Part II-Cistanches Herba Reduces The Weight Gain in High Fat Diet-induced Obese Mice Possibly Through Mitochondrial Uncoupling
Mar 25, 2022
Contact: Audrey Hu Whatsapp/hp: 0086 13880143964 Email: audrey.hu@wecistanche.com
Hoi Shan Wong, Jihang Chen, Pou Kuan Leong, Hoi Yan Leung, Wing Man Chan, Kam Ming Ko
* Division of Life Science, Hong Kong University of Science and Technology, Hong Kong, China.
4. Discussions
HCF1 treatment suppressed the HFD-induced body weight gain in both male and female mice. The HCF1-induced weight loss was associated with significant reductions in the HFD-induced fat pad increases, particularly in visceral fat. Visceral fat, which is a metabolically active tissue, participates in the regulation of various neuroendocrinal functions (Cefalu et al., 1995; Ibrahim, 2010; Nguyen-Duy, Nichaman, Church, Blair, & Ross, 2003; Wozniak, Gee, Wachtel, & Frezza, 2009; Zhang et al., 2012), wherein the secretion of pro-inflammatory cytokines plays an important role in eliciting a systemic inflammatory response (Ibrahim, 2010). Hence, the ability of HCF1 to suppress the HFD-induced increase in visceral fat has implications in the prevention of obesity-related metabolic disorders. Long-term HCF1 treatment also suppressed the HFD-induced ectopic fat deposition, as evidenced by the significant decrease in hepatic TG level in HCF1-cotreated HFD-fed mice. The deposition of ectopic fat, which is commonly found in obese individuals (Iacobellis, Barbarini, Letizia, & Barbaro, 2013), occurs when the supply of dietary lipids exceeds the storage capacity of adipose tissue (Bays, Mandarino, & DeFronzo, 2004), with the resultant accumulation of lipids in non-adipose tissues such as skeletal muscle and liver (Lettner & Roden, 2008). Clinical studies showed a strong correlation between the deposition of ectopic fat and the development of type 2 diabetes. Such a pathogenic effect was found to be mediated by the accumulation of intermediates of lipid metabolism. For instance, the intermediates from incomplete β-oxidation can lead to the malfunction of insulin receptors via diacylglycerol signaling (Snel et al., 2012). Hence, the findings suggest that HCF1 may reduce the accumulation of ectopic fat by decreasing the availability of lipids and thereby produce a beneficial effect on insulin sensitivity.
Cistanche herba is good for weight control
Chengdu Wecistanche mainly produces Cistanche Products for a healthy life.
The HFD-induced elevations in plasma TG and glucose levels, indicative of insulin resistance, are likely due to the impairment in the regulation of insulin-mediated TG synthesis and glucose uptake (Koo, 2013; Leto & Saltiel, 2012; Moore, Coate, Winnick, An, & Cherrington, 2012). The rises in plasma TG and glucose levels are possibly attributed to the deregulation of hepatic TG/glucose anabolism mediated by the phosphoinositide-3-kinase/protein kinase B pathway in insulin signaling (Farese, Sajan, & Standaert, 2005). The ability of HCF1 to inhibit the HFD-induced elevation in plasma TG and glucose levels suggests its beneficial effect on insulin sensitivity. The insulin-sensitizing effect was further supported by the HCF1- induced metabolic changes under both ND and HFD conditions. HCF1 treatment seemed to stimulate glycolysis in ND-fed mice, as indicated by the stimulation of PFK activity, suggesting the increased use of glucose as fuel molecules. On the other hand, HFD feeding triggered a shift of energy metabolism from glucose to fatty acid oxidation, indicative of an adaptive response towards the elevation in plasma TG level, presumably via the peroxisome proliferation-activated receptor-alpha (PPARα) fatty acid sensing mechanism (Georgiadi & Kersten, 2012; Poulsen, Siersbak, & Mandrup, 2012). In the process, the binding of fatty acids or fatty acid derivatives activates PPARα. The resultant nuclear translocation of PPARα promotes fatty acid metabolism-related gene expressions, with the subsequent increase in the fatty acid oxidation (Georgiadi & Kersten, 2012; Poulsen et al., 2012), as was the case in the untreated HFD-fed mice. HCF1 inhibited the HFD-stimulated fatty acid oxidation, presumably mediated by the enhanced insulin sensitivity in HFD-fed mice. Moreover, HFD feeding caused dyslipidemia, as evidenced by significant elevations in hepatic and plasma TC levels, as well as a decrease in the ratio of HDL to LDL (Klop, Elte, & Cabezas, 2013). Given the fact that cholesterol metabolism is in part regulated by the plasma/ hepatic TG level and the insulin-dependent signaling pathway (Dickson-Humphries, Bottenberg, & Kuntz, 2013; Ruderman, Carling, Prentki, & Cacicedo, 2013), the ability of HCF1 to modulate cholesterol metabolism provides evidence to further support its beneficial role in insulin sensitivity.
