Thermogenics Turn Up the Heat in Weight Loss

Managing weight is a fact of life for most adults; the scale goes up and down, and we promise well cut back on those desserts or get back to the gym. At this point, the United States is facing an epidemic of overweight and obesity, with more than two-thirds of Americans weighing more than is considered optimal for their height.

Interestingly, while the federal government has increasingly touted exercise as one of the critical steps in losing and managing weighteven adding it to the federal dietary guidelinesa cover article in Time magazine at the height of the 2009 summer swimsuit season questioned the conventional wisdom. The theory put forth in Why Exercise Wont Make You Thin is exercise stimulates appetite instead of suppressing it and feeds into the mental idea of earning extra calorie intake. And while the author noted muscle does burn more calories than fat, he added the difference in calorie burning is negligible.

One reason for the inefficiency in fat burning? Humans generally lack great quantities of brown fat, which is better at turning nutrients into energy. Researchers at Bostons Joslin Diabetes Center recently published an analysis of amount of brown adipose tissue (BAT) and its influence on thermogenesis, mediated by the expression of uncoupling protein 1 (UCP1), in almost 1,800 adults.¹ They found women generally had a greater mass of functionally active BAT, and reported an inverse correlation between BAT levels and body mass index (BMI).

The question may be how to stimulate BAT activity and thermogenesis in adults. Fortunately, studies are increasingly pointing to the ability of many nutritional ingredients, from macronutrients to botanicals, to upregulate the bodys process of thermogenesisincreasing the metabolic rate to burn energy.

Every individual has a basal metabolic rate (BMR) linked to the amount of energy needed to maintain basic life functions; this generally slows as the body ages and muscle mass and activity level decline. Metabolic energy needs are also influenced by physical activity (basic and more strenuous activity, such as exercise) and digestion. In fact, the metabolic rate increases immediately after eating, as the body works to transport, metabolize and absorb nutrients.

Protein has been shown to significantly increase diet-induced thermogenesis. A review out of Maastricht University, Netherlands, noted sustaining protein intake can affect metabolic targets during weight loss, particularly during calorie restriction, helping to sustain energy expenditure and spare lean body mass.² Additionally, moderately elevated protein intake while reducing overall calories appears to increase thermogenesis, influencing satiety, while maintaining lean muscle mass, further improving the metabolic profile.³ In one recent study, researchers out of Purdue University, West Lafayette, IN, reported women (n=38) consuming a high-protein, energy-deficit diet had greater satiety and fat oxidation compared to a normal protein diet.⁴

Some studies suggest dairy protein in particular may exert positive effects on thermogenesis and accelerated fat loss, supported by higher calcium levels inhibiting lipogenesis and bioavailable protein affecting satiety and lipolysis.5 In one double blind, randomized study at the Minnesota Applied Research Center, subjects (n=106) reduced their caloric intake by 500 calories per day and consumed a specialized whey fraction (as Prolibra, from Glanbia) or an isocaloric ready-to-mix beverage 20 minutes before breakfast and dinner.⁶ The Prolibra group lost significantly more body fat compared to control subject, with a greater preservation of lean muscle.

It may be the amino acids found in protein exert a particular effect on the bodys thermogenic pathways. Italian researchers reported providing an amino acid-infused solution to adults increased protein synthesis and energy expenditure, with the thermic effect not dependent on the dosage of amino acids.⁷ L-leucine specifically may stimulate protein synthesis in muscle cells and promote retention of lean muscle mass during calorie reduction.⁸ It also appears to regulate the oxidative use of glucose by skeletal muscle, sparing protein during energy restriction.⁹

The amino acid L-carnitine may also exhibit some thermogenic properties. A recent French study found providing aged rats with 30 mg/kg body weight of L-carnitine (as L-Carnipure, from Lonza) for 12 weeks restored L-carnitine levels in muscle cells and induced positive changes in body composition including a decrease in abdominal fat mass without any change in food intake.¹⁰ A previous human trial examined the impact of L-carnitine supplementation on fat oxidation, body composition and weight development in 12 slightly overweight adults.¹¹ Supplementation with 3 g/d of L-carnitine (as L-Carnipure) for 10 days significantly increased dietary fat oxidation without impacting protein catabolism.

