COMMENTARIES

Astaxanthin for the Metabolic Syndrome

Hidekatsu Yanai, M.D., Ph.D., F.A.C.P. and Norio Tada, M.D., Ph.D., F.A.H.A., Department of Internal Medicine, and Institute of Clinical Medicine and Research , the Jikei University School of Medicine, Kashiwa, Chiba, Japan, Email: yanaih@jikei.ac.jp

Hidekatsu Yanai


The National Cholesterol Education Program's Adult Treatment Panel III report (ATP III) identified 6 components of the metabolic syndrome that relate to cardiovascular disease: 1) abdominal obesity, 2) dyslipidemia, 3) raised blood pressure, 4) insulin resistance and/or glucose intolerance, 5) proinflammatory state, and 6) prothrombotic state [1].

          Astaxanthin (AX), a red carotenoid pigment, is a biological antioxidant that occurs naturally in a wide variety of living organisms. AX has various potent pharmacological effects, including anti-obesity, anti-inflammatory, anti-diabetic, anti-hypertensive activities, and AX also improves lipid and adiponectin metabolisms. These pharmacological effects of AX may be useful for the treatment of metabolic syndrome. Here, the therapeutic application of AX for the metabolic syndrome will be considered.

 

Anti-obesity Effect

 

Visceral fat accumulation has been shown to play a crucial role in the development of the metabolic syndrome. In the study using obese mice fed a high-fat diet, AX supplementation (6 mg/kg and 30 mg/kg) significantly inhibited the increase in body weight and adipose tissue weight [2]. AX-mediated inhibition of increase in body weight appeared to be dose-dependent [2]. Elevated fatty acid utilization is considered to be the mechanism for anti-obesity of AX; however, further studies should be performed to elucidate the underlying mechanisms for AX-mediated anti-obesity effect.

 

Anti-inflammatory Effect

 

Several cohort studies have suggested that high-sensitivity C-reactive protein evaluation adds prognostic information of the metabolic syndrome, beyond that available from the Framingham Risk Score, suggesting that inflammation plays a crucial role in pathogenesis of the metabolic syndrome [3]. Tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and IL-1? are important proinflammatory cytokines in the metabolic syndrome [4].

          AX inhibited the expression of TNF-α and IL-1β in lipopolysaccharide-stimulated cells of the murine macrophage cell line, by suppressing activation of the nuclear factor-?B (NF-?B) [5], which activates proinflammatory genes encoding cyclooxygenase-2, TNF-α, IL-1β, and IL-6 [6]. AX has been also reported to suppress expression of IL-6 in the laser photocoagulation-treated mice retinal pigment epithelium-choroids, possibly by inhibiting the NF-?B signaling pathway [7]. AX suppresses major proinfalmmatory cytokines elevated in the metabolic syndrome.

 

Anti-diabetic Effect

 

In db/db mice, a rodent model of type 2 diabetes, non-fasting blood glucose was significantly decreased by treatment with AX [8]. During intraperitoneal glucose tolerance test, the AX-treated db/db mice showed significantly lower glucose levels than non-treated mice [8]. The blood glucose level at 120 minutes after glucose injection was 144.9 ± 64.8 mg/dl in the treated group, and 233.0 ± 40.6 mg/dl in the non-treated group [8]. At 120 minutes after glucose injection, serum insulin concentration (8425.0 ± 1509.1 pg/ml) in treated mice was significantly higher than that (2950.0 ± 560.5 pg/ml) in non-treated mice, suggesting the AX-mediated preservation of ?-cell function, possibly by reducing oxidative stress induced by hyperglycemia [8].

          Oral administration of AX (50 mg/kg/day) for 22 weeks significantly reduced fasting glucose levels and homeostasis index of insulin resistance, in spontaneously hypertensive rats (SHR) model of the metabolic syndrome, proposing that AX ameliorates insulin resistance [9].

The relative mesangial area and daily urinary albumin excretion were significantly smaller in AX-treated diabetic db/db mice than that in non-treated db/db mice, after 12 weeks of treatment [10]. Urinary excretion of 8-hydroxydeoxyguanosine as a marker of DNA oxidation, was also suppressed by chronic treatment with AX, suggesting that AX reduced oxidative stress on the kidney and prevented progression of diabetic nephropathy [10].