Desert Cistanche
In order to investigate the mechanism underlying the HCF1- induced weight reduction, the effect of HCF1 on mitochondrial uncoupling was examined. The induction of mitochondrial uncoupling in mouse skeletal muscle, as indicated by the reduction in mitochondrial RCR and the elevated mitochondrial UCP3 expression, was associated with the decreases in body weight and total fat indices in HCF1-co-treated HFD-fed mice. The finding suggests the possible involvement of mitochondrial uncoupling in producing the weight reduction effect in mice, particularly under HFD conditions. While HCF1 induced mitochondrial uncoupling in male and female mice under both ND and HFD conditions, a larger extent of HCF1-induced weight reduction was observed in male mice. The gender difference is presumably due to the larger skeletal muscle mass in males than in female mice. The differential suppressive effect on the HFD-induced increase in subcutaneous and visceral fat by HCF1 co-treatment also lends support to the involvement of mitochondrial uncoupling in weight loss. In addition, the finding that HCF1 caused a more prominent reduction in visceral fat was likely related to the relatively high mitochondrial content in visceral fat when compared with subcutaneous adipose tissue (Krauneoe et al., 2010). On the other hand, while HCF1 produced a dose-dependent effect on weight reduction in ND-fed and HFD-fed mice, its effect on mitochondrial uncoupling was found to be self-limiting. The discrepant observation may be attributed to factors other than the induction of mitochondrial uncoupling. For instance, the increase in lean muscle mass after co-treatment with HCF1 could lead to a larger extent of mitochondrial uncoupling-induced energy consumption in HFD-fed mice. Furthermore, results obtained from the comparative study between the effects of HCF1 and CT on HFDinduced obesity also excluded the possible involvement of inhibition of dietary fat absorption in HCF1-induced weight loss. In the study, both CT and HCF1 treatments caused weight reduction in both ND-fed and HFD-fed mice. Interestingly, the CT-mediated weight reduction effect was associated with significant decreases in plasma LDL levels and the resultant increase in the ratio of HDL to LDL, but not the induction of mitochondrial uncoupling in skeletal muscle. The finding suggests that the weight loss effect of CT may be primarily related to its ability in sequestering bile acid which hinders dietary fat absorption (Chen et al., 2010; Yamato et al., 2012). Also, in contrast to HCF1 which enhanced the glycolytic flux for energy generation, CT failed to produce any detectable effect on energy metabolism. The improved glucose and lipid metabolism by CT co-treatment in HFD-fed mice are events secondary to the CT-induced reduction in dietary fat absorption and hence weight reduction. The differential effect between HCF1 and CT co-treatment suggests that the HCF1-induced weight reduction is unlikely mediated by the impairment in dietary fat absorption.
health benefits of desert cistanche
As assessed by high-performance liquid chromatography (HPLC) and liquid chromatography-mass spectrometry (LC-MS), preliminary findings showed that phytosterols, such as β-sitosterol (BSS), are the major chemical constituents of HCF1. We further demonstrated that both HCF1 and BSS were effective at inducing mitochondrial uncoupling in H9c2 cells in vitro and in rat hearts ex vivo via a ROS-mediated mechanism (Wong, Chen, Leong, & Ko, 2013), suggesting BSS as an active component of HCF1. BSS, which shares a similar chemical structure with cholesterol, was shown to be capable of fluidizing inner mitochondrial membrane by membrane perturbation, with a resultant increase in the mitochondrial electron transport (Shi, Wu, & Xu, 2013). We, therefore, postulate that phytosterols in HCF1, particularly BSS, may increase inner mitochondrial membrane fluidity via the hydrophobic interactions between the pentacyclic skeleton and mitochondrial inner membrane. The associated elevation in mitochondrial electron transport, as was also observed in our previous studies (Wong et al., 2013; Wong & Ko, 2013) may cause a parallel increase in mitochondrial ROS production, which may, in turn, induce the mitochondrial uncoupling and eventually lead to weight loss in vivo.
cistanche health benefits
5. Conclusion
Taken together, HCF1 treatment was found to exert a weight reduction effect in HFD-induced obese mice, presumably by increasing the in vivo energy metabolism, particularly in skeletal muscle via the induction of mitochondrial uncoupling. The weight reduction effect was also associated with improved insulin sensitivity. Further studies using 6-keto cholestanol as a coupler will be conducted to confirm the involvement of HCF1-induced mitochondrial uncoupling in producing the weight reduction effect. Furthermore, studies on the effects of BSS on weight control are warranted. The findings suggest the potential use of HCF1 for the prevention of diet-induced obesity and associated metabolic disorders.