A host of biological active compounds also exert a thermogenic effect on the body, increasing the metabolic rate. Perhaps the best-known of the energy enhancers is caffeine. Studies suggest it not only upregulates UCP-1, -2 and -3 expression in BAT,¹² but also increases oxygen consumption in BAT mitochondria and resting metabolic rate (RMR).¹³ A review from Maastricht University noted a combination of caffeine and ephedrine has been shown to be effective in enhancing release of catecholamines, although ephedrines adverse effects have negated that tool for dietary supplement formulators.¹⁴ They added, however, that green tea, which contains both caffeine and tea catechins, may contain in one extract synergistic compounds to exert a thermogenic and weight reducing effect.

Scientific interest in green teas effects on weight loss is high, not only to understand its mechanisms, but also the synergy between the active compounds. A review from the University of Fribourg, Switzerland, noted while green teas thermogenic effects have been generally attributed to its caffeine content, studies show green tea extract stimulates BAT thermogenesis to a much greater degree than could be attributed to just the amount of caffeine; they suggest there could be interaction between the catechin polyphenols and caffeine in the body.¹⁵ Researchers from DSM Nutritional Products, Basel, Switzerland, agreed in their review, adding green tea, green tea catechins and epigallocatechin gallate (EGCG) have been demonstrated to exert effects on lipogenesis, fat mass and thermogenesis, and that EGCG poses particular promise in the area.¹⁶

Researchers have been exploring the possibilities. In one trial involving 10 healthy men, those who received green tea extract (50 mg caffeine and 90 mg EGCG) had significant effects on fat oxidation and energy expenditure, while those taking just caffeine (50 mg) had no increase in energy expenditure (EE).¹⁷ Similarly, a pilot study in Germany found providing overweight men with EGCG alone (300 mg/d) for only two days significantly increased fat oxidation.¹⁸ Another trial out of Laval University, Quebec, provided adults (n=14) with capsules containing 200 mg of caffeine (from guarana extract) and varying doses of EGCG90, 200, 300 or 400 mgthree times daily.¹⁹ All interventions increased 24-hour EE, with no great differences among the doses of EGCG.

Green tea catechins have also been studied in combination with other possible thermogenic agents beyond caffeine. A pair of studies out of The Royal Veterinary and Agricultural University, Frederiksberg, Denmark, explored the impact of a combination of green tea extract (catechins and caffeine), capsaicin, tyrosine and calcium, either as a simple combination or in an enteric-coated version. In the first trial, a three-way crossover, placebo-controlled, double blind intervention, 19 overweight to obese men consumed the supplements for one week.²⁰ The simple combination was found to increase 24-hour EE without raising the heart rate, while the enteric-coated version had no effect. The second trial involved 80 overweight/obese subjects who initially underwent a four-week hypocaloric diet, and were then randomized to receive a placebo or simple combination.²¹ After eight weeks, subjects taking the supplement had a greater decrease in body fat mass compared to the placebo group and increased rates of thermogenesis.

In fact, research suggests spices such as capsaicin, black pepper and ginger may all exert a thermogenic effect, and even upregulate fat oxidation.²² Capsaicinoids are the major pungent principles in red hot peppers, and commonly referred to collectively as capsaicin. Studies have shown when capsaicin is consumed, it stimulates the sensory neurons to enhance the release of adrenal hormones including epinephrine and norepinephrine.²³ A review out of the University of Memphis, TN, noted capsaicinoids have been shown to reduce ad libitum food intake, increase thermogenesis and increase lipolysis, with few adverse outcomes, generally limited to gastric discomfort associated with higher intake levels.²⁴

