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Natural Yellows - For Obesity and Non-Alcoholic Liver Disease

Excess body weight is associated with many health concerns, and is rapidly  becoming the number one health problem worldwide. among the health risks are diabetes, cardiovascular disease, cancer and premature death. (1)  Individuals of the obese classification are especially subject to deleterious health implications. Obesity results in:

  • Visceral Fat. Excessive adipose tissue, especially dangerous visceral fat surrounding internal organs, and
  • Non-alcoholic fatty liver disease (NAFLD) is the most ubiquitous cause of liver disorder worldwide and is attributed to obesity and diabetes. NAFLD affects approximately 25% of the global population.(22). Insulin resistance is a major contributor to NAFLD. Ultimately, NAFLD may lead to liver cirrhosis and liver failure.

 

Visceral Fat - Obesity results in increases of visceral fat. Visceral fat (also known as belly fat) is the fat that accumulates around organs in the abdominal cavity and is linked to serious diseases, including type 2 diabetes. metabolic syndrome and those affecting organ functioning. Significant levels of inflammatory proteins are generated by visceral fat. In fact, inflammation of the liver which precedes HDLF, is mediated by visceral fat inflammatory proteins.(2)

  • Heart visceral fat - Accumulation of fat surrounding the heart may have profound effects on the myocardium and functioning of the heart. In obese lab animals, the heart visceral fat (white fat) increased inflammation of the heart, including hypertrophy of the cardiomyocytes and fibrosis. Further, these changes to the heart are significantly related to increased rates of heart failure.(3) Such changes were not seen in lean animals which had a significant amount of brown fat adjacent to the heart muscle.
  • Kidney visceral fat - Visceral fat deposits around the kidney are associated with both chronic kidney disease as well as cardiovascular disease.(4)
  • Pancreatic Visceral Fat - Increased levels of pancreatic fat coincide with pancreatic cancer and pre-cancer lesions.(5)

    Nonalcoholic fatty liver disease (NAFLD) - Obesity is a significant risk factor in the development of NAFLD.  Most noteworthy, is the excessive buildup of triglycerides in the liver which causes metabolic disturbances throughout the body. As a result, fatty acid metabolism becomes impaired, which may lead to fatty acid intermediates which causes insulin resistance and cardiovascular disease. 

    Adipose Tissue and Aging - White adipose tissue, associated with obesity,  is the most affected tissue in aging. As the adipose tissue ages, there is a significant increase in oxidative stress and the generation of  inflammatory proteins resulting in  chronic low grade inflammation. In turn, this further damages tissue and accelerates aging. (6) 

    • Telomere Shortening - Telomere shortening is a marker of aging. (7) Appears to be associated with obesity and increased insulin resistance.
    • Insulin Resistance - Insulin resistance prevents blood sugar from being removed from the blood. The result is hyperglycemia which damages structures in the body. Eventually this become diabetes.
    • Diminishes Immune Response - Increased inflammation from adipose tissue contributes to loss of innate immunity response during aging.(8)
    • Impairs Stem Cell Regenerative Ability - Adipose tissue stem cells are impacted by adipose tissue inflammation. The result is the senescence of the stem cells and loss of tissue repair and regeneration.(9).
    • Loss of Healthy Fat Cell (Stromal Cells) Renewal - Healthy adipose tissue requires renewal of adipose stromal cells. The stromal cells ensure the production of new healthy adipose cells. Obesity contributes to the loss of the stromal cells.(10)

    INGREDIENTS:

