You may not have heard about cardiometabolic syndrome (CMS), but you have certainly heard about the various metabolic dysfunctions that characterize CMS. These include insulin resistance (poor ability to use the hormone insulin), impaired glucose tolerance, dyslipidemia (e.g. high cholesterol and triglycerides), hypertension and central adiposity. Now recognized as a disease by the World Health Organization and the American Society of Endocrinology, CMS sufferers are two times more likely to die from coronary heart disease and three times more likely to have a heart attack or stroke than those who do not have the syndrome—and, of course, central adiposity alone is a major contributor to increased cardiometabolic risk.1

Whether a person is dealing with full-blown CMS, or just one or more of its metabolic dysfunctions, the primary treatment strategy appropriately involves diet and exercise. That being said, there are nutraceuticals options that can also help. Perhaps the most valuable option for this purpose is bergamot polyphenol extract.

Bergamot

Known as “bergamot,” Citrus bergamia is a small citrus plant that grows spontaneously in the southern coast of the Calabria region of Italy (coincidentally the ancestral region for the Italian side of my family), where the juice of this fruit was traditionally recognized by the local population as a remedy for “fatty arteries” and heart problems. The medicinal use of bergamot derivatives, forgotten for decades, is now being rediscovered.2

Bergamot juice has a particularly high content and a unique composition of flavonoid polyphenols. Overwhelming scientific evidence indicates that these polyphenols are responsible for majority of bergamot’s pharmacological effects.3 These effects include benefits for cardiometabolic management, fatty liver disease (related to cardiometabolic disease), oxidation modulation and cognitive function.

Cardiometabolic Management

A review4 of the scientific literature has shown that flavonoid polyphenols, in particular citrus flavonoid polyphenols, present in bergamot fruits, influence lipid and sugar metabolism at the molecular level. Anti-diabetic and dyslipidemia-correcting effects of bergamot polyphenols may be explained by their ability to activate AMP kinase (AMPK), which is a central regulator of glucose and fatty acids metabolism and inhibit cAMP phosphodiesterases (PDE), involved in regulation of lipolysis (i.e. fat breakdown) in adipocytes (i.e. fat cells) and liver. Importantly, certain polyphenols can act as HMG-CoA reductase inhibitors, which mimic the action of statins in lowering cholesterol. Another review5 showed similar results, as well as antioxidant/radical scavenging activities.6

A randomized, double-blind, placebo-controlled study was conducted with 237 patients suffering from hyperlipemia. Patients enrolled into the study were divided into three groups: group A, 104 subjects with isolated hypercholesterolemia, HC; group B, 42 patients with hyperlipidemia (hypercholesterolemia and hypertryglyceridemia, HC/HT) and group C, 59 metabolic syndrome patients with mixed hyperlipidemia and glycemia (high blood sugar), HC/HT/HG. Each group was divided into three subgroups. The first received an oral dose of bergamot polyphenolic fraction (BPF) (500 mg/day; A1, B1 and C1), the second received 1,000 mg/day of BPF (A2, B2 and C2) and the third received placebo (APL, BPL, and CPL). The last group “D” or “post-statin” comprised 32 patients who stopped statin (simvastatin) therapy due to muscular pain and a significant elevation of serum creatine-phospho-kinase (CPK). Post-statin patients received 1,500 mg/day of BPF daily after a washout period of 60 days and were asked to observe a 1,600 kcal/day diet. The results were that treatment with BPF (500 and 1,000 mg daily) for 30 consecutive days in patients suffering from isolated HC, mixed hyperlipidemia and metabolic syndrome led to a strong reduction in total cholesterol, LDL-cholesterol and a significant increase in HDL cholesterol in majority of subjects. Placebo patients did not experience these same benefits. In the post-statin patients, this treatment proved to be very efficient, with the vast majority of patients responded experiencing an average -25 percent reduction in total cholesterol and −27.6 percent reduction in LDL cholesterol after 30 days, and without re-appearance of side effects.