Clinical trials are building a strong base of support. Japanese researchers investigated the effects of capsaicin (150 mg) on metabolism and thermogenic activity during exercise, reporting in the male subjects (n=10), intervention did not impact heart rate during exercise, but did increase markers of fat oxidation.²⁵ A larger double blind, placebo-controlled, 12-week study, conducted at the University of Maryland School of Medicine, Baltimore, involved 80 overweight adults randomly assigned to capsinoid (6 mg/d) or placebo groups.²⁶ At studys end, no significant differences appeared between the groups in total changes in adiposity, although the capsinoid group had greater decreases in abdominal adiposity; fat oxidation was also higher in the capsinoid group. Another trial, this time in overweight subjects who had lost 5 to 10 percent body weight, reported capsaicin (135 mg/d) could sustain fat oxidation during a three-month weight-maintenance period, although weight regain was almost similar between the groups.²⁷

Another common spice is black pepper, which has a pungent effect on food and may support food-induced thermogenesis. Studies have shown the ability of piperine, an active constituent in black pepper, to stimulate the release of epinephrine, which activates the beta-receptors that initiate thermogenesis.²⁸ Sabinsa Corp. has supported research into the possible role of its patented black pepper extract (Bioperine®) as a thermonutrient, with the ability to enhance nutrient absorption and related thermogenesis. In one 28-day double blind, crossover study, subjects who received 5 mg of piperine along with a dose of beta-carotene had a 60-percent greater increase in serum beta-carotene levels, which was a result of piperines non-specific thermogenic effects.²⁹ Similar results were reported in a study examining the effects of 5 mg piperine on bioavailability of 90 mg or 120 mg of coenzyme Q10 (CoQ10).³⁰ Supplementation of 120 mg CoQ10 with piperine for 21 days had a statistically significant increase in plasma CoQ10 levels, which was again linked to the thermonutrient effects of piperine.

Another crossover, double blind, placebo-controlled study examined the impact of a combination of piperine (as Bioperine), capsicum extract, niacin and caffeine (as Capsimax Plus Blend, from OmniActive Health Technologies) on metabolic and safety parameters. In the unpublished trial, when the healthy adults (n=25) took the combination blend one hour prior to exercising, they burned three times more calories before, 3 percent more calories during, and 12 times more calories for up to an hour after exercise compared to taking a placebo. The subjects also had a greater oxygen uptake and ventilation when taking the Capsimax Plus Blend.

Also from the botanical kingdom comes the extract many formulators turned to when ephedra (ma huang) was eliminated from the U.S. supplement marketbitter orange (Citrus aurantium). The extract of Citrus aurantium (CA) contains indirect adrenergic amines that stimulate metabolism, enhance amino acid uptake by muscle and increase lipolysis. It appears to have the ability to positively impact sympathetic nervous system (SNS) activity and responsiveness of the body to stimulation of thermogenic beta-adrenoreceptors, without stimulating other beta-adrenoreceptors that control systems such as blood pressure, avoiding the side effects associated with ephedra. Georgetown University researchers noted in a 2002 review that CA extract aids weight loss and increases thermogenesis, and is likely the most effective ephedra substitute.³¹

Studies have supported its efficacy and safety. In a Canadian trial, CA extract (as Advantra Z®, from Nutratech Inc.) increased the thermic effect of food when given with a meal, although the effect was more pronounced in men than in women.³² Additionally, CA was found to increase epinephrine excretion by 2.4 times, without adversely affecting blood pressure. That margin of safety was also reported by University of California, San Francisco, researchers, who reported a multi-component supplement formulation with 5.5 mg synephrine (from CA) did affect blood pressure, whereas an eight-fold higher level (46.9 mg synephrine) from Advantra Z alone did not increase either diastolic or systolic measures.³³