Conflict of Interest
We declare that we have no conflict of interest.
Reference:
Bays, H., Mandarino, L., & DeFronzo, R. A. (2004). Role of the adipocyte, free fatty acids, and ectopic fat in pathogenesis of type 2 diabetes mellitus: Peroxisomal proliferator-activated receptor agonists provide a rational therapeutic approach. The Journal of Clinical Endocrinology and Metabolism, 89, 463–478.
Brand, M. D., Pakay, J. L., Ocloo, A., Kokoazka, J., Wallace, D. C., & Brooks, P. S. (2005). The basal proton conductance of mitochondria depends on adenine nucleotide translocase content. The Biochemical Journal, 392, 353–362.
Carter, S. L., Rennie, C. D., Hamilton, S. J., & Tarnopolsky, M. A. (2001). Changes in skeletal muscle in males and females following endurance training. Canadian Journal of Physiology and Pharmacology, 79, 386–392.
Cefalu, W. T., Wang, Z. Q., Werbel, S., Bell-Farrow, A., Crouse, J. R., 3rd, Hinson, W. H., Terry, J. G., & Anderson, R. (1995). Contribution of visceral fat mass to the insulin resistance of aging. Metabolism: Clinical and Experimental, 44, 954–959.
Cerqueira, F. M., Laurindo, F. R. M., & Kowaltowski, A. J. (2011). Mild mitochondrial uncoupling and calorie restriction increase fasting eNOS, Akt, and mitochondrial biogenesis. PLoS ONE, doi:10.137/journal.pone.0018433.
Chan, S. L., Wei, Z., Chigurupati, S., & Tu, W. (2010). Compromised respiratory adaptation and thermoregulation in aging and age-related diseases. Ageing Research Reviews, 9, 20–40.
Chen, L., McNulty, J., Anderson, D., Liu, Y., Nystrom, C., Bullard, S., Collins, J., Handlon, A. L., Klein, R., Grimes, A., Murray, D., Brown, R., Krull, D., Benson, B., Kleymenova, E., Remlinger, K., Young, A., & Yao, X. (2010). Cholestyramine reverses hyperglycemia and enhances glucose-stimulated glucagon-like peptide 1 release in Zucker diabetic fatty rats. The Journal of Pharmacology and Experimental Therapeutics, 334, 164–170.
Clapham, J. C., Arch, J. R. S., Chapman, H., Haynes, A., Lister, C., Moore, G. B. T., Piercy, V., Carter, S. A., Lehner, I., Smith, S. A., Beeley, L. J., Godden, R. J., Herrity, N., Skehel, M., Changani, K. K., Hockings, P. D., Reid, D. G., Squires, S. M., Hatcher, J., Trail, B., Latcham, J., Rastan, S., Harper, A. J., Cadenas, S., Buckingham, J. A., Brand, M. D., & Abuin, A. (2000). Mice overexpressing human uncoupling protein-3 in skeletal muscle are hyperphagic and lean. Nature, 406, 415–418.
Coelho, W. S., Costa, K. C., & Sola-Penna, M. (2007). Serotonin stimulates mouse skeletal muscle 6-phosphofructo-1-kinase through tyrosine-phosphorylation of the enzyme altering its intracellular localization. Molecular Genetics and Metabolism, 92, 364–370.
Dickson-Humphries, T., Bottenberg, B., & Kuntz, S. (2013). Lipoprotein abnormalities in patients with type 2 diabetes and metabolic syndrome. JAAPA, 26, 12–18.
Diehl, A. M., & Hoek, J. B. (1999). Mitochondrial uncoupling: Role of uncoupling protein anion carriers and relationship to thermogenesis and weight control ‘the benefits of losing control. Journal of Bioenergetics and Biomembranes, 31, 493–506.
