were significantly decreased, and that the relative epididymal fat tissue weights tended to be lower than those in the HFD-fed mice. The plasma levels of Tg in the HFD-fed mice treated with Ba were significantly lower than those in the HFD-fed mice. Therefore, the treatment with Ba was suggested to be effective in preventing insulin resistance as well as the dysfunction of lipid metabolism induced by HFD. In addition, we confirmed that the levels of plasma Tg and NEFA in the Con group were lower than those in the Rcon group. Decreased lipid absorption was reported to be due to reduced pancreatic lipase activity in aging mice 20, suggesting that the decreased plasma levels of Tg and NEFA may be affected by age-related lipid metabolism in SAMP8 even at week 26.
This study demonstrated that Ba treatment decreased the macrophage number and the percentage of fibrotic area, concomitant with a downregulation of cleaved caspase 3 levels in the GMs of HFD-fed mice. In skeletal muscles, obesity is associated with the induction of myocyte inflammation, which adversely regulates myocyte metabolism, leading to insulin resistance 3. Zingerone, a key phenolic compound found in ginger (Zingiber officinale), has been reported to decrease collagen deposition and inflammatory activities such as TNF-α and IL-1β levels in bleomycin-induced pulmonary fibrosis in rats 21, and to reduce myocardial fibrosis and inflammation in streptozotocin-induced diabetic rats 22. Zerumbone, a major component of ginger (Zingiber zerumbet), also inhibits the production of pro-inflammatory cytokines in lipopolysaccharide (LPS)-activated inflammation of human monocyte-derived macrophages 23. In addition, chronic inflammation is closely associated with the initiation of fibrosis and apoptosis, leading to the impairment of insulin resistance 24. Thus, the treatment of Ba may contribute to the attenuation of macrophage infiltration and decreased fibrosis, concomitant with the inhibition of apoptosis in the skeletal muscle of HFD-fed mice.
Interestingly, this study demonstrated that Ba upregulated AMPK activation in the GM of HFD-fed mice. The ethanol extract from the rhizome of ginger (Zingiber zerumbet) upregulated AMPK phosphorylation in the kidneys of diabetic rats 25. In addition, ginger extract upregulated Glut 4 expression via the AMPK pathway in C2C12 myoblast cells 26. Ginger (Zingiber officinale) extract promotes mitochondrial biogenesis through the activation of AMPK in the muscle and liver of mice 27. Furthermore, AMPK activation was associated with inflammation. For instance, metformin, which is known as an antidiabetic drug, is reported to ameliorate low-grade inflammation through the activation of AMPK in HFD-fed mice 28. Therefore, Ba treatments may be involved in the improvement of glucose metabolism as well as chronic inflammation in the GMs through the activation of AMPK.
This study showed an increase in phosphorylated Akt and mTOR levels in the GMs of HFD-fed mice. Although the Akt/mTOR pathway is considered to be essential for muscle hypertrophy 29, the sustained activation of mTOR complex 1 (mTORC1) is reported to lead to abnormal mitochondria, oxidative stress, and damage and loss of fibers 30. In addition, the increased activation of mTOR in the skeletal muscle and liver is involved in obesity-related insulin resistance 10. Moreover, diet-induced obesity increases vascular dysfunction through long-term activation of the Akt/mTOR pathway 31. Notably, we demonstrated that the increased phosphorylation of Akt and mTOR decreased in the GMs of HFD-fed mice treated with Ba. Zingerone attenuated cell proliferation by inhibiting the PI3K/Akt/mTOR pathway in human prostate cancer PC3 cells 32. In addition, resveratrol, a natural polyphenol, suppresses fatty acid-induced insulin resistance by increasing AMPK activity and inhibiting mTOR in L6 rat skeletal myotubes 33. Taken together, these results suggest that the alteration of the AMPK/Akt/mTOR pathway may play a role in the improvement of insulin resistance as well as damage of muscle fibers in the GMs of HFD-fed mice.
In conclusion, we showed that Ba decreased the plasma levels of glucose, insulin, and HOMA-IR, concomitant with macrophage infiltration and fibrotic areas in the GMs of HFD-fed SAMP8 mice. Furthermore, Ba treatment downregulated Akt and mTOR phosphorylation and upregulated AMPK phosphorylation in GMs. Although further investigation is required to clarify the detailed mechanism in aged SAMP8 mice, our study suggests that Ba may attenuate HFD-induced insulin resistance and chronic inflammation through modulation of the AMPK/Akt/mTOR pathway in the GMs of HFD-fed young SAMP8 mice. The treatment of Bangle could be a useful preventive strategy for obesity-related insulin resistance and may lead to improved hyperlipidemic and hyperglycolytic conditions in skeletal muscles.
The authors thank Keiko Tamakuma for providing technical assistance. This study was supported by a research grant (Shiteigata-grant) from Aomori University of Health and Welfare.
The authors have no competing interests.
AMPK, AMP-activated protein kinase; Ba, Bangle (Zingiber purpureum) extract; Con, SAMP8 control; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; GM, gastrocnemius muscle; Glc, glucose; HFD, high-fat diet; HOMA-IR, homeostatic model assessment insulin resistance; IL-6, interleukin-6; LPS, lipopolysaccharide; mTOR, mammalian target of rapamycin; NEFA, non-esterified fatty acid; PI3K, phosphoinositide 3-kinase; Rcon, SAMR1 control; SAMP8, senescence-accelerated prone mice; Tg, triacylglycerol; TNF-α, tumor necrosis factor-α
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Published with license by Science and Education Publishing, Copyright © 2021 Shin Sato, Nagomi Takahashi and Yuuka Mukai
This work is licensed under a Creative Commons Attribution 4.0 International License. To view a copy of this license, visit
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