Recent trials on bitter orange have focused on its ability to work synergistically with exercise to increase fat oxidation. Researchers from the University of Chichester, West Sussex, England, examined the ability of a combination of CA (Advantra Z), green tea and guarana to influence metabolic rate and thermogenesis; two groups of 10 men received two 500 mg capsules of the active formula or placebo and tested either at rest or during treadmill walking.³⁴ The intervention positively influenced fat oxidation and ATP production, particularly at rest. In another trial, researchers out of the University of California, San Francisco, examined the effects of a combination of caffeine and Citrus aurantium (as AdvantraZ), as the Ripped Fuel Extreme Cut® supplement, on 10 healthy adults and found supplementation prior to moderately intense exercise modestly improved exercise tolerance.³⁵

Another Asian botanical, Garcinia cambogia, yields an extract known as hydroxycitric acid (HCA), which influences several aspects of weight management. A recent review from InterHealth Nutraceuticals noted studies using cDNA microarrays found HCA supplementation can alter gene expression involved in lipolytic and adipogenic pathways in adipocytes, and also appears to upregulate the expression of serotonin receptor genes in abdominal fat.³⁶ Animal trials also found garcinia extract may modulate a number of genes associated with adipogenesis, fighting visceral fat accumulation.³⁷

Ongoing studies support the efficacy of HCA in thermogenesis. An in vitro trial using subcutaneous preadipocytes from obese women found HCA-SX (as Super CitriMax®, from InterHealth) could markedly induce leptin expression and downregulate fat- and obesity-related genes.³⁸ A trial in mice further found garcinia extract could exert leptin-like activity to prevent body weight gain during sucrose loading.³⁹ A review out of Georgetown University, Washington, examined a range of studies on HCA-SX (as Super CitriMax).⁴⁰ It noted clinical studies on HCA-SXs safety and efficacy have found a dosage of 2,800 mg/d HCA could significantly reduce food intake and serum leptin levels, while increasing levels of serotonin and excretion of urinary fat metabolites, a biomarker of fat oxidation. No significant adverse effects were reported.

More recent studies in the botanical field have looked at the impact of green coffee bean extract (GCBE) on metabolism. A Japanese study found GCBE could reduce visceral fat content and body weight in mice given olive oil, possibly by inhibiting fat absorption and activating fat metabolism in the liver; further, the chlorogenic acid in GCBE may particularly aid in hepatic function.⁴¹ Even as GCBE contains caffeine, which may increase blood pressure, studies on the extract suggest its chlorogenic acid may offset increases in blood pressure.⁴²

Interestingly, studies have also shown yerba mate (Ilex paraguariensis), a natural source of xanthenes similar to caffeine, may exert a thermogenic effect, attenuating adiposity and upregulating UCP-1 and other genes linked to metabolism.^43,44 And like GCBE, yerba maté contains chlorogenic acid as well as caffeic acid, possibly exerting an anti-glycation effect.⁴⁵

Other specialty compounds are also under investigation for their possible thermogenic effects. Fucoxanthin, a carotenoid found primarily in brown algae, has been high profile in the nutrition industry in the last two years. One review out of Japan noted feeding fucoxanthin to mice tended to reduce body weight, possibly by enhancing UCP-1 expression in white adipose tissue (WAT) leading to fat oxidation and mitochondrial energy production.⁴⁶ In another trial, the researchers, from Hokkaido University, noted providing fucoxanthin to mice along with medium-chain triacylglycerols (MCT) enhanced absorption of the carotenoid, and increased UCP-1 expression, significantly reducing abdominal fat weight in the animals.⁴⁷ They reported similar findings when using fish oil in place of MCTs.⁴⁸ The researchers noted that because fucoxanthin exerts its effects in WAT, rather than BAT, it may be more efficacious in human adults, who tend to have a higher percentage of WAT.

Clinical trials are ongoing to assess fucoxanthins influence on thermogenesis. However, one unpublished three-month clinical trial involved 19 overweight adults who received a placebo or 2 mg/d or 4 mg/d of a proprietary blend of fucoxanthin and other ingredients (as ThinOgen Plus, from Beijing Gingko Group). At studys end, 94.5 percent of the 2 mg group and 99 percent of the 4 mg group reported weight loss, with measurable losses in abdominal fat areas.