Given its benefits for reducing cholesterol, the question has been posed regarding bergamot’s potential benefit for people who are already using statin medications. Could concurrent use reduce the amount of statin medication required? If so, this would be a positive outcome, especially considering that some patients experience statin-induced side effects. This was examined in prospective, open-label, parallel group, placebo-controlled study7 on 77 patients with elevated serum LDL-C and triglycerides, some of whom used the statin drug rosuvastatin (Crestor). Patients were randomly assigned to a control group receiving placebo (n=15), two groups receiving orally administered rosuvastatin (10 and 20 mg/daily for 30 days; n=16 for each group), a group receiving BPF alone orally (1,000 mg/daily for 30 days; n=15) and a group receiving BPF (1,000 mg/daily given orally) plus rosuvastatin (10 mg/daily for 30 days; n=15). The results were that both doses of rosuvastatin and BPF reduced total cholesterol, LDL-C, the LDL-C/HDL-C ratio in hyperlipidemic patients, compared to the placebo group. The cholesterol lowering effect was accompanied by reductions of various biomarkers of oxidative vascular damage. Researchers concluded that the addition of BPF to rosuvastatin significantly enhanced rosuvastatin-induced effect on serum lipemic profile compared to rosuvastatin alone. This lipid-lowering effect was associated with significant reductions of biomarkers used for detecting oxidative vascular damage, suggesting a multi-action enhanced potential for BPF in patients on statin therapy.

Nonalcoholic Fatty Liver Disease

Nonalcoholic fatty liver disease (NAFLD) is a term used to describe a range of liver conditions that are not caused by alcohol consumption. The main characteristic of NAFLD is too much fat stored in liver cells. NAFLD is common around the world, especially in Western nations. In the United States, it is the most common form of chronic liver disease, affecting an estimated 80 to 100 million people. Although it occurs in every age group, NAFLD is especially common in people in their 40s and 50s who are at high risk of heart disease because of such risk factors as obesity and type 2 diabetes. NAFLD is also closely linked to metabolic syndrome, which is a cluster of abnormalities including increased abdominal fat, poor ability to use the hormone insulin, high blood pressure and high blood levels of triglycerides.

Experimental and epidemiological evidence suggests that dietary polyphenols may prevent NAFLD. To investigate this, a study8 was conducted in which BPF was fed to rats who received a diet likely to cause NAFLD. The results were that BPF effectively counteracted the pathogenic increase of serum triglycerides and had also had moderate effects on blood glucose and obesity in this animal model. Significantly, BPF strongly reduced fatty accumulation in the liver as documented by a significant decrease in total lipid content (-41.3 percent), ultrasound examination and histological analysis of liver sections. This study demonstrates that the liver and its lipid metabolism are main targets of bergamot flavonoid polyphenols, supporting the concept that supplementation of BPF is an effective strategy to prevent NAFLD.

Now, while the results of the rat study were impressive, human research is more relevant. Recent evidence9 shows that BPF supplementation in patients with metabolic syndrome and NAFLD induces a significant reduction of fasting plasma glucose, serum LDL cholesterol and triglycerides alongside with an increase of HDL cholesterol. In addition, a significant reduction of both ultrasonographic, TC scans and metabolic biomarkers of NAFLD as well as a significant reduction of small dense LDL particles were found after BPF treatment suggesting a beneficial effect.

An example of a relevant study10 is one in which the effect of BPF was examined in 107 patients with metabolic syndrome and NAFLD. Patients were divided into two groups: one receiving placebo and the second receiving BPF 650 mg twice a day for 120 consecutive days. In the group receiving BPF, a significant reduction of fasting plasma glucose, serum LDL cholesterol and with an increase of HDL cholesterol was found. This effect was accompanied by significant reduction of both ultrasonographic and metabolic biomarkers of NAFLD. Moreover, a significant reduction of small dense LDL particles, as detected via proton NMR Spectroscopy, was found after BPF treatment. This data confirmed the beneficial effect of bergamot-extract in patients with metabolic syndrome, an effect highlighted by significant reduction of small dense LDL particles and by improvement of NAFLD biomarkers. This suggests a potential preventive role of bergamot derivatives in reducing cardiometabolic risk.

Oxidation Modulation

Another modern lifestyle issue is oxidative stress caused by free radicals. In fact, oxidant/antioxidant imbalance has been reported to trigger cell damage that in turn contributes to a number of diseases. A study11 was conducted to evaluate the effect of the flavonoid polyphenol fraction of bergamot juice, on H2O2-induced oxidative stress in human lung epithelial cells. Researchers tested the antioxidant properties of the extract in cell-free experimental models and then we assayed their capability to prevent the cytotoxic effects induced by H2O2. The results demonstrated that both citrus juice extracts reduced the generation of reactive oxygen species and membrane lipid peroxidation, improved mitochondrial functionality, and prevented DNA-oxidative damage in lung cells. The data indicate that the mix of flavonoids present in bergamot juices may be of use in preventing oxidative cell injury.

