By Steve Blechman

A new report appeared on Wednesday December 18, 2019 in the prestigious New England Journal of Medicine that reported that nearly half of American adults will be obese within a decade. The report was led by scientists at Harvard and George Washington Universities. The new research predicts that by 2030 about 50% U.S. adults will be obese. The Centers for Disease Control and Prevention says that 40% of U.S. adults are obese today. This is extremely alarming because obesity has been shown to raise the risk of heart disease, cancer, diabetes and many other health problems!

The low-carb Mediterranean diet has been shown to be very effective for weight loss, a most recent study published in the journal Nutrition for March 2020 found that in the short term, “integration of morning carbohydrate restriction into a Mediterranean hypocaloric diet resulted in greater weight loss than standard hypocaloric Mediterranean diet.”

A study published in the British Medical Journal (November 2018) reported that a low-carbohydrate, randomized trial was better than a high-carbohydrate diet and resulted in enhanced energy expenditure during weight-loss maintenance. Weight loss is often accompanied by a slowing of resting metabolism. By enhancing energy expenditure, it helps to maintain weight loss. The researchers found that on a low-carb diet, you burn 250 more calories per day versus high-carb. The study published in Diabetes Care (November 5, 2018) showed participants maintained weight loss over a one year period by staying on an energy-restricted Mediterranean diet with daily exercise. Few studies have followed individuals for a year or more to see if they kept the weight off!

A breakthrough, long-term diet study was published in the American Heart Association journal Circulation on measuring body fat! This diet study used magnetic resonance imaging (MRI) technology for the first time, measuring changes in body and organ fat during 18 months on a Mediterranean/low-carb diet, with and without moderate physical exercise. MRI is a diagnostic technique that produces computerized images of organs and internal body tissues using a magnetic field and radio waves. This is the best approach to date for measuring body fat, compared to weighing people as a result of diet and exercise. The scale, skinfold calipers or underwater weighing aren’t giving you the whole picture!

The research was conducted between Ben-Gurion University of the Negev and Harvard University. The research group was led by Drs. Iris Shai, Yftach Gepner, Ilan Shelaf and Dan Schwarzfuchs from Ben-Gurion University. Dr. Meir Stampfer was also a lead author for the study, and is from the prestigious Harvard University. Dr. Stampfer is a well-known authority on nutrition and obesity. The study analyzed the implementation of positive dietary changes and how this could help in reducing body fat, particularly visceral (abdominal) body fat.

Also, a recent study in the May 7^, 2019 Journal of Hepatology further confirms that, “a Mediterranean and low-carbohydrate diet decreases hepatic fat more than a low-fat diet, beyond visceral fat changes.” “The beneficial effect of the Mediterenean diet over low fat diet is mainly meditated by a decrease in hepatic fat.” The Mediterranean low-carb diet was significantly superior to a low-fat diet in decreasing fat storage, including visceral (deep abdominal) liver and heart fat. A study published in the journal Radiology, December 2018, showed that MRI is effective for monitoring liver fat in obese patients. High visceral fat has been shown to increase metabolic syndrome, inflammation, cardiovascular disease and diabetes. Losing deep, subcutaneous visceral fat, as well as haptic (liver) fat, was associated with improved insulin sensitivity and improved lipid profile.

People who strictly follow the Mediterranean diet tend to have a lower body mass index (BMI), which is a measure of the proportion of weight to height and waist circumference— according to a large population study led by Simona Bertoli from the Nutritional Research Center in Milan, Italy. The Mediterranean diet is high in fish, seafood, antioxidant-rich vegetables, red wine and berries rich in polyphenols, beans, lentils, nuts, legumes and extra-virgin olive oil (EVOO) that are rich in healthy monounsaturated and polyunsaturated fats and low in saturated fats. Extra-virgin olive oil contains a polyphenol called oleuropein and can increase brown fat thermogenesis. Brown fat is a special kind of fat cell that generates heat and helps regulate bodyweight and energy expenditure. Recently, a study published in JAMA (The Journal of the American Medical Association) on April 25, 2018 found that the Mediterranean diet fights against frailty. It’s just another study that supports the Mediterranean diet to preserve lean body mass and health during aging. Low-calorie diets can cause the loss of lean body mass. A healthy weight loss is one that preserves lean body mass while dieting. Muscle is more metabolically active than fat, which can result in more calories burned in a 24-hour period, which can help you keep the weight off!

Last year I reported why the low-carb Mediterranean diet was the best diet for 2019 and it is still the best diet based on the latest scientific research. For the past two years, U.S. News & World Report ranked the Mediterranean diet as the best overall diet for healthy eating, tied with the Dash Diet. The Mediterranean diet was also ranked number one for the easiest diet to follow; best diet for diabetes; best heart-healthy diet and best plant-based diet too.

A Harvard study that appeared in JAMA on December 7, 2018 was reported by ScienceDaily on the same day and stated, “Investigators identify, assess underlying mechanisms that may explain the diet's 25 percent reduction in cardiovascular risk for American women.” In the report, researchers said, “Our study has a strong public health message that modest changes in known cardiovascular disease risk factors, particularly those relating to inflammation, glucose metabolism and insulin resistance, contribute to the long-term benefit of a Mediterranean diet on cardiovascular disease risk. This understanding may have important downstream consequences for the primary prevention of cardiovascular disease,” said lead author Shafqat Ahmad, Ph.D., a research fellow at the Brigham and at the Harvard Chan School.

