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[Weight Management] Vol. 16 No. 9 September 2011

Ingredients for Improved Weight Management

By Steve Myers, Senior Editor

Top Weight Management Approaches

 Influencing hormones can prompt satiety and decrease overall intake.  Increasing metabolic rate contributes to burning , a process called thermogenesis.  Blocking fat and carbs can decrease absorption and subsequent storage, body fat deposits.

The research on natural weight management ingredients continues to be a hot area. However, unlike in decades past, the focus isn’t just on simple weight-loss but on controlling appetite, boosting satiety, burning fat, blocking fat and carbs, and swapping fat mass for lean muscle mass.

Satiety, the feeling of fullness after a satisfying , is regulated by several hormones including . Produced in adipose tissue, leptin helps control appetite and energy intake by targeting receptors in the hypothalamus region of the brain. In short, it tells the brain when the stomach is full, resulting in feelings of satiety.

Niacin-bound formulated with Gymnema sylvestre and Garcinia cambogia, which contains hydroxycitric acid (HCA), appears to target leptin. In a Georgetown University Medical Center, Washington, study, obese adults received either 2,800 mg/d of HCA (as Super CitriMax®, from InterHealth); 4,667 mg of combined HCA, -bound chromium (as ChromeMate®, also from InterHealth) and G. sylvestre extract; or placebo.1 The researchers reported HCA reduced body weight and body mass index (BMI), suppressed appetite and increased serum leptin; the combination supplement had an even greater effect, compared to placebo.

Additional results on leptin-related peptides were published in 2011, when researchers investigated a synergistic formulation (Merastin™, from InterHealth and Laila) of the extracts of Sphaeranthus indicus and Garcinia mangostana on several weight management factors in human subjects.2 They reported significant net reductions in body weight, BMI, and waist and hip circumferences in the Merastin-supplemented group versus placebo. Those taking Merastin also had reduced blood , triglycerides, glucose and low-density lipoprotein (LDL)/high-density lipoprotein (HDL) ratio, and an increase in fat metabolites. Further, the intervention modulated serum adipokines such as adiponectin and plasminogen activator inhibitor-1 (PAI-1) levels, more significantly than did placebo—adiponectin is complementary and similar to leptin in the way it interacts with the brain in weight reduction; PAI-1 is increased in and metabolic syndrome.

Another hunger hormone is ghrelin, which is manufactured in the stomach. Ghrelin levels are high when hungry, such as before a meal, but they fall after a filling meal. Like leptin, it also signals the hypothalamus region of the brain; lack of sleep can negatively affect ghrelin levels and activity. The hunger management system also features several peptides. Cholecystokinin (CCK) aids in the digestion of and in the small intestine; it binds to CCK receptors in the central nervous system (CNS), where it influences anxiety and nausea, as well as satiety and hunger. Glucagon-like peptide-1 (GLP-1) and peptide YY (PYY) each provide signaling support in promoting fullness in both the brain and stomach. www.naturalproductsinsider.com Page 1

[Weight Management] Vol. 16 No. 9 September 2011

A good deal of satiety research including ghrelin and supporting peptides has featured proteins, fats and fibers. Based on Dutch research, a high-protein breakfast may decrease postprandial ghrelin levels more than a high-carb breakfast does.3 According to Purdue scientists, morning is the ideal time for this high-protein meal, as their research showed such a meal at breakfast more 4 significantly influenced satiety than did eating such a meal at other times during the day.

The type of protein consumed is also a factor in satiety promotion. A pair of Dutch trials found a high- meal (25-percent protein) led to 33-percent higher satiety than a low-casein meal (10-percent protein),5 and a high-soy meal (25-percent protein) was more satiating than a low-soy meal (10- percent), based on measurements of various hunger hormones, insulin and the .6 University of Toronto research found postprandial ghrelin, GLP-1, insulin and CCK may play a role in protein satiety.7 Overweight men taking preloads of casein, , lactose or glucose experienced a 71-percent higher CCK plasma concentration at 90 minutes after the protein preloads, compared with control preloads. The hormone increases were linked to subsequent increases in satiety and reduced appetite among the high-protein subjects.