Another specialty compound with thermogenic effects is 3-acetyl-7-oxo-dehydroepiandrosterone, better known as 7-oxo-DHEA, a natural substance produced by the adrenal glands. Studies have shown 7-oxo DHEA has the ability to enhance the activity of three thermogenic enzymes: glycerol-3-phosphate dehydrogenase, malic enzyme and fatty acyl CoA oxidase.^49,50 By doing so, 7-oxo-DHEA increase heat production and utilization of fat stores for energy. Safety studies have found 7-oxo-DHEA (as 7-Keto®, from Humanetics) is safe for human consumption at a dose of 200 mg/d.⁵¹ Initial clinical trials found adults taking 7-oxo-DHEA (as 7-Keto) lost significantly more weight and body fatup to three times as muchthan subjects taking placebo.^52,53 Interestingly, supplementation also increased RMR even while the subjects followed a calorie-restricted diet, which normally decreases RMR.

A follow-up investigation examined whether 7-oxo-DHEA (as 7-Keto) could increase RMR in overweight subjects on a calorie-restricted diet.⁵⁴ The randomized, double blind, placebo-controlled trial included 45 adults placed on a calorie-restricted diet and given 7-oxo-DHEA or placebo during 7-day treatment periods with washout between. RMR decreased 3.9 percent during placebo treatment, but increased by 1.4 percent while taking 7-oxo-DHEA.

While fats generally do not exert a thermogenic effect on the body, there are some studies suggesting certain nutritional fats may impact metabolic rate. Conjugated linoleic acid (CLA) has been studied for more than 25 years for its ability to reduce fat mass and retain lean body mass during weight loss. A study out of Norway reported healthy adults who exercised regularly and took 0.6 mg tid of CLA (as Tonalin®, from Cognis Nutrition & Health) for 12 weeks had a significant reduction in body fat, although not body weight.⁵⁵ Supplementing with 5 g/d of CLA (as Tonalin) for seven weeks during resistance weight training similarly resulted in decreases in fat mass and increases in lean tissue mass in healthy adults (n=76).⁵⁶ Long-term studies have shown overweight adults who consumed CLA (as Tonalin) for one year or two years showed a reduction in body fat mass, which was not related to diet and/or training.^57,58

Evolving scientific research will likely provide even greater substantiation for the beneficial metabolic effects of nutrients to help consumers lose weight. Whether coupled with exercise, or used in combinations to offer thermogenic and appetite suppressant effects, these powerful compounds may hold the key to unlocking long-term sustainable weight management.

References on the next page...

References for ThermogenicWeight Loss

1. Cypess AM et al. Identification and importance of brown adipose tissue in adult humans. N Engl J Med. 2009 Apr 9;360(15):1509-17.

2. Westerterp-Plantenga MS et al. Dietary protein, weight loss, and weight maintenance. Annu Rev Nutr. 2009;29:21-41.

3. Paddon-Jones D et al. Protein, weight management, and satiety. Am J Clin Nutr. 2008 May;87(5):1558S-1561S.

4. Leidy HJ, Mattes RD, Campbell WW. Effects of acute and chronic protein intake on metabolism, appetite, and ghrelin during weight loss. Obesity (Silver Spring). 2007 May;15(5):1215-25.

5. Zemel MB. The role of dairy foods in weight management. J Am Coll Nutr. 2005 Dec;24(6 Suppl):537S-46S.

6. Frestedt JL et al. A whey-protein supplement increases fat loss and spares lean muscle in obese subjects: a randomized human clinical study. Nutr Metab (Lond). 2008 Mar 27;5:8.

7. Giordano M, Castellino P. Correlation between amino acid induced changes in energy expenditure and protein metabolism in humans. Nutrition. 1997 Apr;13(4):309-12.