Results of an Italian study published in the International Journal of Cardiology, November 24, 2018, found the Mediterranean diet was instrumental in lowering cardiovascular risk in patients who take statin drugs. What the researchers found was in the population group, statins reduced cardiovascular disease and death risk only in the group with the combination of the statin drug and Mediterranean diet. Inflammation and lowering LDL cholesterol is likely to be the synergistic benefit of combining the Mediterranean diet and statin drugs in lowering mortality risk. The combined benefits of the Mediterranean diet and statins may be an optimal option for preventing cardiovascular disease mortality compared to statins alone. The LDL-lowering effect of statins, combined with the anti-inflammatory benefits of the Mediterranean diet, provides added benefits for lowering cardiovascular mortality. The Journal of American College of Cardiology in December 2019 conducted a high-quality observational study that has concluded that regular consumption of chili pepper (capsaicin) is associated with lower risk of death in a large sample of the Italian population (22, 811 men and women). Research has shown that the alkaloid in chili peppers called capsaicin is effective for weight loss, fat loss, and activating brown adipose tissue (BAT).

In a randomized controlled study in young adults that appeared in the journal Atherosclerosis, October 17, 2018, a high-saturated fat, low-carb diet (less than 20 grams per day) on average increased LDL-C (the bad cholesterol) by 44% in healthy adults! The response from this high-saturated fat, low-carb diet averaged 5% to 107% increase of LDL-C. This is very concerning! It is important that LDL-C should be measured in those following a high-saturated fat, low-carb diet such as traditional Atkins diet or ketogenic diet. What’s also concerning is there was a significant increase in Apolipoprotein-B (Apo-B)! High Apo-B levels are a very high risk for atherosclerosis and cardiovascular disease! Any diet that restricts carbohydrate and calories will result in weight loss, but a high-saturated fat diet that raises LDL cholesterol is not healthy, even though you are losing weight!

Several studies have shown that a low-carb, ketogenic Mediterranean diet is a healthier alternative to low-carb, high-saturated fat diets for weight loss. It has the favorable effect on non-atherogenic lipid profiles lowering LDL cholesterol, triglycerides, lowering blood pressure and inflammation and improving fasting blood glucose levels and reduction in weight circumference (Nutrition Journal, October 26, 2008; Nutrition Journal, October 12,2011; Nutrients, December 18, 2013). This study showed that the Mediterranean style diet may also lower women’s stroke risk, which was reported by the American Heart Association’s journal Stroke in October 2018.

The low-carb Mediterranean diet is clearly the best diet for weight loss and optimal health! It was reported in ScienceDaily that the Mediterranean Diet can slow aging. According to the article, “A series of six articles appearing in the March issue of The Journals of Gerontology, Series A: Biological Sciences and Medical Sciences finds new correlations between a Mediterranean diet and healthy aging outcomes -- while also underscoring the need for careful approaches to the use of data in order to measure the diet's potential benefits.” Another study reported in the October 2018 journal Ophthalmology found that the Mediterranean diet was beneficial in preventing macular degeneration, a major cause of blindness.

Also, it was reported that only 12% of Americans are considered metabolically healthy! (November 28, 2018, ScienceDaily). The obesity epidemic is upon us! Diabetes is rampant. Studies have shown that people with diabetes, or high blood sugar, do better and benefit more on a diet lower in carbohydrates. The research has shown that the low-carb Mediterranean diet is clearly the best diet for weight loss and metabolic health!

A very concerning study published in the journal Cell Metabolism, December 20, 2018, showed that cholesterol-lowering statin drugs can reduce brown adipose tissue. Statins lower brown fat! … Which can lower energy expenditure and increase glucose intolerance. Reduction in brown fat has been shown to raise diabetes risk. Studies also indicate that statins can raise blood sugar and diabetes. Could statins, by reducing brown fat, be contributing to increasing high blood sugar and diabetes? This is a startling finding! People on statins may benefit from the Thermo Heat^® Low Carb Mediterranean Diet. The body has two forms of fat— white fat and brown fat. Brown fat burns calories. The more brown fat you have, the more calories you burn. The capability of harnessing one’s own brown fat for fat burning is revolutionary! The ability to get lean by producing extra brown fat and enhancing and activating existing brown fat represents a promising way to burn fat. Several landmark discoveries and approaches to this are being explored at major research centers and universities worldwide, with great excitement! Brown fat research is a hot topic today!

Top 10 Thermogenic and Brown Fat-Activating Supplements

By Robert A. Schinetsky

Caffeine

What can be said about caffeine that hasn’t already been stated 1,000 times before?

It is a powerful central nervous stimulant well-documented to increase energy, alertness, wakefulness, exercise performance, and mental focus. It also helps reduce appetite and boost metabolism.

And, it can be found just about everywhere these days, from pre-workouts to weight-loss support supplements to even peanut butter and protein powder. 

Research has shown that consuming just 100mg of caffeine (about the amount you get in an 8 oz cup of strong drip coffee) can boost thermogenesis and increase energy expenditure up to 100 calories per day. More recent research has shown when caffeine is combined with other common fat-burning supplements, the dose needed is as low as 77mg.

Now, you might be wondering if these metabolism-boosting effects caffeine dwindle with continued use— apparently not, according to some research. In fact, studies have shown that even in habitual caffeine users (~100-200mg per day), ingesting a 100mg dose of the consummate stimulant resulted in a significant thermogenic effect lasting over 3 hours.

p-Synephrine

Naturally occurring in Citrus Aurantium (bitter orange), p-synephrine is a fat-burning alkaloid widely used to help boost metabolism and rid the body of excess weight. The manner in which p-synephrine encourages fat loss is due to its affinity for beta-3 adrenergic receptors found in brown fat.

Without getting too mired down in human biology, fat cells have two types of receptors that affect fat loss when stimulated. Specifically,

- Alpha receptors -- hinder fat burning by turning “off” lipolysis (the release of stored fatty acids into the bloodstream)

- Beta receptors -- encourage fat burning as they trigger lipolysis when activated

Research has shown that p-synephrine has high affinity for beta-3 receptors with virtually no binding affinity for alpha-1 and alpha-2 as well as beta-1 and beta-2 adrenoreceptors.[8] This is important as stimulation of beta-1 and beta-2 adrenoceptors typically leads to increases in heart rate and/or blood pressure.