A protein extract from potatoes (as Slendesta™, from Kemin ) has demonstrated an effect on hunger via the CCK mechanism. Proprietary studies conducted at Iowa State University revealed the proteinase inhibitor II (PI2) found in Slendesta promotes satiety and . In one study, participants taking Slendesta before a meal experienced significantly greater fullness and a decreased appetite compared to those taking a control supplement; CCK levels rose and remained elevated for a longer period of time post meal in those taking Slendesta. In the other study, supplementation with either 300 mg/d or 600 mg/d of Slendesta (providing 15 mg or 30 mg PI2, respectively) for 12 weeks resulted in statistically significant reductions in weight, and waist and hip measurements.

As with protein, various types of fibers have shown an impact on satiety and ghrelin. A -based trial involving tube-fed patients found consumption of a formula containing 10 g/L of pea fiber and 5 g/L of fructo-oligosaccharide (FOS) insoluble fiber resulted in higher mean fullness, minimum fullness and minimum satiety, compared to the standard enteral formula.8 In a trial involving healthy adults taking 21 g/d FOS for 12 weeks, researchers noted supplementation not only reduced body weight, but had a positive effect on glucose, ghrelin and PYY levels, resulting in reduced calorie intake.9

A 2011 review reported gut microflora health affects obesity by supporting fermentation of indigestible carbohydrates to short-chain fatty acids (SCFAs) that provide excess energy to the body.10 They said alteration in the ratio of bacteroidetes and firmicutes can change fermentation patterns that could explain weight gain.

A novel chitin-glucan fiber ingredient (as ARTINIA™, from Stratum ) promoted the growth of beneficial , and suppressed weight gain and inhibited fat deposits in a Belgium animal study.11 Obese mice on a high-fat supplemented with ARTINIA experienced significantly decreased high-fat-induced body weight gain and fat mass development. Researchers noted unlike prebiotics that more specifically target the Bifidobacteria species, ARTINIA's effect was independent of GLP-1 production, because expression of portal GLP-1 and its precursor proglucagon was not modified by the supplementation. www.naturalproductsinsider.com Page 2

[Weight Management] Vol. 16 No. 9 September 2011

Fats and fatty acids can address hunger, appetite and weight management through both hormonal and mechanical methods. The long-chain fatty acids in Korean pine nut oil, namely pinolenic acid, impact appetite via hormone regulation. Proprietary research found 3 g/d of pinolenic acid (as PinnoThin™, from Stepan Specialty Products) controlled hunger by stimulating the release of the hormones CCK and GLP1. A 2006 study showed capsules with 3 g PinnoThin given in conjunction with a light breakfast to overweight women (BMI=25 to 30) induced CCK after 30 minutes and GLP1 after 60 minutes, relative to placebo.12

Fats can employ a method called “ileal brake” to curtail digestion of in the small intestines (ileum); this process also triggers a satiety response. The ileal brake was the central mechanism in a series of unpublished trials on a patent-protected combination of oat and palm oils (as Olibra®, now Fabuless™, from DSM Food Specialties). Two University of Ulster, Ireland, studies showed 200 g of yogurt (5 g Fabuless and 1 g milk fat), given to men in one trial and women in the other, significantly lowered mean energy intakes after the test yogurt, compared to controls. Similar reductions were noted for fat, protein and carbohydrate intakes in both of the studies. In other Ulster research, 200 g of yogurt containing Fabuless was effective on satiety in obese men and women.13 And a Dutch trial found Fabuless reduced appetite in overweight women (aged 18 to 55), limiting weight re-gain after six weeks of weight loss and 18 weeks of Fabuless supplementation.14 Compared to placebo, the women taking Fabluess also reported a steady BMI and decreased appetite.

A 2010 research report from Uppsala University, Sweden, detailed how Fabuless given to healthy- weight subjects just about doubled total lipids, mainly as free fatty acids, compared to controls; also, higher amounts of lipids in the middle section of the small intestine and the presence of crystals influenced appetite via the ileal brake mechanism.15 The researchers confirmed Fabuless enhanced the satiety messaging between the gut and the brain.