Cognitive Function

Given bergamot’s positive effects in cardiometabolic parameters and as an antioxidant, it’s not surprising that these improvements could offer a novel treatment strategy for cognitive dysfunctions. Consequently, an eight-week study12 was conducted to explore the efficacy of BPF supplementation on cognitive/executive functioning in a sample of patients with schizophrenia receiving second-generation antipsychotics. Twenty outpatients treated with second-generation antipsychotics assumed BPF at an oral daily dose of 1,000 mg/day. Brief Psychiatric Rating Scale, Wisconsin Card Sorting Test (WCST), Verbal Fluency Task-Controlled Oral Word Association Test, and Stroop Color-Word Test were administered. The results were that BPF supplementation significantly improved WCST "perseverative errors" (P = 0.004) and semantic fluency test (P = 0.004). Moreover, a trend for other cognitive variable (WCST "categories," phonemic fluency and Stroop Color-Word Test) improvement was observed. The findings provide evidence that BPF administration may be proposed as a potential supplementation strategy to improve cognitive outcome in schizophrenia.

Promoting Weight Loss

There are two hormones and one hormone-like protein with primary responsibility for helping to control body weight. These are leptin, ghrelin and adiponectin.

Leptin

Leptin is a hormone that is produced by the body's fat cells. It is often referred to as the "satiety hormone" or the "starvation hormone." Its main role is regulating how many calories we eat and burn, as well as how much fat we carry on our bodies. It is now believed that leptin resistance may be the main biological abnormality in obesity. People who are obese have a lot of body fat in their fat cells, and very high levels of leptin. However, the problem with people with leptin resistance is that the leptin signal isn't working, and it erroneously thinks that the body is starving, even though it has more than enough energy stored.

This tricks us to eat more and reduce energy expenditure:

• Eating more—The brain thinks that we must eat so that we don't starve to death.

• Reduced energy expenditure—The brain thinks we need to conserve energy, so it makes us feel lazier and makes us burn fewer calories at rest.

• For the great majority of people, trying to exert willpower over the leptin-driven starvation signal is next to impossible.

So what causes leptin resistance? There are three factors. First, inflammatory signaling in the hypothalamus is likely an important cause of leptin resistance in both animals and humans. Second, having elevated free fatty acids in the bloodstream may increase fat metabolites in the brain and interfere with leptin signaling. Third, having elevated levels of leptin in the first place seems to cause leptin resistance.

Ghrelin

Ghrelin, the "hunger hormone," plays a key role in weight gain because it signals your brain to eat. Its levels increase during a diet and intensify hunger, making it hard to lose weight. Ghrelin is produced in the gut, and travels through the bloodstream and to the brain, where it tells the brain to become hungry and seek out food. Ghrelin's main function is to increase appetite. It makes you consume more food, take in more calories and store fat. The higher your ghrelin levels, the hungrier your get. The lower your levels, the fuller you feel and the easier it is to eat fewer calories. So, if you want to lose weight, lowering your ghrelin levels can be beneficial.

Adiponectin

Adiponectin is a protein secreted from adipose tissue. Plasma levels of adiponectin are especially low in individuals with visceral obesity and are associated with raised levels of several different markers of inflammation. Adiponectin is protective and appears to reduce inflammation. Several clinical studies have shown that low production of adiponectin correlates with the development of insulin resistance and type 2 diabetes. Thus, in theory, increasing the availability of adiponectin might help reverse insulin resistance and thereby decrease the risk of diabetes. NAFLD is common among people with obesity. Low adiponectin levels also correlate with the severity of fat accumulation in the liver. Obese people have lower blood levels of adiponectin than normal weight individuals. Furthermore, reduction of obesity increases adiponectin levels.

Effect of Bergamonte BPE-Complex

There is research on a new Bergamonte BPE-Complex by HP Ingredients. This full-spectrum bergamot extract mimics the characteristics of the original fruit, providing >38 percent bergamot flavonoids actives, comprised of neoeriocitrin, naringin, neohesperidin, melitidin and bruteridin. The clinical research showed that this bergamonte extract had meaningful effects on leptin, ghrelin and adiponectin. Specifically, after 120 days it:

• Reduced leptin by 12 percent (650 mg) and 21.36 percent (1,300 mg)

• Reduced ghrelin by 6.89 percent (650 mg) and 14.90 percent (1,300 mg)

• Increased adiponectin by 18.65 percent (650 mg) and 21.76 percent (1,300 mg)

This was accompanied by a reduction of body weight by -10.04 percent (650 mg) and -14.91 percent (1,300 mg), as well as reduction of BMI by -10.12 percent (650 mg) and -15.85 percent (1,300 mg) respectively.

