The Key To Healthy Weight: Good Fat In, Excess Fat Out

The increase in prevalence of obesity in the U.S. during the 20th century, which has accelerated in the first two decades of the current century, has been attributed at least in part to a marked increase in consumption of high-fat processed-food rich in the polyunsaturated omega-6 fatty acid linoleic acid, a precursor to arachidonic acid.¹

Linoleic acid is classified as an essential fatty acid (needs to be supplied through food and cannot be produced by the human body, i.e., endogenously) for human health with a typically recommended daily dose of 3 grams. However, this essential nutrient is commonly found in most processed foods and is over-consumed in the Western diet by 5 to 30 times, causing a dramatic imbalance. The concern with the excess dietary linoleic acid is that its consumption may increase content of the cell membrane-bound omega-6 arachidonic acid and contribute to chronic overproduction of endocannabinoids.

New evidence has emerged that saturated fat of animal origin, which is an energy “white” storage fat, may not necessarily be the culprit in obesity, but rather certain vegetable oils (e.g., safflower, sunflower, corn, soy and peanut oils), which are rich in omega-6 linoleic acid and are omnipresent in our daily processed food. The animal saturated fat may or may not be a source of omega-6 vs. omega-3 fatty acids depending on feed received by the animals.

For example, beef from grain (corn) fed animals would have higher proportions of omega-6 to omega-3 fatty acids while grass fed animals would provide meat high in omega-3 fatty acids. Therefore, animal fat, eggs, dairy and butter from nutritionally sound stock will provide healthy storage fat with a healthy proportion of omega-3/6 fatty acids, which eaten in moderation and combined with a sensible lifestyle, will not contribute to obesity—giving credit to the Atkins diet. Therefore omega-6, omega-3 fatty acids, saturated fatty acids and contained fat-soluble vitamins A, D, E and K2 are all important to maintain metabolic health, however, their excessive and unbalanced consumption will contribute to metabolic deterioration, overweight and obesity conditions.

Risk Factors vs. Causes of Obesity
Obesity and overweight conditions in pandemic proportions resemble unmanageable health problems from another time in human history: before the discovery of antibiotics when infectious diseases decimated populations due to the disease process that was poorly understood and left without effective treatment. The cause was unknown and therefore the treatment was unknown. Similar to times when bacteria and antibiotics were unknown and blood-letting was a common and a futile practice to treat infectious diseases, now we are presented with an urgent need to discover a true cause and the equivalent solution to the pandemic proportions of obesity and metabolic deterioration.

The reason “why” we are losing the battle with obesity may be as simple as the lack of distinction between the cause of obesity and the risk factors that increase the likelihood of developing overweight or obese conditions. The calorie-dense Western-type diet, super-sizing meals, overeating, snacking and sedentary lifestyle qualify as the risk factors. However, a common cause of obesity may ultimately not be in the calories, carbs and fats but in the mechanism that directly and actively promotes obesity.

Each of us has a natural protective metabolic mechanism against obesity, which can be overwhelmed when the body is frequently barraged by food. When we arrive to that turn-around point the body can respond with misguided pathological mechanisms, which in time become the cause of obesity and/or type 2 diabetes mellitus. One such mechanism is excess dietary fatty acids that gradually incapacitate hepatocytes (liver cells), and compromise one of the major functions of the liver: oxidation and utilization of fat for energy. A liver burdened with accumulated fat is referred to clinically as non-alcoholic fatty liver disease (NAFLD).

Targeting the Cause: Fat Regulating Fat
Although NAFLD was discovered and named in 1980, only recently has it been increasingly recognized as a leading cause of chronic liver disease in the western world.^2-5 Nutritional intervention such as balanced diet is well-known as the first line of defense against NAFLD. However, the emerging target mechanisms in dietary intervention against NAFLD and co-morbid conditions is the endocannabinoid system (ECS) and its role in regulating metabolic functions, satiety and energy homeostasis.⁶ The ECS, which also regulates mood, memory and pain sensation, owes its name to Cannabis indicis, since it mediates/mimics the psychoactive effects of cannabis.