Both alone and in combination with caffeine, P-synephrine has been shown to exert a thermogenic effect in the body by increasing resting metabolic rate, lipolysis, and exercise performance as well as reducing food intake.

Forskolin

Forskolin is one of the most intriguing thermogenic supplements. Yet it is not a stimulant, like so many other common fat-loss ingredients. 

Forskolin hails from the Indian plant coleus forskohlii. It’s the active component buried within the plant that’s been documented to activate an enzyme in brown fat called adenylyl cyclase. Activation of this enzyme leads to increases in cyclic AMP (cAMP) levels, which typically only occurs when noradrenaline (one of the body’s fat-burning catecholamines) binds to a beta-receptor. When this occurs, thermogenesis is activating.

Since forskolin increases cAMP levels in brown fat without binding to beta-receptors or causing an increase in noradrenaline, this means it also promotes thermogenesis.

In fact, various animal studies have documented that forskolin increases oxygen consumption and thermogenic activity of brown fat.

This means that for those seeking accelerated fat loss, it may behoove them to stack forskolin with a beta-receptor agonist such as p-synephrine. Together these compounds both agonize beta-receptors and increase cAMP levels which promotes increased cAMP levels, lipolysis, and most importantly, calorie burning.

Research has even shown that forskolin supplementation accelerates fat loss and may also increase testosterone levels.

Dopamine Activators

Dopamine is one of the most powerful and important neurotransmitters/hormones in the human body. Not only is it responsible for allowing us to experience reward, motivation, and pleasure, it’s also vital to maintaining focus, motor control, and the ability to make decisions.

There’s one other “trick” you can add to the list of things dopamine does -- ignite brown fat and thermogenesis.

The next question is, “how do we increase dopamine?”

Well, there’s several ways you can do that, including caffeine and exercise. But, since we’ve already commented on caffeine, let’s instead shift to compounds that directly impact dopamine production, namely the two powerful dopamine precursors, L-Tyrosine and L-Dopa.

Research has shown that supplementation with either of these potent dopaminergic activators increases dopamine production and function, which ignites a cascade of physiological processes in the body that results in increased energy expenditure in a dose-dependent manner.

In other words, the more dopamine you have circulating in your body, the greater amount of energy expenditure that occurs.

Since supplementation with both L-Tyrosine and L-Dopa has been shown to significantly increase dopamine levels in the body, it stands to reason that supplementation with them supports increased thermogenic effects in the body, leading to better fat loss.

Pungent Spices (Capsaicin, Piperine, Ginger (Gingerols), Cinnamon)

Without spices, many of your favorite foods wouldn’t be much better than the bland bro-tastic meal of baked chicken breast and steamed broccoli.

Spices give culinary fare nuance, depth and bite. They help inject life into that broiled, grilled, or pan-fried hunk of animal flesh and tantalize your taste buds to keep you coming back for more.

They can also help ignite your internal fire and rev your metabolism, too. 

Best of all, you don’t have to scour the Far East to unearth these potent flavor bombs, most of you reading this likely have these spices in your own kitchen right now. 

Research has identified four key spices that boost metabolism and enhance fat loss. Those four spices are:

- Capsaicin (present in chili peppers)

- Piperine (present in black pepper)

- Gingerol (present in ginger)

- Cinnamaldehyde (present in cinnamon)

Capsaicin is the tongue-numbing alkaloid that gives chili peppers their distinctive bite. It binds directly to the TRPV1 receptor in the oral cavity, causing noradrenaline to be released, which as we mentioned above is very good for stimulating brown fat thermogenesis.

Several interesting pieces of research have shown that ingesting just a single dose of capsaicin can ramp up brown fat thermogenesis. And, when used continuously for six weeks, capsaicin supplementation leads to reduced body fat.

But that’s not all, the same study also found significant thermogenic activity in brown fat in individuals with very low amounts of brown fat. This indicates that capsaicin, consumed consistently, may lead to an increase in brown fat stores in the body.

Now, there’s a bit of decision-making you have to do when deciding on what form of capsaicin to purchase as there are several variations floating around the market. By and large, these “alternative” forms of capsaicin use an enteric-coating or time-release technology to delay the release of the capsaicin alkaloids into the body.

The reason for this is that in some people ingesting pure capsaicin can lead to an intense warming sensation in the body and a bit of GI upset.

Coating the capsaicin helps avoid this GI upset, but it comes with a cost.

You see, capsaicin targets the the TRPV1 receptors, the majority of which are located in the oral cavity and upper GI tract. By using an enteric-coated, delayed-release form of capsaicin, you are bypassing many of the prime targets for capsaicin, which could significantly reduce the compound’s metabolism-boosting potential.

In fact, researchers estimate that an individual would need to consume roughly 2-3 times the amount of enteric-coated capsaicin to account for its delayed release.

Now, there’s a close capsaicin relative known as dihydrocapsiate. It’s found in the CH-19 sweet pepper and is touted to be about 1,000 times more potent than capsaicin in terms of lighting up your taste buds.

It’s also been noted that dihydrocapsiate shares the same beneficial metabolic qualities as capsaicin without inducing the unwanted GI side effects.

Despite sharing some similarities, capsiate has been noted to be less effective than capsaicin, especially during periods of negative energy balance (i.e. dieting).

The takeaway on capsaicin is that if you want to take full advantage of the compound’s potential use the pure, simple form. And, if you’re worried about minor GI upset, you can take your serving of capsaicin alongside a meal, which reduces feelings of heartburn.

Moving on from the powers of capsaicin, we turn our attention to three other distinct spices in black pepper, ginger, and cinnamon. Each of these culinary staples contains a unique chemical which has been shown to induce thermogenesis (and increase energy expenditure) via activation of TRPV1 family of receptors.