    • Berberine - Inhibits the inflammation of the liver associated NAFLD. Inflammation is a key event in the progression of NAFLD. (11) Also enhances brown adipose fat activity, which promotes thermogenesis, which dissipates harmful white adipose tissue,(12) Furthermore, berberine inhibits the proliferation of white fat adipocytes, thereby suppressing the formation of fat associated with obesity.(13) Berberine also reduces insulin resistance which improves glucose tolerance and NAFLD.(14).
    • Apigenin - Reduces abdominal visceral obesity and weight. Abdominal visceral fat promotes metabolic syndrome including inhibition of adipocytes  (fat cells). Does not affect subcutaneous fat, which lies just under the skin.(15) Apigenin also improves NAFLD and Insulin resistance.(16) 
    • Saffron - Improves insulin sensitivity,(16) Possesses a protective effect against NAFLD and fatty liver induced damage.(17)
    • Curcumin - Reduces insulin resistance by enhancing GLUT4 gene expression (the receptor for Glucose transport into the cell).(18)
    • Fisetin - Offers protection to suppress NAFLD initiation and progression.(19)
    • Rosmarinic Acid - Ameliorates liver damage by NAFLD, by increasing antioxidant enzymes and activating AMPK. inhibiting hepatic fibosis and inflammation of the liver.(20) Rosmarinic acid also acts as an anti-obesity agent by inhibiting adipogenesis (the formation of fat tissue), and increasing lipolysis (the breakdown of fat), Also reduced adipocyte associated inflammation.(21)
    • Pterostilbene -  Enhances brown adipose tissue activation. Increases thermogenesis and promotes browning of white adipose tissue,(23) Offers protective effect on liver steatosis.(24)
    • Ursolic Acid - Targets insulin resistance and mitigating the effects of liver fibrosis. (25,26) Obesity disrupts insulin signaling, thereby promoting insulin resistance. Furthermore, visceral fat in obesity sets off cascading generation of proinflammatory cytokines. Ursolic acid may improve these conditions. 

     

    YELLOW LONGEVITY® (Berberine | Apigenin | Saffron)

    VASCULAR VX™

     CURCUMIN PXC(Curcumin | Fisetin | Pterostilbene) 

     HYPER LONGEVITY™ (Ursolic Acid | Rosmarinic Acid)

     

    REFERENCES:

    (1)  Unamuno Xm et al. Adipokine dysregulation and adipose tissue inflammation in human obesity. Eur J Clin Invest. 2018 Sep

    (2)  Casagrande BP, et al. Hepatic inflammation precedes steatosis and is mediated by visceral fat accumulation.  J Endocrinol. 2020 Mar 1

    (3) Conceição G, et al. Fat Quality Matters: Distinct Proteomic Signatures Between Lean and Obese Cardiac Visceral Adipose Tissue Underlie its Differential Myocardial Impact. Cell Physiol Biochem. 2020 Apr 23

    (4) Huang N, et al. Novel insight into perirenal adipose tissue: A neglected adipose depot linking cardiovascular and chronic kidney disease. World J Diabetes, 2020 Apr 15

    (5) Sreedhar UL, et al. A Systematic Review of Intra-pancreatic Fat Deposition and Pancreatic Carcinogenesis. J Gastrointest Surg. 2019 Nov 20

    (6) Yu Q, et al. Sample multiplexing for targeted pathway proteomics in aging mice. Proc Natl Acad Sci USA. 2020 Apr 24

    (7) Mangge H, et al. Telomere shortening associates with elevated insulin and nuchal fat accumulation. Sci Rep. 2020 Apr 22

    (8) Goldberg EL, et al. How Inflammation Blunts Innate Immunity in Aging. Interdiscip Top Gerontol Geiatr.  2020

    (9) Conley SM, et al. Human Obesity Induces Dysfunction and Early Senescence in Adipose Tissue-Derived Mesenchymal Stromal/Stem Cells. Front Cell Dev Biol. 2020 Mar 26

    (10) Eckel-Mahan K, et al. Adipose Stromal Cell Expansion and Exhaustion: Mechanisms and Consequences. Cells 2020 Apr 2

    (11) Wang Y, et al. Berberine inhibits free fatty acid and LPS-induced inflammation via modulating ER stress response in macrophages and hepatocytes. PLoS One. 2020 May 1

    (12) Horvath C, et al. Feeding brown fat: dietary phytochemicals targeting non-shivering thermogenesis to control body weight. Proc Nutr Soc, 2020 Apr 

    (13) Wang C, et al. Berberine inhibits adipocyte differentiation, proliferation and adiposity through down-regulating galectin-3.