A 2011 study on oil (as Superba™, from Aker Biomarine) found the ingredient normalized the endocannabinoid system, which is dysregulated in obesity.16 Researchers noted feeding a high-fat diet to mice, compared to animals given a low-fat diet, resulted in an elevation of endocannabinoids (EC), lipid messengers that can activate specific receptors; this influenced not only enzyme activities, but also appetite, energy balance, mood, memory and pain perception, indicating the EC system contributes to visceral fat accumulation. Subsequently, eight weeks of Superba supplementation reduced EC levels in several different tissues, and helped lower triglycerides, cholesterol and a marker of inflammation.

Several botanicals have shown potential in appetite control. In a study from St. John's National Academy of Health Sciences, Bangalore, India, adult men and women, aged 25 to 60 years with a BMI greater than 25, took either 1 g/d of Caralluma fimbriata (as Slimaluma, from Gencor Pacific) or placebo for 60 days.17 Results showed waist circumference and hunger levels declined in the Slimaluma group compared to placebo; researchers noted glycosides in C. fimbriata likely inhibited the hunger sensory mechanism of the hypothalamus. In 2010, researchers using a diet-induced obesity animal model found 90 days of Slimaluma supplementation in rats fed a cafeteria diet produced significant and dose-dependent inhibition of food intake, with dose-related prevention of gains in body weight, weight and fat pad mass.18 Then in 2011, a study found treating mouse pre-adipocyte cell line samples with Slimaluma resulted in inhibition of pre-adipocyte cell division, indicating Slimaluma has the potential to inhibit hyperplastic obesity.19 www.naturalproductsinsider.com Page 3

[Weight Management] Vol. 16 No. 9 September 2011

French researchers reported an eight-week study in mildly overweight women showed consumption of a novel extract of saffron stigma (as Satiereal®, from P.L. Thomas) produces a reduction of snacking and creates a satiating effect that could contribute to body weight loss.20

Similarly, University of Kansas researchers reported in 2005 oral ingestion of an extract of Coleus forskohlii (as ForsLean®, from Sabinsa) for a 12-week period favorably altered body composition while increasing bone mass and serum free testosterone levels in overweight and obese men.21 Then in 2008, an unpublished study found Sabinsa’s LeanGard®—a blend of ForsLean, G. cambogia (as Garcitrin®) and black pepper/peperine extract (as Bioperine®)—taken by overweight adults enhanced overall weight loss and reductions in body fat, in addition to supporting increased in .

Chili peppers contain capsaicin, which has been studied for hunger management. Dutch researchers found feeding a capsaicin or capsaicin-free lunch to subjects with a BMI between 25 and 27 (aged 17 to 45) did not appear to affect overall satiety, but did impact hunger hormones in certain incidences.22 A combination of capsaicin and reduced energy intake in a University of Copenhagen, Denmark, study, which reported the formula suppressed hunger and increased satiety more during negative energy balance than during positive energy balance.23

Capsaicin blends appear to not just impact satiety. A proprietary randomized, double blind, placebo- controlled study found a vegetarian beadlet formula (as Capsimax™ Plus Blend, from OmniActive Health Technologies)—containing capsicum extract, Bioperine, niacin ( B3) and — helped male and female subjects (age 10 to 30) burn three times more calories before, 3-percent more calories during and 12-times more calories for up to an hour after exercise, compared to when they took a placebo.

This method of burning calories is the hallmark of a group of ingredients dubbed thermogenics. In thermogenesis, heat is produced as a by-product of metabolism in each cell, such as when fat is oxidized as part of metabolism. Resting metabolic rate (RMR), which is crucial to basic life and survival, is important to heat production, but can wax and wane with age, body composition and activity level. In thermogenic research, the focus is on RMR, energy expenditure (EE) and burning calories into heat versus storing them in the body.