Ursolic Acid

Prevalently found in apple peels and the Ayurvedic herb Holy Basil, ursolic acid is an intriguing thermogenic supplement. Research has noted that the compound may be capable of increasing the amount of brown fat in the body via increasing activity of uncoupling protein (UCP-1).

Additional research indicates that ursolic acid may have anabolic properties too, increasing muscle mass and limiting protein degradation. An animal study from the University of Iowa documented that ursolic acid prevented muscle breakdown following food deprivation (fasting) and spinal cord injury.

Together, these actions make ursolic acid an incredibly intriguing supplement to consider using regardless if your goal is to burn fat, build muscle, or recomp.

Ursolic acid owes its pro-muscle building effects to mimicking the effects of the favorite whipping boy of low-carb dieters, insulin. Specifically, ursolic acid beneficially impacts insulin signaling in skeletal muscle (a very good thing for hypertrophy) while also limiting activity of a gene associated with atrophy.

Olive Leaf Extract

The Mediterranean Diet has been lauded for over a decade for its heart-healthy benefits and is perennially highlighted as one of the best diets for overall health and weight loss.

In addition to a heavy emphasis on nutrient rich, whole foods, the Mediterranean diet also promotes the regular consumption of olive oil, a tasty liquid chock-full of monounsaturated fats. 

As most of you know, olive oil comes from pressing olives found on the olive tree. The leaves of the olive tree (as well as olive oil itself) are rich in a potent polyphenol called oleuropein.

So, how does this olive oil chemical enhance fat burning?

Above, we mentioned a protein in fat cells called UCP-1 (uncoupling protein-1).

Since their discovery, uncoupling proteins have generated an immense amount of interest from dieters and obesity researchers due to their ability to cause cells to dissipate energy as heat, instead of storing it as fat or using that energy to generate ATP.

It’s also important to note that UCPs account for roughly 10% of the mitochondrial protein content in BAT and play a significant thermogenic role in it as well.

Animal studies have found that supplementing with oleuropein increases levels of the fat-burning hormones adrenaline and noradrenaline, and it also ramps up uncoupling activity, which would lead to increased energy expenditure.

Additional studies indicate that supplementation with olive leaf extract support thyroid function and may increase thyroid hormone T3 2.5x above baseline. As you’re probably aware, dieting for prolonged periods of time can result in reduced thyroid function and a slower metabolic rate.

Supplementing with oleuropein in the form of olive leaf extract may provide two separate mechanisms for enhancing weight loss and shedding unwanted body fat.

Kaempferol

No doubt you’ve heard of many of the compounds on this list, but one you probably haven’t encountered is a little chemical called kaempferol.

Kaempferol is another potent polyphenol noted to have some fairly impressive thermogenic properties. It’s naturally occurring in a variety of dietary staples including broccoli, tea, and grapefruit and has been noted to stimulate thermogenesis in muscle cells.

Believe it or not, fat cells aren’t the only ones that burn energy via thermogenesis, muscle cells do too. As you’re aware, skeletal muscle is one of the main factors impacting your basal metabolic rate (BMR) -- the more muscle you have, the higher your BMR is.

And, you’re also probably aware that muscle contractions generate heat, which is part of the reason you feel hot and start sweating during intense exercise. Well, researchers have recently discovered that skeletal muscle also performs non-shivering thermogenesis, meaning it can give off heat and burn energy outside of exercise.

Kaempferol has been documented to increase skeletal muscle thermogenesis and it also stimulates thyroid hormone production, which subsequently activates thermogenesis in brown fat.

What this means is that kaempferol has the extremely rare ability to induce thermogenesis in different types of cells in the body.

Melatonin

Melatonin is a hormone naturally produced by the body most often associated with sleep and helping set the body’s internal clock, a.k.a. circadian rhythm. 

But, that just begins to scratch the surface of the many roles melatonin serves in the body.

It also plays a role in energy metabolism and bodyweight maintenance. Numerous studies have noted that melatonin supplementation leads to reductions in total bodyweight and abdominal fat.

Here’s the kicker -- those reductions in weight and fat mass can occur without subjects eating less food or increasing their amount of physical activity. This suggests that the boost in energy expenditure is due to brown fat activation.

And, as it turns out, there is some human research showing melatonin supplementation promotes weight loss. A study from Aarhus University in Denmark found that women using 5mg of melatonin (the amount typically contained in most sleep aids) per day reduced body fat by almost 7% and increased lean mass by 5.2%. 

Bile Acids

Bile acids are produced from cholesterol and serve an important role in digestion where they act as emulsifiers for fat to improve digestion.  

The use of bile acids as a supplement has been considered as a means to enhance fat loss due to their ability to stimulate thyroid hormone function, which ramps up thermogenesis in brown fat.

More specifically bile acids can bind to the TGR5 receptor located in the cellular membrane of brown fat. Following this activation of TGR5, expression of the enzyme deiodinase increases.

Deiodinase stimulates the production of the active thyroid hormone T3 (triiodothyronine). As we explained above, increasing thyroid function is very good for raising metabolism,[40] and more specifically thermogenesis. With greater T3 comes an increase in uncoupling protein-1 activity, which boosts BAT activity.

In fact, researchers from Maastricht University Medical Center in the Netherlands observed that ingesting supplemental chenodeoxycholic acid (one of the acids found in bile) increased brown fat activity in adult women.

The Best Thermogenic, BAT-Activating Supplement

Most thermogenic fat burners you’ll find do very little in the way of actually helping you burn fat. 

But, that doesn’t mean all fat burners are junk. In fact, fat burners can be particularly effective for helping you shed those unwanted pounds -- if they’re formulated with scientifically backed ingredients.

AML ThermoHeat is that fat burner. 