8. Jitomir J, Willoughby DS. Leucine for retention of lean mass on a hypocaloric diet. J Med Food. 2008 Dec;11(4):606-9.

9. Layman DK, Walker DA. Potential importance of leucine in treatment of obesity and the metabolic syndrome. J Nutr. 2006 Jan;136(1 Suppl):319S-23S.

10. Bernard A et al. L-Carnitine Supplementation and Physical Exercise Restore Age-Associated Decline in Some Mitochondrial Functions in the Rat. J Gerentol. 2008;63:1027-33.

11. Wutzke KD, Lorenz H. The effect of L-carnitine on fat oxidation, protein turnover and body composition in slightly overweight subjects. Metabolism. 2004;53(8):1002-1006.

12. Kogure A et al. Effects of caffeine on the uncoupling protein family in obese yellow KK mice. Clin Exp Pharmacol Physiol. 2002 May-Jun;29(5-6):391-4.

13. Yoshioka K et al. Caffeine activates brown adipose tissue thermogenesis and metabolic rate in mice. J Nutr Sci Vitaminol (Tokyo). 1990 Apr;36(2):173-8

14. Diepvens K, Westerterp KR, Westerterp-Plantenga MS. Obesity and thermogenesis related to the consumption of caffeine, ephedrine, capsaicin, and green tea. Am J Physiol Regul Integr Comp Physiol. 2007 Jan;292(1):R77-85. Epub 2006 Jul 13.

15. 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.

16. 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.

17. Dulloo AG et al. Efficacy of a green tea extract rich in catechin polyphenols and caffeine in increasing 24-h energy expenditure and fat oxidation in humans. Am J Clin Nutr. 1999 Dec;70(6):1040-5.

18. Boschmann M, Thielecke F. The effects of epigallocatechin-3-gallate on thermogenesis and fat oxidation in obese men: a pilot study. J Am Coll Nutr. 2007 Aug;26(4):389S-395S.

19. Bérubé-Parent S et al. Effects of encapsulated green tea and Guarana extracts containing a mixture of epigallocatechin-3-gallate and caffeine on 24 h energy expenditure and fat oxidation in men. Br J Nutr. 2005 Sep;94(3):432-6.

20. 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.

21. Belza A, Frandsen E, Kondrup J. Body fat loss achieved by stimulation of thermogenesis by a combination of bioactive food ingredients: a placebo-controlled, double-blind 8-week intervention in obese subjects. Int J Obes (Lond). 2007 Jan;31(1):121-30. Epub 2006 Apr 25.

22. Westerterp-Plantenga M et al. Metabolic effects of spices, teas, and caffeine. Physiol Behav. 2006 Aug 30;89(1):85-91. Epub 2006 Mar 30.

23. Kawada T et al. Some pungent principles of spices cause the adrenal medulla to secrete catecholamine in anesthetized rats. Proc Soc Exp Biol Med. 1988;188:229-33.

24. Bloomer RJ, Canale RE, Fisher-Wellman KH. The potential role of capsaicinoids in weight management. AgroFood. 2009;20(4):60-62.

25. Shin KO, Moritani T. Alterations of autonomic nervous activity and energy metabolism by capsaicin ingestion during aerobic exercise in healthy men. J Nutr Sci Vitaminol (Tokyo). 2007 Apr;53(2):124-32.

26. Snitker S et al. Effects of novel capsinoid treatment on fatness and energy metabolism in humans: possible pharmacogenetic implications. Am J Clin Nutr. 2009 Jan;89(1):45-50. Epub 2008 Dec 3.

27. Lejeune MP, Kovacs EM, Westerterp-Plantenga MS. Effect of capsaicin on substrate oxidation and weight maintenance after modest body-weight loss in human subjects. Br J Nutr. 2003 Sep;90(3):651-59.

28. Kawada T et al. Some pungent principles of spices cause the adrenal medulla to secrete catecholamine in anesthetized rats. Proc Soc Exp Biol Med. 1988 Jun;188(2):229-33.