Farese, R. V., Sajan, M. P., & Standaert, M. L. (2005). Insulin sensitive protein kinases (atypical protein kinase C and protein kinase B/Akt): Actions and defeats in obesity and type II diabetes. Experimental Biology and Medicine (Maywood, N.J.), 230, 593–605.
Finkelstein, E. A., Khavjou, O. A., Thompson, H., Trogdon, J. G., Pan, L., Sherry, B., & Dietz, W. (2012). Obesity and severe journal of functional foods 10(2014)292-304 303, obesity forecasts through 2030. American Journal of Preventive Medicine, 42, 563–570.
Georgiadi, A., & Kersten, S. (2012). Mechanisms of gene regulation by fatty acids. Advances in Nutritional, 3, 127–134.
Harper, J. A., Dickinson, K., & Brand, M. D. (2001). Mitochondrial uncoupling as a target for drug development for the treatment of obesity. Obesity Reviews, 2, 255–265.
Holloway, G. P., Bonen, A., & Spriet, L. L. (2009). Regulation of skeletal muscle mitochondrial fatty acid metabolism in lean and obese individuals. The American Journal of Clinical Nutrition, 89, 455S–462S.
Holloway, G. P., Thrush, A. B., Heigenhauser, G. J. F., Tandon, N. N., Dyck, D. J., Bonen, A., & Spriet, L. L. (2006). Skeletal muscle mitochondrial FAT/CD36 content and palmitate oxidation are not decreased in obese women. American Journal of Physiology. Endocrinology and Metabolism, 292, E1782–E1789. Iacobellis, G., Barbarini, G., Letizia, C., & Barbaro, G. (2013).
Epicardial fat thickness and nonalcoholic fatty liver disease in obese subjects. Obesity (Silver Spring), 22, 332–336. Ibrahim, M. M. (2010). Subcutaneous and visceral adipose tissue: structural and functional differences. Obesity Reviews, 11, 11– 18.
Jiang, N., Zhang, G., Qu, J., Ma, G., Cao, D., Wen, L., Liu, S., Ji, L. L., & Zhang, Y. (2009). Upregulation of uncoupling protein-3 in skeletal muscle during exercise: A potential antioxidant function. Free Radical Biology and Medicine, 46, 138–145.
Karlic, H., Lohninger, S., Koeck, T., & Lohninger, A. (2002). Dietary l-carnitine stimulates carnitine acyltransferases in the liver of aged rats. The Journal of Histochemistry and Cytochemistry, 50, 205–212.
Klop, B., Elte, J. W., & Cabezas, M. C. (2013). Dyslipidemia in obesity: Mechanisms and potential targets. Nutrients, 5, 1218– 1240.
Koo, S. H. (2013). Nonalcoholic fatty liver disease: Molecular mechanisms for the hepatic steatosis. Clinical and Molecular Hepatology, 19, 201–215.
Korshunov, S. S., Skulachev, V. P., & Starkoc, A. A. (1997). High protonic potential actuates a mechanism of production of reactive oxygen species in mitochondria. FEBS Letters, 416, 15– 18.
Krauneoe, R., Boushel, R., Hansen, C. N., Schjerling, P., Qvortrup, K., Stockel, M., Mikines, K. J., & Dela, F. (2010). Mitochondrial respiration in subcutaneous and visceral adipose tissue from patients with morbid obesity. The Journal of Physiology, 588, 2023–2032.
Leong, P. K., Leung, H. Y., Wong, H. S., Chen, J., Ma, C. W., Yang, Y., & Ko, K. M. (2013). Long-term treatment with an herbal formula MCC reduces the weight gain in high fat diet-induced obese mice. Chinese Medicine, 4, 63–71.
Leto, D., & Saltiel, A. R. (2012). Regulation of glucose transport by insulin: Traffic control of GLUT4. Nature Reviews. Molecular Cell Biology, 13, 383–396.
Lettner, A., & Roden, M. (2008). Ectopic fat and insulin resistance. Current Diabetes Reports, 8, 181–191.
Leung, H. Y., & Ko, K. M. (2008). Herba Cistanche extract enhances mitochondrial ATP generation in rat hearts and H9c2 cells. Le Pharmacien Biologiste, 46, 418–424.
Li, B., Nolte, L. A., Ju, J., Han, D. H., Coleman, T., Holloszy, J. O., & Semenkovich, C. F. (2000). Skeletal muscle respiratory uncoupling prevents diet-induced obesity and insulin resistance in mice. Nature Medicine, 6, 1115–1120.