ThermoHeat has been meticulously formulated to help activate brown fat, boost metabolism, increase energy expenditure, and most importantly, lose weight. Try AML ThermoHeat, Thermo Heat Nighttime, Thermo Heat Multi and Thermo Heat Fat Burning Protein for yourself today and see what a real fat burner, built on science, can do for your weight-loss goals.

 References:

1. Projected U.S. State-Level Prevalence of Adult Obesity and Severe Obesity Zachary J. Ward, M.P.H., Sara N. Bleich, Ph.D., Angie L. Cradock, Sc.D., Jessica L. Barrett, M.P.H., Catherine M. Giles, M.P.H., Chasmine Flax, M.P.H., Michael W. Long, Sc.D., and Steven L. Gortmaker, Ph.D.  December 19, 2019. N Engl J Med 2019; 381:2440-2450 DOI: 10.1056/NEJMsa1909301

2. Carbohydrate restriction in the morning increases weight loss effect of a hypocaloric Mediterranean type diet: a randomized, parallel group dietary intervention in overweight and obese subjects, Dimitrios Dellis, Dimitrios Tsilingiris, Ioanna Eleftheriadou, Anastasios Tentolouris, Pavlos P. Sfikakis, Georgios Dellis, Menia Karanasiou, Aikaterini Meimari, Charilaos Dimosthenopoulos, Spyros Lazarou, Nikolaos Tento louris,Nutrition, March 2020 https://doi.org/10.1016/j.nut.2019.110578.
3. Chili Pepper Consumption and Cardiovascular Mortality. J. David Spence J Am Coll Cardiol. 2019 Dec, 74 (25) 3150-3152. DOI: 10.1016/j.jacc.2019.08.1071