The ECS consists of circulating endocannabinoids derived from cell membrane omega-6 fatty acids, mainly arachidonic acid, and the corresponding network of cannabinoid receptors 1 and 2 (i.e., CB1 and CB2) scattered throughout the body, especially in some of the oldest parts of the central nervous system (CNS) (i.e., limbic system, hypothalamus and medulla oblongata).⁷ Those brain structures command the most basic functions of the organism like motivation and drive (e.g., compulsive behavior, functions of the autonomic nervous system and endocrine system).

The high-fat diet and obesity stimulate the ECS and upregulate CB1 and B2 receptors by increasing synthesis of endocannabinoids activating CB1 and CB2 receptors.⁸ The overactive ECS increases appetite, builds up insulin resistance, slows down glucose metabolism and increases fat storage production (lipogenesis and adipogenesis) by exerting its action in the CNS, the liver (hepatocytes), adipose tissue (adipocytes), skeletal muscle and pancreatic islet cells.

The overactive ECS and accumulating liver fat results in shutting off metabolic functions of hepatocytes and beta-oxidation of fatty acids for vital energy, reduced sensitivity to insulin, glucose intolerance, further increasing the appetite levels and fueling NAFLD.⁹ The increase in circulating endocannabinoids, activation of CB1 and CB2 receptors and NAFLD positively and significantly correspond with increased body mass index, waist circumference, abdominal adiposity, overweight and obesity, pre-diabetes, diabetes and metabolic syndrome.

The First Step: Healthy-Fat Diet
Endocannabinoids are predominantly products derived from dietary fats. A healthy diet consisting of whole, unprocessed foods low in polyunsaturated omega-6 and high in polyunsaturated omega-3 fatty acids, is—and should be considered—the first approach to down-regulate the overactive ECS and its metabolic consequences.^10-14 Providing metabolic health-promoting omega-3 fatty acids and replacing omega-6 fatty acids also serves to gradually diminish synthesis and availability of endocannabinoids. The stress is on “gradually diminish synthesis” as opposed to the pharmacological approach of blocking overactive ECS and CB receptors—the latter mechanism being known to effectively reverse metabolic deterioration and obesity, but also to negatively affect the mood (e.g., Rimonabant).

The task of gradual nutritional intervention to normalize the ECS is accomplished in two ways: 1) consuming an omega-3 fatty acid rich diet that would compete with omega-6 fatty acids for enzymes (desaturase and elongase) in the gastrointestinal tract, and 2) providing omega-3 long chain polyunsaturated fatty acids (i.e., EPA and DHA), which would directly substitute long chain polyunsaturated omega-6 fatty acids (e.g., arachidonic acid) in the cell membrane. Dietary omega-3 polyunsaturated fatty acids (marine food, krill and fish oils, vegetables and fruits) are known to improve NAFLD and related overweight and obesity conditions, presumably by slowing down metabolic pathways leading to synthesis of endocannabinoids.^15-19

Preventing Excess Dietary Fat Absorption
While healthy lifestyle and diet that includes omega-3 polyunsaturated fatty acids may be a cornerstone targeting overactive ECS, the intervention to prevent excess gastrointestinal fat absorption may provide an additional and critically important synergistic effect.

Inhibition of pancreatic lipase in dietary fat digestion and absorption has been utilized in weight management and has been proven as an effective strategy in metabolic health. This strategy has been supported with studies of known pancreatic lipase inhibitor Orlistat (120 mg tid) vs. placebo in obese subjects evaluating positive impact on weight loss, glycemic control and composition of omega-3 fatty acids in skeletal muscle.²⁰ 

However, excessive pancreatic lipase inhibition (e.g., tetrahydrolipstatin, Orlistat, Alli), also has several known side effects, including unpleasant gastrointestinal issues—steatorrhea (oily, loose stools with excessive intestinal putrefaction and flatus due to unabsorbed fats reaching the large intestine), fecal incontinence, frequent bowel movements and urgency, compromised absorption of fat-soluble vitamins and nutrients, increased appetite and diminished effectiveness over time.