In research results presented at the XI International Congress on Obesity in July 2010, Stockholm, a single consumption of capsaicin at the right dose is enough to increase EE, especially in people with a higher amount of brown adipose tissue (BAT)—the best for burning calories. A 2010 study reported rats fed high-fat diets with capsaicin lost 8 percent of their body weight and showed changes in the levels of at least 20 key fat-based proteins that help break down fats.24

Green tea has shown weight-management benefits independent of the effects of caffeine. While caffeine affects uncoupling proteins (UCPs) necessary for BAT thermogenesis, increases consumption in BAT mitochondria and raises RMR, Swiss researchers have suggested an interaction between the tea’s (, or EGCG) and caffeine in the body may be the mechanism behind its strong effect on fat burning.25 In a study on energy output in healthy men, green tea extract (50 mg caffeine and 90 mg EGCG) had significant effects on fat oxidation and energy expenditure in the intervention group, while those taking just caffeine (50 mg) showed no increase in EE.26 In a Danish study, green tea reduced body mass and increased www.naturalproductsinsider.com Page 4

[Weight Management] Vol. 16 No. 9 September 2011 thermogenesis in obese subjects who underwent a hypocaloric diet for four weeks before eight weeks of supplementation with a combination of green tea extract ( and caffeine), capsaicin, and .27

PhosphoLean®, from Chemi Nutra, combines the thermogenic EGCG with n-oleyl-phosphatidyl- ethanolamine (NOPE), which contains that bind to intestinal receptors that signal reduced appetite. An new unpublished, double blind study showed taking PhosphoLean 30 minutes before helped patients stick to a low-calorie diet (to induce hunger) and an escalating exercise program.

Another thermogenic ingredient with a growing body of supporting research is 3-acetyl-7-oxo- , known as 7-oxo-DHEA. A natural substance produced by the adrenal glands, 7-oxo DHEA affects the activity of three thermogenic enzymes: glycerol-3-phosphate dehydrogenase, malic enzyme and fatty acyl CoA oxidase, leading to increased heat production and utilization of fat stores for energy.28,29 Research has shown adults taking 7-oxo-DHEA (as 7-Keto®, from Humanetics) experienced as much as three-times more weight and body fat loss than subjects taking placebo.30,31 Supplementation increased RMR in subjects on a calorie-restricted diet (which normally decreases RMR). In addition, randomized, double blind, placebo-controlled research showed 7-Keto supplementation increased RMR (1.4 percent) in overweight subjects who adhered to a calorie-restricted diet and a washout period before the seven-day intervention.32

Thermogenesis by Citrus aurantium is due to stimulating the metabolism that enhances amino acid uptake by muscle tissue and increases lipolysis (the process of breaking down fats into fatty acids). Canadian researchers found C. aurantium (as Advantra Z®, from Nutratech Inc.) given as a meal supplement increased the thermogenic benefit of the food, without adversely affecting blood pressure.33 A University of California, San Francisco, study found a multiple-ingredient formula containing 5.5 mg of the C. aurantium active did raise blood pressure, but C. aurantium alone (containing the much higher dose of 49.6 mg synephrine) did not adversely affect either systolic or diastolic measurements.34

Further, a 2011 FDA study on potential birth defects concluded administration of CA and its constituent synephrine-p in rats was not linked to fetal or maternal toxicity.

Then, in 2011, Phytotherapy Research published a definitive review of C. aurantium safety by a multi- academic panel of experts, who drew from 89 studies and other reference sources.35 They concluded, “The use of extract and p-synephrine appears to be exceedingly safe with no serious adverse effects being directly attributable to these ingredients.” Yet another 2011 research publication concluded ingestion of a weight-management supplement containing Advantra Z, caffeine and green tea extract does not to increased cardiovascular stress.36

While many thermogenics concentrate on BAT, a carotenoid from brown algae appears to stimulate white adipose tissue (WAT), which is more prevalent in adults. This carotenoid, fucoxanthin, may promote UCP-1 expression in WAT, increasing fat oxidation and mitochondrial energy production, according to one review.37 Another trial noted adding medium-chain triacylglycerols (MCTs) to fucoxanthin supplementation appears to boost the UCP-1 expression and fat loss, at least in animals researched, and adding to fucoxanthin produced similar results.38,39 www.naturalproductsinsider.com Page 5