4. The beneficial effects of Mediterranean diet over low-fat diet may be mediated by decreasing hepatic fat content. August 7, 2019. Gepner, Yftach et al.Journal of Hepatology, Volume 71, Issue 2, 379 – 388 doi: 10.1016/j.jhep.2019.04.013.
5. Ebbeling Cara B, Feldman Henry A, Klein Gloria L, Wong Julia M W, Bielak Lisa, Steltz Sarah K et al. Effects of a low carbohydrate diet on energy expenditure during weight loss maintenance: randomized trial BMJ 2018; 363 :k4583
6. Effect of a Lifestyle Intervention Program With Energy-Restricted Mediterranean Diet and Exercise on Weight Loss and Cardiovascular Risk Factors: One-Year Results of the PREDIMED-Plus Trial. Jordi Salas-Salvadó, Andrés Díaz-López, Miguel Ruiz-Canela, Josep Basora, MontseFitó, Dolores Corella, Luís Serra-Majem, Julia Wärnberg, Dora Romaguera, RamonEstruch, Josep Vidal, J. Alfredo Martínez, Fernando Arós, Clotilde Vázquez, EmilioRos, Jesús Vioque, José López-Miranda, Aurora Bueno-Cavanillas, Josep A. Tur, Francisco J. Tinahones, Vicente Martín, José Lapetra, Xavier Pintó, Lidia Daimiel,Miguel Delgado-Rodríguez, Pilar Matía, Enrique Gómez-Gracia, Javier Díez-Espino,Nancy Babio, Olga Castañer, José V. Sorlí, Miquel Fiol, María Ángeles Zulet, MònicaBulló, Albert Goday, Miguel A. Martínez-González, for the PREDIMED-Plus investigators. Diabetes Care Nov 2018, dc180836; DOI:2337/dc18-0836
7. Effect of Distinct Lifestyle Interventions on Mobilization of Fat Storage Pools: The CENTRAL MRI Randomized Controlled Trial. Yftach Gepner, Ilan Shelef, Dan Schwarzfuchs, Hila Zelicha, Lilac Tene, Anat Yaskolka Meir, Gal Tsaban, Noa Cohen, Nitzan Bril, Michal Rein, Dana Serfaty, Shira Kenigsbuch, Oded Komy, Arik Wolak, Yoash Chassidim, Rachel Golan, Hilla Avni-Hassid, Avital Bilitzky, Benjamin Sarusi, Eyal Goshen, Elad Shemesh, Yaakov Henkin, Michael Stumvoll, Matthias Blüher, Joachim Thiery, Uta Ceglarek, Assaf Rudich, Meir J. Stampfer and Iris Shai. Circulation 2017;CIRCULATION AHA.117.030501, 2017.
8. Monitoring Fatty Liver Disease with MRI Following Bariatric Surgery: A Prospective, Dual-Center Study Dustin Pooler, Curtis N. Wiens, Alan McMillan, Nathan S. Artz, Alexandra Schlein, Yesenia Covarrubias, Jonathan Hooker, Jeffrey B. Schwimmer, Luke M. Funk, Guilherme M. Campos, Jacob A. Greenberg, Garth Jacobsen, Santiago Horgan, Tanya Wolfson, Anthony C. Gamst, Claude B. Sirlin, and Scott B. Reeder Radiology 0 0:0 
9. S. News Reveals Best Diets Rankings for 2018. January 3, 2018 US News & World Report.
10. Ahmad S, Moorthy MV, Demler OV, et al. Assessment of Risk Factors and Biomarkers Associated With Risk of Cardiovascular Disease Among Women Consuming a Mediterranean Diet. JAMA Netw Open.2018;1(8):e185708. doi:10.1001/jamanetworkopen.2018.5708
11. Brigham and Women's Hospital. "What's behind Mediterranean diet and lower cardiovascular risk? Investigators identify, assess underlying mechanisms that may explain diet's 25 percent reduction in cardiovascular risk for American women." ScienceDaily. ScienceDaily, 7 December 2018. www.sciencedaily.com/releases/2018/12/181207125240.htm
12. Marialaura Bonaccio, Augusto Di Castelnuovo, Simona Costanzo, Mariarosaria Persichillo, Amalia De Curtis, Chiara Cerletti, Maria Benedetta Donati, Giovanni de Gaetano, Licia Iacoviello. Interaction between Mediterranean diet and statins on mortality risk in patients with cardiovascular disease: Findings from the Moli-sani Study. International Journal of Cardiology, 2018; DOI: 1016/j.ijcard.2018.11.117
13. Istituto Neurologico Mediterraneo Neuromed I.R.C.C.S. "Statins are more effective for those who follow the Mediterranean diet." ScienceDaily. ScienceDaily, 21 December 2018. www.sciencedaily.com/releases/2018/12/181221123751.htm
14. Effect of low carbohydrate high fat diet on LDL cholesterol and gene expression in normal-weight, young adults: A randomized controlled study. Retterstøl, Kjetil et al. Atherosclerosis, October 17, 2018, Volume 279, 52-61,
15. Spanish Ketogenic Mediterranean diet: a healthy cardiovascular diet for weight loss. Nutrition Journal, 2008, Volume 7, Number 1, Page 1. Joaquín Pérez-Guisado, Andrés Muñoz-Serrano, Ángeles Alonso-Moraga
16. Long-term successful weight loss with a combination biphasic ketogenic Mediterranean diet and Mediterranean diet maintenance protocol. Paoli, A., Bianco, A., Grimaldi, K. A., Lodi, A., & Bosco, G. (2013). Nutrients, 5(12), 5205-17. doi:10.3390/nu5125205
17. Effect of ketogenic Mediterranean diet with phytoextracts and low carbohydrates/high-protein meals on weight, cardiovascular risk factors, body composition and diet compliance in Italian council employees. Paoli, A., Cenci, L., & Grimaldi, K.A. (2011). Nutrition journal, 10, 112. doi:10.1186/1475-2891-10-112