    (14) Yu SJ, et al. Berberine alleviates insulin resistance by reducing peripheral branched-chain amino acids.  Am J Physiol Endocrinol Metab. 2019 Jan

    (15) Su T, et al. Apigenin inhibits STAT3/CD36 signaling axis and reduces visceral obesity.  Pharmacol Res. 2020 Feb

    (16) Jung UJ, et al. Apigenin Ameliorates Dyslipidemia, Hepatic Steatosis and Insulin Resistance by Modulating Metabolic and Transcriptional Profiles in the Liver of High-Fat Diet-Induced Obese Mice.  Nutrients. 2016 May

    (16) Yaribeygi H, et al.  Antidiabetic potential of saffron and its active constituents. J Cell Physiol, 2019 Jun

    (17) Mashmoul M, et al. Protective effects of saffron extract and crocin supplementation on fatty liver tissue of high-fat diet-induced obese rats. BMC Complement Altern Med. 2016 Oct

    (18) Al-Saud NBS.  Impact of curcumin treatment on diabetic albino rats. Saudi J Biol Sci. 2020 Feb;27

    (19) Gaballah HH, et al, Mitigative effects of the bioactive flavonol fisetin on high-fat/high-sucrose induced nonalcoholic fatty liver disease in rats. 

    (20) Kim M, et al.  Lemon Balm and Its Constituent, Rosmarinic Acid, Alleviate Liver Damage in an Animal Model of Nonalcoholic Steatohepatitis. Nutrients. 2020 Apr 22

    (21) Rui Y, et al. Rosmarinic acid suppresses adipogenesis, lipolysis in 3T3-L1 adipocytes, lipopolysaccharide-stimulated tumor necrosis factor-α secretion in macrophages, and inflammatory mediators in 3T3-L1 adipocytes. Food Nutr Res. 2017 Jun

    (22) Younossi ZM, et al. Global epidemiology of nonalcoholic fatty liver disease-Meta-analytic assessment of prevalence, incidence, and outcomes. Hepatology, 2016 Jul;

    (23) Milton-Laskibar L, et al.  Effects of resveratrol and its  derivative pterostilbene on brown adipose tissue thermogenic activation and on white adipose tissue browning process. J Physiol Biochem. 2020 Mar 13

     (24) Gomez-Zorita S, et al. Effects of Pterostilbene on Diabetes, Liver Steatosis and Serum Lipids. Curr Med Chem. 2019 Oct 29

    (25) Gonzales-Garibay AS, et al,  Effect of Ursolic Acid on Insulin Resistance and Hyperinsulinemia in Rats with Diet-Induced Obesity: Role of Adipokines Expression.  J Med Food. 2020 Mar;23

    (26) 

    Brown Adipose Tissue - Obesity Benefits of Glucoraphanin and Pterostilbene

    Energy generation from brown adipose tissue (thermogenesis) is important for maintaining longevity, reducing obesity and supporting energy homeostasis. Brown adipose tissue (BAT) is central to physiological energy homeostasis. Enhancing brown adipose tissue reduces obesity, diabetes, insulin resistance and non-alcoholic fatty liver..

    BAT dissipates energy in the form of heat through increased theromgenesis.(1) Browning of white adipose tissue, which converts characteristics of white adipose tissue to brown adipose tissue, increases expression of the thermogenic mitochondrial protein UCP-1. The uncoupling protein 1 (UCP-1) is a potent protein which shifts energy from ATP to heat.

    Greater amounts of brown adipose tissue and the thermogenic capacity of the tissue are indicative of youth. With age, brown adipose tissue is decreased, while white adipose tissue becomes predominant and accelerates aging via inflammation and insulin resistance. .

    GLUCORAPHANIN - Is a precursor of sulforaphane. 
    In laboratory mice fed a high fat diet, glucoraphanin supplementation promoted increased energy expenditures via an increase in UCP-1 protein expression in adipose deposit areas. Furthermore, results included decreases in weight, increased insulin sensitivity and improved glucose tolerance.(2)

    PTEROSTILBENE - Studied in obese rats, pterostilbene increased the thermogenic capability of the BAT through an upregulation of Ucp1 protein expression..(3)

     

    XGEVITY (Glucoraphanin)

    PURPLE LONGEVITY (Pterostilbene)

     

    (1) Galmozzi A, et al. ThermoMouse: an in vivo model to identify modulators of UCP1 expression in brown adipose tissue. Cell Rep. 2014. Dec.