29. Badmaev V, Majeed M, Norkus EP. Piperine, an alkaloid derived from black pepper increases serum response of beta-carotene during 14-days of oral beta-carotene supplementation. Nutr Res. 1999;19(3):381-88.

30. Badmaev V, Majeed M, Prakash L. Piperine derived from black pepper increases the plasma levels of coenzyme Q10 following oral supplementation. J Nutr Biochem. 2000;11:109-13.

31. Preuss HG et al. Citrus aurantium as a thermogenic, weight-reduction replacement for ephedra: an overview. J Med. 2002;33(1-4):247-64.

32. 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.

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

34. Sale C et al. Metabolic and physiological effects of ingesting extracts of bitter orange, green tea and guarana at rest and during treadmill walking in overweight males. Int J Obes. 2006. DOI:10.1038/sj.ijo.0803209.

35. Haller CA et al. Human pharmacology of a performance-enhancing dietary supplement under resting and exercise conditions. Br J Clin Pharmacol. 2008. DOI:10.1111/j.1365-2125.2008.03144.x

36. Lau FC et al. Nutrigenomic analysis of diet-gene interactions on functional supplements for weight management. Curr Genomics. 2008 Jun;9(4):239-51.

37. Kim KY et al. Garcinia cambogia extract ameliorates visceral adiposity in C57BL/6J mice fed on a high-fat diet. Biosci Biotechnol Biochem. 2008 Jul;72(7):1772-80. Epub 2008 Jul 7.

38. Roy S et al. Transcriptome of primary adipocytes from obese women in response to a novel hydroxycitric acid-based dietary supplement. DNA Cell Biol. 2007 Sep;26(9):627-39.

39. Hayamizu K et al. Effect of Garcinia cambogia extract on serum leptin and insulin in mice. Fitoterapia. 2003 Apr;74(3):267-73.

40. Preuss HG et al. An overview of the safety and efficacy of a novel, natural(-)-hydroxycitric acid extract (HCA-SX) for weight management. J Med. 2004;35(1-6):33-48.

41. Shimoda H, Seki E, Aitani M. Inhibitory effect of green coffee bean extract on fat accumulation and body weight gain in mice. BMC Complement Altern Med. 2006 Mar 17;6:9.

42. Watanabe T et al. The blood pressure-lowering effect and safety of chlorogenic acid from green coffee bean extract in essential hypertension. Clin Exp Hypertens. 2006 Jul;28(5):439-49.

43. Arçari DP et al. Antiobesity Effects of yerba maté Extract (Ilex paraguariensis) in High-fat Diet-induced Obese Mice. Obesity (Silver Spring). 2009 May 14. [Epub ahead of print]

44. Pang J, Choi Y, Park T. Ilex paraguariensis extract ameliorates obesity induced by high-fat diet: potential role of AMPK in the visceral adipose tissue. Arch Biochem Biophys. 2008 Aug 15;476(2):178-85. Epub 2008 Feb 26.

45. Gugliucci A et al. Caffeic and chlorogenic acids in Ilex paraguariensis extracts are the main inhibitors of AGE generation by methylglyoxal in model proteins. Fitoterapia. 2009 Sep;80(6):339-44. Epub 2009 May 4.

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

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

48. 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.

49. 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.

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

51. Davidson M et al. Safety and pharmacokinetic study with escalating disease of 3-acetyl-7-oxo-dehydroepiandrosterone in healthy male volunteers. Clin Invest Med. 2000;23:300-10.

52. 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.

53. 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.

54. 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.

55. Thom E, Wadstein J, Gudmundsen O. Conjugated linoleic acid reduces body fat in healthy exercising humans. J Intl Med Res. 2001;29:392-6.

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

57. Gaullier JM et al. Conjugated linoleic acid supplementation for 1 y reduces body fat mass in healthy overweight humans. Am J Clin Nutr. 2004;79:1118-25.

58. 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.