18. The Endocrine Society. "Mediterranean diet is linked to higher muscle mass, bone density after menopause." ScienceDaily. ScienceDaily, 18 March 2018. www.sciencedaily.com/releases/2018/03/180318144826.htm
19. Effect of combined use of a low-carbohydrate, high-protein diet with omega-3 polyunsaturated fatty acid supplementation on glycemic control in newly diagnosed type 2 diabetes: a randomized, double-blind, parallel-controlled trial, Kai Liu, Bin Wang, Rui Zhou, He-Dong Lang, Li Ran, Jian Wang, Ling Li, Chao Kang, Xiao-Hui Zhu, Qian-Yong Zhang, Jun-Dong Zhu, Steve Doucette, Jing X Kang, Man-Tian Mi; The American Journal of Clinical Nutrition, Volume 108, Issue 2, 1 August 2018, Pages 256-265, https://doi.org/10.1093/ajcn/nqy120
20. Acute effects of three high-fat meals with different fat saturations on energy expenditure, substrate oxidation and satiety. Casas-Agustench, P. et al. Clinical Nutrition, Volume 28, Issue 1, 39-45 2009
21. The effect of dietary oleic, linoleic, and linolenic acids on fat oxidation and energy expenditure in healthy men. Jones, Peter J.H. et al. Metabolism - Clinical and Experimental, Volume 57, Issue 9, 1198-1203
22. The influence of the type of dietary fat on postprandial fat oxidation rates: monounsaturated (olive oil) vssaturated fat (cream). LS Piers, KZ Walker, RM Stoney, MJ Soares and K O’Dea. International Journal of Obesity(2002) 26, 814-821 (2002)
23. Oleuropein, a Phenolic Compound in Extra Virgin Olive Oil, Increases Uncoupling Protein 1 Content in Brown Adipose Tissue and Enhances Noradrenaline and Adrenaline Secretions in Rats, Journal of Nutritional Science and Vitaminology, Released November 11, 2008 Yuriko Oi-Kano, Teruo Kawada, Tatsuo Watanabe, Fumihiro Koyama, Kenichi Watanabe, Reijirou Senbongi, Kazuo Iwai
24. Miroslav Balaz, Anton S. Becker, Lucia Balazova, Leon Straub, Julian Müller, Gani Gashi, Claudia Irene Maushart, Wenfei Sun, Hua Dong, Caroline Moser, Carla Horvath, Vissarion Efthymiou, Yael Rachamin, Salvatore Modica, Caroline Zellweger, Sara Bacanovic, Patrik Stefanicka, Lukas Varga, Barbara Ukropcova, Milan Profant, Lennart Opitz, Ez-Zoubir Amri, Murali K. Akula, Martin Bergo, Jozef Ukropec, Christian Falk, Nicola Zamboni, Matthias Johannes Betz, Irene A. Burger, Christian Wolfrum. Inhibition of Mevalonate Pathway Prevents Adipocyte Browning in Mice and Men by Affecting Protein Prenylation. Cell Metabolism, 2018; DOI: 1016/j.cmet.2018.11.017
25. ETH Zurich. "Cholesterol-lowering drugs reduce brown adipose tissue." ScienceDaily. ScienceDaily, 21 December 2018. www.sciencedaily.com/releases/2018/12/181221123745.htm
26. The Gerontological Society of America. "Can a Mediterranean diet pattern slow aging?" ScienceDaily. ScienceDaily, 30 March 2018. www.sciencedaily.com/releases/2018/03/180330145322.htm
27. Valeria Tosti, Beatrice Bertozzi, Luigi Fontana; Health Benefits of the Mediterranean Diet: Metabolic and Molecular Mechanisms, The Journals of Gerontology: Series A, Volume 73, Issue 3, 2 March 2018, Pages 318-326, https://doi.org/10.1093/gerona/glx227
28. Voelker R. The Mediterranean Diet’s Fight Against Frailty. 2018;319(19):1971-1972. doi:10.1001/jama.2018.3653
29. Joana Araújo, Jianwen Cai, June Stevens. Prevalence of Optimal Metabolic Health in American Adults: National Health and Nutrition Examination Survey 2009-2016. Metabolic Syndrome and Related Disorders, 2018; DOI: 1089/met.2018.0105
30. Effect of a high-fat Mediterranean diet on bodyweight and waist circumference: a prespecified secondary outcomes analysis of the PREDIMED randomised controlled trial. Lancet Diabetes EndocrinologyDr Ramon Estruch, MD  ^†Prof Miguel Angel Martínez-González, MD et al. June 06, 2016DOI:https://doi.org/10.1016/S2213-8587(16)30085-7
31. Adherence to the Mediterranean diet is associated with lower platelet and leukocyte counts: results from the Moli-sani study. Marialaura Bonaccio, Augusto Di Castelnuovo, Amalia De Curtis, Simona Costanzo, Mariarosaria Persichillo, Maria enedetta Donati, Chiara Cerletti, Licia Iacovielloand Giovanni de Gaetano on behalf of the Moli-sani Project Investigators. Blood 2014 123:3037-3044; doi: https://doi.org/10.1182/blood-2013-12-541672
32. Mediterranean Diet Reduces Risk of Incident Stroke in a Population With Varying Cardiovascular Disease Risk Profiles. Paterson, K. E., Myint, P.K., Jennings, A., Bain, L., Lentjes, M., Khaw, K. T., & Welch, A.A. (Oct 2018). Stroke, 49 (10), 2415-2420. Advance online publication. doi:10.1161/STROKEAHA.117.020258
33. Mediterranean Diet and Incidence of Advanced Age-Related Macular Degeneration. Merle, Bénédicte M.J.Ajana, Soufiane et al. Ophthalmology, Volume 0, Issue 0, October 2018.