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Brown seaweed also may boost weight management. An unpublished monocentric, randomized, placebo-controlled, parallel double blind clinical study on a brown seaweed extract (as ID-alG™, from Bio Serae Laboratories) supplementation, showed 60 overweight women given either 400 mg/d of ID- alG or placebo for two months experienced improved caloric intake control and reduced fat storage. A proprietary blend of fucoxanthin-rich brown seaweed extract and oil (as Xanthigen, from P.L. Thomas) reduced body and liver fat content, and improved liver function tests in obese, non-diabetic women.40 The 2010 double blind, randomized, placebo-controlled study conducted by the Russian Academy of Natural Sciences, Moscow, looked at food intake, body composition, resting energy expenditure (REE) and several blood parameters weekly for 16 weeks in 151 non-diabetic, obese premenopausal women with liver fat content either above 11 percent (NAFLD, n = 113) or below 6.5 percent (NLF, n = 38). In addition to improvements in body and liver fat and function, Xanthigen increased REE.

Brown seaweed appears to be multifaceted in weight management. A blend of phlorotannins (PHT) from the brown seaweeds Ascophyllum nodosum and Fucus vesiculosus (as InSea2™, from innoVactiv) has shown promise in inhibiting α-amylase and α-glucosidase enzymes (carb processors) in vitro, as well as blocking table sugar digestion in vivo, according to an unpublished trial. A 2010 Laval University, Quebec, human clinical study confirmed the ability of inSea2 to block carbs/starch, resulting in reduced blood glucose levels and improved insulin response following a high-starch meal.41

An extract of white bean (Phaseolus vulgaris) also slows the absorption of starches. A 2010 study involving subjects who took P. vulgaris (as Phase 2 Carb Controller™, from Pharmachem Labs) for 60 days resulted in significantly reduced body weight and waist size after one month of supplementation compared to placebo.42 The supplement group also had reduced BMI results, with a more pronounced effect in the first month of the trial than in the second month. The researchers suggested Phase 2 might interfere with the digestion of complex carbohydrate to simple, absorbable sugars, potentially reducing carbohydrate-derived calories.

Phase 2 is one component of a three-phase weight management line, which also includes Phase 1 Hunger Controller, which contains the vegetable-based fat ingredient Olibra, and Phase 3 Sugar Controller designed for blood glucose support.

Dietary fat is a similar target. Conjugated (CLA) reduces new fat deposits and supports new lean muscle development by inhibiting a lipase enzyme that ordinarily breaks down dietary fat for storage in the body. A Norwegian trial in healthy adults who exercised regularly and took either Tonalin® CLA (from BASF) (0.6 mg tid ) for 12 weeks had significant loss of body fat, but not overall weight, compared to the placebo group.43 In another trial, fat-mass reduction and lean muscle mass increases were attributed to supplementation with 5 g/d of Tonalin for seven weeks in conjunction with resistance weight training in healthy adults.44 Further, adults taking CLA for one or two years experienced significant body mass reductions due to CLA, not diet or training.45 CLA was also found to decrease body fat in 6- to 10-year-old children who were either overweight or obese.46

The numerous approaches to using natural ingredients in weight management reflect the ongoing consumer drive toward more convenient, less invasive ways to control weight. Whether controlling hunger and appetite, blocking or burning fat (and carbs) or limiting fat storage in the body, several www.naturalproductsinsider.com Page 6

[Weight Management] Vol. 16 No. 9 September 2011 nutritional and botanical ingredients have generated significant and promising research results that could benefit weight management formulas.

References:

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2. Lau FC et al. “Efficacy of LOWAT™ – A Natural Weight Management Herbal Formula in Human Subjects.” FASEB J. 2011;25:(Meeting Abstract Supplement) 601.10.

3. . Blom WA et al. "Effect of a high-protein breakfast on the postprandial ghrelin response." Amer J Clin Nutr. 2006; 83(2):211-20.

4. Leidy HJ et al. "Increased dietary protein consumed at breakfast to an initial and sustained feeling of fullness during energy restriction compared to other meal times." Br J Nutr. 2009 Mar;101(6):798-803.

5. Veldhorst MA et al. “Comparison of the effects of a high- and normal-casein breakfast on satiety, ‘satitey’ hormones, plasma amino acids and subsequent energy intake.” Br J Nutr. 2009 Jan;101(2):295-303.

6. Hochstenbach-Waelen A et al. "Effects of high and normal soyprotein breakfasts on satiety and subsequent energy intake, including amino acid and 'satiety' hormone responses." Eur J Nutr. 2009 Mar;48(2):92-100.