Conclusion

Cardiometabolic syndrome and its various metabolic dysfunctions are prevalent in modern society, and substantially increase the likelihood of dying from coronary heart disease and having a heart attack or stroke. Likewise, NAFLD is frequently associated with this disorder. Research indicates that bergamot polyphenol extract (Bergamonte) provides a range of benefits for cardiometabolic management, fatty liver disease, oxidation modulation, cognitive function and weight control. VR

References:

1 Saljoughian M. Cardiometabolic Syndrome: A Global Health Issue. U.S. Pharmacist. February 16, 2017. Retrieved November 28, 2018 from www.uspharmacist.com/article/cardiometabolic-syndrome-a-global-health-issue.

2 Walker R, Janda E, Mollace V. Chapter 84: The Use of Bergamot-derived Polyphenol Fraction in Cardiometabolic Risk Prevention and its Possible Mechanisms of Action. In Watson RR, Preedy VR, Zibadi S. Polyphenols in Human Health and Disease. Volume 2. 2014:1087-110.

3 Jandaa E, Lascalaa A, Martinoa C, Ragusab S, Nuceraa S, Walkera R, Gratteria S, Mollacea V. Molecular mechanisms of lipid- and glucose-lowering activities of bergamot flavonoids. PharmaNutrition. 2016; 4S:S8–S18.

4 Jandaa E, Lascalaa A, Martinoa C, Ragusab S, Nuceraa S, Walkera R, Gratteria S, Mollacea V. Molecular mechanisms of lipid- and glucose-lowering activities of bergamot flavonoids. PharmaNutrition. 2016; 4S:S8–S18.

5 Cappello AR, Dolce V, Iacopetta D, Martello M, Fiorillo M, Curcio R, Muto L, Dhanyalayam D. Bergamot (Citrus bergamia Risso) Flavonoids and Their Potential Benefits in Human Hyperlipidemia and Atherosclerosis: an Overview. Mini Rev Med Chem. 2016;16(8):619-29.

6 Mollace V, Sacco I, Janda E, Malara C, Ventrice D, Colica C, Visalli V, Muscoli S, Ragusa S, Muscoli C, Rotiroti D, Romeo F. Hypolipemic and hypoglycaemic activity of bergamot polyphenols: from animal models to human studies. Fitoterapia. 2011 Apr;82(3):309-16.

7 Gliozzi M, Walker R, Muscoli S, Vitale C, Gratteri S, Carresi C, Musolino V, Russo V, Janda E, Ragusa S, Aloe A, Palma E, Muscoli C, Romeo F, Mollace V. Bergamot polyphenolic fraction enhances rosuvastatin-induced effect on LDL-cholesterol, LOX-1 expression and protein kinase B phosphorylation in patients with hyperlipidemia. Int J Cardiol. 2013 Dec 10;170(2):140-5.

8 Parafati M, Lascala A, Morittu VM, Trimboli F, Rizzuto A, Brunelli E, Coscarelli F, Costa 2, Britti D, Ehrlich J, Isidoro C, Mollace V, Janda E. 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 Sep;26(9):938-48.

9 Gliozzi M, Maiuolo J, Oppedisano F, Mollace V. The effect of bergamot polyphenolic fraction in patients with non alcoholic liver steato-hepatitis and metabolic syndrome. PharmaNutrition. October 2016;4 Suppl:S27-S31.

10 Gliozzi M, Carresi C, Musolino V, Palma E, et al. The Effect of Bergamot-Derived Polyphenolic Fraction on LDL Small Dense Particles and Non Alcoholic Fatty Liver Disease in Patients with Metabolic Syndrome. Advances in Biological Chemistry. 2014;4:129-37.

11 Ferlazzo N, Visalli G, Smeriglio A, Cirmi S, Lombardo GE, Campiglia P, Di Pietro A, Navarra M. Flavonoid Fraction of Orange and Bergamot Juices Protect Human Lung Epithelial Cells from Hydrogen Peroxide-Induced Oxidative Stress. Evidence-Based Complementary and Alternative Medicine. 2015;2015:ID 957031, 14 pages.

12 Bruno A, Pandolfo G, Crucitti M, Cedro C, Zoccali RA, Muscatello MRA. Bergamot Polyphenolic Fraction Supplementation Improves Cognitive Functioning in Schizophrenia: Data From an eight-Week, Open-Label Pilot Study. J Clin Psychopharmacol. 2017 Aug;37(4):468-471.

Gene Bruno, MS, MHS, the dean of academics for Huntington College of Health Sciences, is a nutritionist, herbalist, writer and educator. For more than 30 years he has educated and trained natural product retailers and health care professionals, has researched and formulated natural products for dozens of dietary supplement companies, and has written articles on nutrition, herbal medicine, nutraceuticals and integrative health issues for trade, consumer magazines and peer-reviewed publications. He can be reached at gbruno@hchs.edu.