    (2) Nagata N, et al. Glucoraphanin Ameliorates Obesity and Insulin Resistance Through Adipose Tissue Browning and Reduction of Metabolic Endotoxemia in Mice. Diabetes. 2017 Feb 16.

    (3) Aguirre L, et al. Effects of pterostilbene in brown adipose tissue from obese rats. Physiol Biochem. 2017 Feb 27

    Short Chain Fatty Acids - Optimizing Metabolic Energy and Longevity

    How and to what extent microbes influence on health is a relatively new area of study. Amazingly,  the influence of gut microbiota on general health and longevity is only now becoming understood. Recent attention is scientific areas concern the importance of intestinal microbes and how they affect not only health of the the gut but also overall health of the body.(1) An area of keen interest is the production of Short Chain Fatty Acids (SCFAs) by microbial fermentation in the gut and how it can significantly improve health.(2)

    Short Chain Fatty Acids (SCFAs - acetic acid, propionic acid and butyric acid) are produced as a fermentation byproduct of soluble fiber (e.g nuts, seeds, certain vegetables) by microbes in the large intestine.

     

    Among the beneficial effects of SCFA's include:

    • IMPROVES HEALTH OF INTESTINES. SCFA's are used as nutrients by the cells in the intestine to improve intestinal health, reducing inflammation and improving  gut barrier dysfunction. Gut barrier dysfunction contributes to chronic low grade inflammation and metabolic endotoxaemia.
    • REDUCING INSULIN RESISTANCE - Insulin Resistance s a major factor in the development and disease progression in diabetes. Furthermore, insulin resistance is significant in aging, and loss of glucose homeostasis accelerates the aging process.(3)
    • IMPROVING TYPE 2 DIABETES METABOLIC CONTROL - SCFA's are now considered as key molecules in mitigating some of the effects of diabetes including reduction in serum levels of glucose, insulin resistance. Furthermore, SCFA's increase the production of Glucogen-like Peptide-1 (GLP-1)  which is protective against diabetic effects. (4)
    • OBESITY - Development of obesity is affected by decreased SCFA production by microbiota in the intestine. Increased gut permeability, inflammation and increased energy are significant contributors to obesity.

       

      THE ROLE OF TAURINE IN SHORT CHAIN FATTY ACID PRODUCTION.

      Furthermore, research indicates that taurine supplementation may significantly improve the intestinal microbiotic environment by increasing the production of SCFAs  and decreasing inflammatory concentrations of serum  lipopolysaccharides (LPS). LPS induced inflammation is a common issue facilitated by the processed western diet.(5)

       

      LONGEVITY NATURALLY (High Taurine Complex)

       

      REFERENCES:

      (1) Andoh A. Physiological Role of Gut Microbiota for Maintaining Human Health. Digestion. 2016 Feb 9

      (2) KeenanMJ, et al. Improving healthspan via changes in gut microbiota and fermentation. Age (Dordr). 2015 Oct.

      (3) Hartl FU. Cellular Homeostasis and Aging. Annu Rev Biochem. 2016 Apr 6.

      (4) Puddu A, et al. Evidence for the gut microbiota short-chain fatty acids as key pathophysiological molecules improving diabetes. Mediators Inflamm. 2014

      (5) Yu H, et al. Effects of taurine on gut microbiota and metabolism in mice. Amino Acids. 2016 Mar 30. 

      Most Powerful Predictor of Heart Disease and Diabetes - Triglycerides and HDL

      What is the most precise predictive measure of cardiovascular disease (and diabetes)? Common dogma continues to hold LDL ("bad" cholesterol) as the most accurate measure. However, recent studies research indicate a much stronger correlation between high triglyceride-to-HDL ratios in predicting both cardiovascular disease and the development of diabetes. In a study by the American Heart Association, individuals with the highest triglyceride-HDL ratios were 16x's more likely to suffer a cardiovascular event (i.e. heart attack) as compared to individuals with the lowest triglyceride-HDL ratios. The triglyceride-to-HDL ratio is significantly stronger in predicting cardiovascular events than "high cholesterol" numbers or LDL-to-HDL ratios.(1)