7. Bowen J et al. "Appetite regulatory hormone responses to various dietary proteins differ by body mass index status despite similar reductions in ad libitum energy intake." J Clin Endocrinol Metab. 2006;91(8):2913-9.

8. Whelan K et al. "Appetite during consumption of enteral formula as a sole source of nutrition: the effect of supplementing pea-fibre and fructo-oligosaccharides." Br J Nutr. 2006 Aug;96(2):350-6.

9. Parnell JA and Reimer RA. "Weight loss during oligofructose supplementation is associated with decreased ghrelin and increased peptide YY in overweight and obese adults." Am J Clin Nutr. 2009 Jun;89(6):1751-9.

10. Di Felippo C et al. “Impact of diet in shaping gut revealed by a comparative study in children from Europe and rural Africa.” Proc Nat Acad Sci. Aug. 2, 2011. Online ahead of print.

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11. Neyrinck AM et al. “Dietary modulation of clostridial cluster XIVa gut bacteria (Roseburia spp.) by chitin–glucan fiber improves host metabolic alterations induced by high-fat diet in mice.” J Nutri Biochem. 2011; 149(3): 183-190.

12. Einerhand AW et al. "Korean pine nut fatty acids affect appetite sensations, plasma CCK and GLP1 in overweight subjects." FASEB Journal. 2006;20:A829.

13. Burns AA et al. "Short-term effects of yoghurt containing a novel fat emulsion on energy and macronutrient intakes in non-obese subjects." Int. J Obesity. 2000; 24(11):1419-25.

14. Burns AA et al. "The effects of yoghurt containing a novel fat emulsion on energy and macronutrient intakes in non-overweight, overweight and obese subjects." Int J Obesity. 2001; 25(10):1487-95.

15. Knutson L et al. “Gastrointestinal metabolism of a vegetable-oil emulsion in healthy subjects.” AJCN. Online ahead of print June 23, 2010.

16. Piscitelli F et al. “Effect of dietary supplementation on the endocannabinoidome of metabolically relevant tissues from high-fat-fed mice.” Nutr Metab (Lond). 2011 Jul 13;8(1):51.

17. Kuriyan R et al. "Effect of Caralluma fimbriata extract on appetite, food intake and anthropometry in adult Indian men and women." Appetite. 2007 May;48(3):338-44.

18. Kamalakkannan S et al. “Antiobesogenic and Antiatherosclerotic Properties of

Caralluma fimbriata Extract.” J Nutr Metab. 2010;2010:285301.

19. Kamalakkannan S et al. “Effect of Caralluma Fimbriata Extract on 3T3-L1 Pre-Adipocyte Cell Division.” Food Nutri Sci. 2011; 2(4): 329-336.

20. Gout B et al. “Satiereal, a Crocus sativus L extract, reduces snacking and increases satiety in a randomized placebo-controlled study of mildly overweight, healthy women.” Nutrition Research 30 (2010) 305–313.

21. Godard MP et al. “Body composition and hormonal adaptations associated with forskolin consumption in overweight and obese men.” Obes Res. 2005 Aug;13(8):1335-43.

22. Smeets AJ and Westerterp-Plantenga MS. "The acute effects of a lunch containing capsaicin on energy and substrate utilisation, hormones, and satiety." Eur J Nutr. 2009 Jun;48(4):229-34.

23. Reinbach HC et al. "Effects of capsaicin, green tea and CH-19 sweet pepper on appetite and energy intake in humans in negative and positive energy balance." Clin Nutr. 2009 Jun;28(3):260-5.

24. Joo JI et al. “Proteomic analysis for antiobesity potential of capsaicin on white adipose tissue in rats fed with a high fat diet.” J Proteome Res. 2010 Jun 4;9(6):2977-87. www.naturalproductsinsider.com Page 8

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25. Dulloo AG et al. “Green tea and thermogenesis: interactions between catechin-polyphenols, caffeine and sympathetic activity.” Int J Obes Relat Metab Disord. 2000 Feb;24(2):252-8.