 

Anti-hypertensive Effect

 

In SHR, the administration of AX at the doses of 50 mg/kg for 5 weeks demonstrated a significant reduction in the systolic blood pressure (BP) (-4%) and in the diastolic BP (-10%), and also delayed the incidence of stroke in stroke-prone SHR [11]. AX significantly reduced the contractile responses of the aortic preparations to?α-adrenergic receptor agonist, phenylephrine, suggesting that AX may decrease BP by ameliorating the sympathetic pathway [12]. AX also demonstrated a significant reduction of the contractile responses to angiotensin II [12].

          Sympathetic overactivity, oxidative stress, activated renin-anigiotensin system have been suggested to be possible factors to develop hypertension in the metabolic syndrome [13]. AX may be effective for the management of hypertension in the metabolic syndrome.

 

Improvement in Lipid and Adiponectin Metabolism

 

Plasma triglyceride levels in mice fed a high-fat diet plus AX (6 mg/kg and 30 mg/kg) for 60 days, were significantly lower than those in mice fed a high-fat diet alone [2]. Plasma total cholesterol levels in AX (30 mg/kg)-treated mice were significantly lower than those in non-treated mice fed a high-fat diet [2].

          Oral administration of AX (50 mg/kg/day) for 22 weeks significantly increased plasma adiponectin and high-density lipoprotein cholesterol levels, and significantly decreased plasma triglyceride and non-esterified fatty acids levels, in SHR model of the metabolic syndrome [9].

 

Conclusions

 

AX ameliorates all constituents of the metabolic syndrome, and also improves adipocytokines in the metabolic syndrome, suggesting the usefulness of AX for the management and prevention of the metabolic syndrome.

References

  1.    Third report of the National Cholesterol Education Program (NCEP) expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (Adult Treatment Panel III). Final report. 2002. Circulation 106: 3143-421.
  2.    Ikeuchi M, Koyama T, Takahashi J, Yazawa K. 2007. Effects of astaxanthin in obese mice fed a high-fat diet. Biosci Biotechnol Biochem 71: 893-99.
  3.    Ridker PM, Wilson PW, Grundy SM. 2004. Should C-reactive protein be added to metabolic syndrome and to assessment of global cardiovascular risk? Circulation 109: 2818-25.
  4.    Fernández-Real JM, Ricart W. 2003. Insulin resistance and chronic cardiovascular inflammatory syndrome. Endocr Rev 24: 278-301.
  5.    Lee SJ, Bai SK, Lee KS, et al. 2003. Astaxanthin inhibits nitric oxide production and inflammatory gene expression by suppressing I(kappa)B kinase-dependent NF-kappaB activation. Mol Cells 16: 97-105.
  6.    Makarov SS. 2000. NF-kappaB as a therapeutic target in chronic inflammation: recent advances. Mol Med Today 6: 441-48.
  7.    Izumi-Nagai K, Nagai N, Ohgami K, et al. 2008. Inhibition of choroidal neovascularization with an anti-inflammatory carotenoid astaxanthin. Invest Ophthalmol Vis Sci 49: 1679-85.
  8.    Uchiyama K, Naito Y, Hasegawa G, Nakamura N, Takahashi J, Yoshikawa T. 2002. Astaxanthin protects beta-cells against glucose toxicity in diabetic db/db mice. Redox Rep 7: 290-93.
  9.    Hussein G, Nakagawa T, Goto H, et al. 2007. Astaxanthin ameliorates features of metabolic syndrome in SHR/NDmcr-cp. Life Sci 80: 522-29.
  10.    Naito Y, Uchiyama K, Aoi W, et al. 2004. Prevention of diabetic nephropathy by treatment with astaxanthin in diabetic db/db mice. Biofactors 20: 49-59.
  11.    Hussein G, Nakamura M, Zhao Q, et al. 2005. Antihypertensive and neuroprotective effects of astaxanthin in experimental animals. Biol Pharm Bull 28: 47-52.
  12.    Hussein G, Goto H, Oda S, et al. 2005. Antihypertensive potential and mechanism of action of astaxanthin: II. Vascular reactivity and hemorheology in spontaneously hypertensive rats. Biol Pharm Bull 28: 967-71.
  13.    Yanai H, Tomono Y, Ito K, Furutani N, Yoshida H, Tada N. 2008. The underlying mechanisms for development of hypertension in the metabolic syndrome. Nutr J 7: 10.

 

 

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