1.  Seale P, Lazar MA. Brown fat in humans: turning up the heat on obesity. Diabetes. 2009;58(7):1482-4.
2. Goldstein ER, Ziegenfuss T, Kalman D, et al. International society of sports nutrition position stand: caffeine and performance. J Int Soc Sports Nutr. 2010;7(1):5. Published 2010 Jan 27. doi:10.1186/1550-2783-7-5
3. Dulloo AG, Geissler CA, et al. Normal caffeine consumption: influence on thermogenesis and daily energy expenditure in lean and postobese human volunteers. Am J Clin Nutr 1989;49, 44-50.
4. Yoneshiro, Takeshi, et al. "Tea catechin and caffeine activate brown adipose tissue and increase cold-induced thermogenic capacity in humans." The American Journal of Clinical Nutrition, vol. 105, no. 4, 2017, pp. 873-881.
5. Astrup A, Toubro S, Cannon S. Caffeine: A double-blind, placebo-controlled study of its thermogenic, metabolic, and cardiovascular effects in healthy volunteers. Am J Clin Nutr. 1990;51:759–67.
6. Stohs SJ, Preuss HG, et al. Effects of p-synephrine alone and in combination with selected bioflavonoids on resting metabolism, blood pressure, heart rate and self-reported mood changes. Int J Med Sci 2015;8, 295-301.
7. Molinoff, Perry B. "Alpha- and beta-Adrenergic Receptor Subtypes Properties, Distribution and Regulation." Drugs, vol. 28, no. Supplement 2, 1984, pp. 1-15.
8. Stohs SJ, Preuss HG, Shara M. A review of the receptor-binding properties of p-synephrine as related to its pharmacological effects. Oxid Med Cell Longev. 2011;2011:1–9. doi: 10.1155/2011/482973.
9. Ratamess NA, Bush JA, Kang J, et al. The effects of supplementation with P-Synephrine alone and in combination with caffeine on resistance exercise performance. Journal of the International Society of Sports Nutrition. 2015;12:35. doi:10.1186/s12970-015-0096-5.
10. Ratamess NA, Bush JA, Kang J, et al. The Effects of Supplementation with p-Synephrine Alone and in Combination with Caffeine on Metabolic, Lipolytic, and Cardiovascular Responses during Resistance Exercise. J Am Coll Nutr. 2016;35(8):657-669. doi:10.1080/07315724.2016.1150223.
11. Zhao J, Cannon B and Nedergaard J. alpha1-Adrenergic stimulation potentiates the thermogenic action of beta3-adrenoreceptor-generated cAMP in brown fat cells. J Biol Chem 1997;272, 32847-32856.
12. Scarpace PJ and Matheny M. Thermogenesis in brown adipose tissue with age: post-receptor activation by forskolin. Pflugers Arch 1996;431, 388-394.
13. Arias-Carrion, O., & Poppel, E. (2007). Dopamine, learning, and reward-seeking behavior. Acta Neurobiologiae Experimentalis, 67(4), 481–488.
14. Treadway MT, Buckholtz JW, Cowan RL, et al. Dopaminergic Mechanisms of Individual Differences in Human Effort-Based Decision-Making. J Neurosci. 2012;32(18):6170 LP-6176.
15. Hull KM and Maher TJ. Effects of L-tyrosine on mixed-acting sympathomimetic-induced pressor actions. Pharmacol Biochem Behav 1992;43, 1047-1052.
16. Tharakan B, Dhanasekaran M, et al. Anti-Parkinson botanical Mucuna pruriens prevents levodopa induced plasmid and genomic DNA damage. Phytother Res 2007;21, 1124-1126.
17. Katzenschlager R, Evans A, et al. Mucuna pruriens in Parkinson's disease: a double blind clinical and pharmacological study. J Neurol Neurosurg Psychiatry 2004;75, 1672-1677.
18. Ruttimann Y, Schutz Y, et al. Thermogenic and metabolic effects of dopamine in healthy men. Crit Care Med 1991;19, 1030-1036.
19. Yoneshiro T, Aita S, et al. Nonpungent capsaicin analogs (capsinoids) increase energy expenditure through the activation of brown adipose tissue in humans. Am J Clin Nutr 2012;95, 845-850.
20. Saito M and Yoneshiro T. Capsinoids and related food ingredients activating brown fat thermogenesis and reducing body fat in humans. Curr Opin Lipidol 2013;24, 71-77.
21. Yoneshiro T, Aita S, et al. Recruited brown adipose tissue as an antiobesity agent in humans. J Clin Invest 2013;123, 3404-3408.
22. Yoneshiro T and Saito M. Transient receptor potential activated brown fat thermogenesis as a target of food ingredients for obesity management. Curr Opin Clin Nutr Metab Care 2013;16, 625-631.
23. McNamara FN, Randall A and Gunthorpe MJ. Effects of piperine, the pungent component of black pepper, at the human vanilloid receptor (TRPV1). Br J Pharmacol 2005;144, 781-790.
24. Godard, Michael P., et al. "Body Composition and Hormonal Adaptations Associated with Forskolin Consumption in Overweight and Obese Men." Obesity Research, vol. 13, no. 8, 2005, pp. 1335-1343.
25. Jagtap M, Chandola HM, Ravishankar B. Clinical efficacy of Coleus forskohlii (Willd.) Briq. (Makandi) in hypertension of geriatric population. Ayu. 2011;32(1):59-65.
26. Kunkel SD, Elmore CJ, et al. Ursolic acid increases skeletal muscle and brown fat and decreases diet-induced obesity, glucose intolerance and fatty liver disease. PLoS One 2012;7, e39332
27. Jia, Yaoyao, et al. "Ursolic acid improves lipid and glucose metabolism in high-fat-fed C57BL/6J mice by activating peroxisome proliferator-activated receptor alpha and hepatic autophagy." Molecular Nutrition & Food Research, vol. 59, no. 2, 2014, pp. 344-354.
28. Chu, Xia, et al. "Ursolic acid increases energy expenditure through enhancing free fatty acid uptake and β-oxidation via an UCP3/AMPK-dependent pathway in skeletal muscle." Molecular Nutrition & Food Research, vol. 59, no. 8, 2015, pp. 1491-1503.
29. Kunkel SD, et al. mRNA expression signatures of human skeletal muscle atrophy identify a natural compound that increases muscle mass. Cell Metab. (2011)
30. da-Silva WS, Harney JW, et al. The small polyphenolic molecule kaempferol increases cellular energy expenditure and thyroid hormone activation. Diabetes 2007;56, 767-776.
31. Busiello RA, Savarese S, Lombardi A. Mitochondrial uncoupling proteins and energy metabolism. Front Physiol. 2015;6:36. Published 2015 Feb 10. doi:10.3389/fphys.2015.00036
32. Oi-Kano, Yuriko, et al. "Oleuropein aglycone enhances UCP1 expression in brown adipose tissue in high-fat-diet-induced obese rats by activating β-adrenergic signaling." The Journal of Nutritional Biochemistry, vol. 40, 2017, pp. 209-218.
33. Al-Qarawi, A. A., Al-Damegh, M. A. and ElMougy, S. A. (2002), Effect of freeze dried extract of Olea europaea on the pituitary–thyroid axis in rats. Phytother. Res., 16: 286–287. doi:10.1002/ptr.855.
34. Periasamy M, Herrera JL, Reis FCG. Skeletal Muscle Thermogenesis and Its Role in Whole Body Energy Metabolism. Diabetes Metab J. 2017;41(5):327-336.
35. Wolden-Hanson T, Mitton DR, et al. Daily melatonin administration to middle-aged male rats suppresses body weight, intraabdominal adiposity, and plasma leptin and insulin independent of food intake and total body fat. Endocrinology 2000;141, 487-497.
36. Tan DX, Manchester LC, et al. Significance and application of melatonin in the regulation of brown adipose tissue metabolism: relation to human obesity. Obes Rev 2011;12, 167-188.
37. Amstrup, Anne K., et al. "Reduced fat mass and increased lean mass in response to 1 year of melatonin treatment in postmenopausal women: A randomized placebo-controlled trial." Clinical Endocrinology, vol. 84, no. 3, 2015, pp. 342-347.
38. Watanabe M, Houten SM, et al. Bile acids induce energy expenditure by promoting intracellular thyroid hormone activation. Nature 2006;439, 484-489.
39. Broeders, Evie P.M., et al. "The Bile Acid Chenodeoxycholic Acid Increases Human Brown Adipose Tissue Activity." Cell Metabolism, vol. 22, no. 3, 2015, pp. 418-426.
40. Mullur R, Liu YY, Brent GA. Thyroid hormone regulation of metabolism. Physiol Rev. 2014;94(2):355-82.
41. Holtzer P (2002): Sensory neurone responses to mucosal noxae in the upper gut: relevance to mucosal integrity and gastrointestinal pain. Mot. 14, 459–475.
42. Ward SM, Bayguinov J, Won K-J, Gryndy D & Berthoud HR (2003): Distribution of vanilloid receptor (VR1) in the gastrointestinal tract. J. Comp. Neurol. 465, 121–135.
43. Belza, A., and A. B. Jessen. "Bioactive food stimulants of sympathetic activity: effect on 24-h energy expenditure and fat oxidation." European Journal of Clinical Nutrition, vol. 59, no. 6, 2005, pp. 733-741.
44. Reinbach, H.C., 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." Clinical Nutrition, vol. 28, no. 3, 2009, pp. 260-265.
45. Ludy MJ, Moore GE, Mattes RD. The effects of capsaicin and capsiate on energy balance: critical review and meta-analyses of studies in humans. Chem Senses. 2011;37(2):103-21.