26. Wolfram S, Wang Y, Thielecke F. “Anti-obesity effects of green tea: from bedside to bench.” Mol Nutr Food Res. 2006 Feb;50(2):176-87

27. . Belza A, Jessen AB. “Bioactive food stimulants of sympathetic activity: effect on 24-h energy expenditure and fat oxidation.” Eur J Clin Nutr. 2005 Jun;59(6):733-41.

28. Lardy H et al. “Ergosteroids: Induction of thermogenic enzymes in liver of rats treated with steroids derived from dehydroepiandrosterone.” Proc Natl Acad Sci. 1995;92:6617-19.

29. Lardy H et al. “Ergosteroids II: Biologically active metabolites and synthetic derivatives of dehydroepiandrosterone.” Steroids. 1998;63:158-65.

30. Kalman DS et al. “A randomized, double-blind, placebo controlled study of 3-acetyl-7-oxo- dehydroepiandrosterone in healthy overweight adults.” Curr Ther Res. 2000;61:435-442.

31. Zenk JL et al. “The effect of 7-Keto Naturalean on weight loss: A randomized, double-blind, placebo-controlled trial.” Curr Ther Res. 2002;63:263-72.

32. Zenk JL et al. “HUM5007, a novel combination of thermogenic compounds and 3-acetyl-7-oxo- dehydroepiandrosterone: Each increase the resting metabolic rate of overweight adults.” J Nutr Biochem. 2007;18:629-34.

33. Gougeon R et al. “Increase in the thermic effect of food in women by adrenergic amines extracted from citrus aurantium.” Obes Res. 2005 Jul;13(7):1187-94.

34. Haller CA, Benowitz NL, Jacob P 3rd. “Hemodynamic effects of -free weight-loss supplements in humans.” Am J Med. 2005 Sep;118(9):998-1003.

35. Stohs SJ et al. “The Safety of Citrus aurantium (Bitter Orange) and its Primary Protoalkaloid p- Synephrine.” Phytother Res. 2011 Apr 8. doi: 10.1002/ptr.3490.

36. Seifert JG et al. “Effect of acute administration of an herbal preparation on blood pressure and heart rate in humans.” Int J Med Sci. 2011 Mar 2;8(3):192-7.

37. Maeda H et al. “Seaweed carotenoid, fucoxanthin, as a multi-functional .” Asia Pac J Clin Nutr. 2008;17 Suppl 1:196-9.

38. Maeda H et al. “Effect of medium-chain triacylglycerols on anti-obesity effect of fucoxanthin.” J Oleo Sci. 2007;56(12):615-21.

39. Maeda H et al. “Dietary combination of fucoxanthin and fish oil attenuates the weight gain of white adipose tissue and decreases blood glucose in obese/diabetic KK-Ay mice.” J Agric Food Chem. 2007 Sep 19;55(19):7701-6. Epub 2007 Aug 23. www.naturalproductsinsider.com Page 9

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40. Abidov M et al. “The effects of Xanthigen in the weight management of obese premenopausal women with non-alcoholic fatty and normal liver fat.” Diabetes Obes Metab. 2010 Jan;12(1):72-81.

41. LaMarche B et al. “Study of the acute impact of polyphenols from brown seaweeds on glucose control in healthy men and women.” FASEB J. 2010;24 (Meeting Abstract Supplement) 209.4.

42. Celleno L et al. “A Dietary supplement containing standardized Phaseolus vulgaris extract influences body composition of overweight men and women.” Int J Med Sci. 2007 Jan 24;4(1):45-52.

43. . Thom E, Wadstein J, Gudmundsen O. “ reduces body fat in healthy exercising humans.” J Intl Med Res. 2001;29:392-6.

44. Pinkoski C et al. “The effects of conjugated linoleic acid supplementation during resistance training.” Med Sci Sports Exerc. 2006;38(2):339-48.

45. Gaullier JM et al. “Supplementation with conjugated linoleic acid for 24 months is well tolerated by and reduces body fat mass in healthy, overweight humans.” J Nutr. 2005;135:778-84.

46. Racine NM et al. “Effect of conjugated linoleic acid on body fat accretion in overweight or obese children.” Am J Clin Nutr. 2010 May;91(5):1157-64.

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