      HIGH TRIGLYCERIDES - the dangerous effect of high levels of triglycerides on the cardiovascular system is multi-faceted. Negative effects of high triglyceride levels:

      • Increases Insulin Resistance - Reduces the ability of the body to utilize glucose, increasing diabetes risk and accelerates cardiovascular disease.(2)
      • Lowers Levels of Healthy HDL. HDL helps keep the arteries clean by transporting cholesterol away from the arteries.
      • Increases Levels of Harmful Small Dense LDL. Small sized LDL (Low Density Lipoproteins), also known as VLDL (Very Low Density Lipoprotein, are the most dangerous, and are primarily responsible for arterial plaques, arteriosclerosis and increased risk of heart attacks.
      • Triglycerides (optimal levels 50-100 mg/dl) 
      • Triglycerides above 150 mg/dl can be a sign of diabetes and cardiovascular disease
      • HDL should be higher than 40 mg/dl

      TRIGLYCERIDE-to-HDL RATIO:

      • Targeted Ratio: An ideal ratio < 2:1 (for example - Triglycerides 90 / HDL 45)
      • Disease Ratio Risk: Anything > 3.5:1 increases risk for cardiovascular disease and diabetes.

          CITRUS BERGAMOT (Bergamonte®) POLYPHENOLS

          Bergamote® (an extract from Bergamot citrus in Italy), is called by some advocates as the ideal natural cardiovascular support supplement. Bergamonte decreases the triglyceride-to-HDL ratio by both decreasing plasma triglycerides and increasing HDL.(3)

          • Cardiovascular Benefits:
            • Significantly improves Triglyceride-HDL ratio by lowering triglycerides while increasing HDL
            • Significantly lowers harmful VLDL levels corresponding to reduced triglycerides
            • Attenuation of Cardiac Fibrosis. Bergamot polyphenols activate AMPK, an enzyme involved in cellular energy homeostasis and longevity.(4) Recent research indicates that increased AMPK activation may also play a role in attenuation of cardiac fibrosis and repair.(5) Cardiac fibrosis decreases the functional ability of the heart muscle and occurs with normal aging and disease.
            • Attenuation (and prevention) of Non-Alcoholic Fatty Liver Disease (NAFLD) - Bergamot improves lipid metabolism by the liver and significantly reduces lipid content. The resulting healthier liver metabolism REDUCES the high output of liver triglyercides into the blood stream by the liver - decreasing serum triglyceride levels. NAFL is the most common form of liver disease in western countries.(6)
            • AMPK activation represents an important method of lowering serum triglycerides produced by the liver.(7)

            Bergamonte® is a registered trademark of HP Ingredients

           

           VASCULAR STRENGTH  (with Bergamonte®)

           

          REFERENCES:

          (1) Turak O, et al. The Role of Plasma Triglyceride/High-Density Lipoprotein Cholesterol Ratio to Predict New Cardiovascular Events in Essential Hypertensive Patients.Journal of Clinical Hypertension. Jan 2016.

          (2) Bertsch RA, et al. Study of the use of lipid panels as a Marker of Insulin Resistance to Determine Cardiovascular Risk.  Perm J. 2015 Fall.

          (3) HP Ingredients Research. 2016

          (4) Proshkina EN, et al. Basic mechanisms of longevity: A case study of Drosophila pro-longevity genes. Ageing Res. Rev. 2015 Nov;

          (5) Daskaopoulos EP, et al. AMPK in cardiac fibrosis and repair. Actions beyond metabolic regulation. J Mol. Cell Cardiol. 2016 Jan.

          (6) Parafati M, et al. Bergamot polyphenol fraction prevents nonalcoholic fatty liver disease via stimulation of lipophagy in cafeteria diet-induced rat model of metabolic syndrome. J Nutr Biochem. 2015 Sept. 

          (7) Zang M, et al. Polyphenols stimulate AMP-activated protein kinase, lower lipids, and inhibit accelerated atherosclerosis in diabetic LDL receptor-deficient mice. Diabetes. 2006 Aug.