McTigue, K. M., Garrett, J. M., & Popkin, B. M. (2002). The natural history of the development of obesity in a cohort of young U.S. adults between 1981 and 1998. Annals of Internal Medicine, 136, 857–864.
Moore, M. C., Coate, K. C., Winnick, J. J., An, Z., & Cherrington, A. D. (2012). Regulation of hepatic glucose uptake and storage in vivo. Advances in Nutritional, 3, 286–294.
Nguyen-Duy, T. B., Nichaman, M. Z., Church, T. S., Blair, S. N., & Ross, R. (2003). Visceral fat and liver fat are independent predictors of metabolic risk factors in men. American Journal of Physiology. Endocrinology and Metabolism, 284, E1065–E1071.
Poulsen, L. I., Siersbak, M., & Mandrup, S. (2012). PPARs: Fatty acid sensors controlling metabolism. Seminars in Cell and Developmental Biology, 23, 631–639.
Ricquier, D., & Bouillaud, F. (2000). Mitochondrial uncoupling proteins: From mitochondria to the regulation of energy balance. The Journal of Physiology, 529, 3–10.
Rodriguez, A. M., & Palou, A. (2004). Uncoupling proteins: Gender dependence and their relation to body weight control. International Journal of Obesity (2005), 28, 500–502.
Rodriguez, A. M., Quevedo-Coli, S., Roca, P., & Palou, A. (2001). Sex-dependent dietary obesity, induction of UCPs, and leptin expression in rat adipose tissues. Obesity Research, 9, 579–588.
Ruderman, N. B., Carling, D., Prentki, M., & Cacicedo, J. M. (2013). AMPK, insulin resistance, and metabolic syndrome. The Journal of Clinical Investigation, 123, 2764–2772.
Shi, C., Wu, F., & Xu, J. (2013). The incorporation of β-sitosterol into mitochondrial membrane enhances mitochondrial function by promoting inner mitochondrial membrane fluidity. Journal of Bioenergetics and Biomembranes, 45, 301–305.
Shi, J., Finckenberg, P., Martonen, E., Ahlroos-Lehmus, A., Pilvi, T. K., Korpela, R., & Mervaala, E. M. (2012). Metabolic effects of lactoferrin during energy restriction and weight regain in diet-induced obese mice. Journal of Functional Foods, 4, 66–78.
Siddiqua, M., Hamid, K., Ar-Rashid, M. H., Akther, M. S., & Choudhuri, M. S. K. (2010). Changes in lipid profile of rat plasma after chronic administration of laghobanondo Rosh (LNR)—an ayurvedic formulation. Biology and Medicine, 2, 58– 63.
Snel, M., Jonker, J. T., Schoones, J., Lamb, H., de Roos, A., Pijl, H., Smit, J. W., Meinders, A. E., & Jazet, I. M. (2012). Ectopic fat and insulin resistance: Pathological and effect of diet and lifestyle interventions. International Journal of Endocrinology, 2012, Article ID 983814.
Wong, H. S., Chen, N., Leong, P. K., & Ko, K. M. (2013). Β-sitosterol enhances cellular glutathione redox cycling by reactive oxygen species generated from mitochondrial respiration: Protection against oxidant injury in H9c2 cells and rat hearts.
Phytotherapy Research, doi:10.1002/ptr.5087; published online. Wong, H. S., & Ko, K. M. (2013). Herba Cistanches stimulates cellular glutathione redox cycling by reactive oxygen species generated from mitochondrial respiration in H9c2 cardiomyocytes. Le Pharmacien Biologiste, 51, 63–73.
Wozniak, S. E., Gee, L. L., Wachtel, M. S., & Frezza, E. E. (2009). Adipose tissue: The new endocrine organ? A review article. Digestive Diseases and Sciences, 54, 1847–1856.
Yamato, M., Shiba, T., Ide, T., Seri, N., Kudo, W., Ando, M., Yamada, K., Kinugawa, S., & Tsutsui, H. (2012). High-fat diet-induced obesity and insulin resistance were ameliorated via enhanced fecal bile acid excretion in tumor necrosis factor-alpha receptor knockout mice. Molecular and Cellular Biochemistry, 359, 161–167.
Zhang, Y., Yu, Y., Li, X., Meguro, S., Hayashi, S., Katashima, M., Yasumasu, T., Wang, J., & Li, K. (2012). Effects of catechin enriched green tea beverage on visceral fat loss in adults with a high proportion of visceral fat: A double-blind, placebo-controlled, randomized trial. Journal of Functional Foods, 4, 315– 322.