Therefore, to safely and effectively control an overactive endocannabinoid system, there is a continuous need to develop safe and effective regimens preventing gastrointestinal absorption and accumulation of excess dietary fat. The herbal composition FB3 Fusion Ingredient that features Coleus forskohlii, Salacia reticulata and Sesamum indicum—standardized for diterpene forskolin, kotanol and salacinol, and sesamin, respectively—has been shown to inhibit pancreatic lipase with differing degrees and dynamics.

The potential of three herbal extracts in FB3 Fusion Ingredient preventing dietary fat absorption has been emphasized by the in vitro synergy between C. forskohlii and S. reticulata inhibiting pancreatic lipase at a higher rate than the fat-blocking activity generated by each component alone. The in vitro addition of S. indicum to the formula has been found to synergistically assist inhibition of the pancreatic lipase in a lower dose range, while moderating the pancreatic lipase inhibition in a higher dose range. This dual mechanism of S. indicum has been postulated as a safety mechanism preventing any potential side effects resulting from excessive inhibition of pancreatic lipase activity.

Based on the preclinical and clinical evaluation, FB3 Fusion Ingredient shows potential for safe and effective prevention of excessive dietary fat absorption.²¹  

The Metabolic Health Strategy
What becomes apparent in the field of research for a universally safe and effective weight loss strategy is that healthy living and nutrition alone will not prevent the pandemic proportions of obesity and diabetes. A strategy addressing the cause, rather than risk factors, is required that would—like the aforementioned antibiotic comparison—prevent and stop obesity and related metabolic conditions regardless of geography of the affected population.

The endocannabinoid system in the human body operates via one of the oldest structures in the brain, the limbic system, which regulates most basic functions commanding daily life. Therefore, normalizing the ECS, preventing excess fat intake and body fat build-up may prevent metabolic deterioration. Pharmacological blocking of the ECS has been found effective in sustained weight loss, including normalizing excessive food consumption and independently preventing body fat accumulation. However, the detrimental effect on mood by blocking endocannabinoid receptors rules out ECS blocking as a viable strategy for metabolic health.

On the other hand, the aforementioned strategy for a gradual substitution of the most commonly consumed fatty acid, linoleic acid, with omega-3 fatty acids to prevent NAFLD and obesity emerges as a plausible cause-oriented strategy normalizing the overexpressed ECS. The proposed strategy, in addition to healthy lifestyle and diet, is based on incorporating consumption of the botanical food supplement FB3 Fusion Ingredient to prevent excess dietary fat absorption based upon the safe and effective pancreatic lipase inhibition mechanism.

Based on emerging experimental data, such a strategy would not only prevent build-up of excessive storage “white” fat but may also enhance absorption of omega-3 polyunsaturated fatty acids while synergistically helping to normalize the overactive ECS. In addition, improving cell membrane composition with lipids, the oldest class of information biomolecules, may help upregulate the oldest parts of the brain, the limbic system, to regain metabolic health.

References

1. Alvheim AR, Torstensen BE, Lin YH, Lillefosse HH, Lock EJ, Madsen L, Frøyland L, Hibbeln JR, Malde MK. Dietary linoleic acid elevates the endocannabinoids 2-AG and anandamide and promotes weight gain in mice fed a low fat diet. Lipids 2014 Jan;49(1):59-69.
2. Moore JB.Symposium 1: Overnutrition: consequences and solutions Non-alcoholic fatty liver disease: the hepatic consequence of obesity and the metabolic syndrome. Proc Nutr Soc. 2010 Feb 17:1-10.
3. Vuppalanchi R, Chalasani N. Nonalcoholic fatty liver disease and nonalcoholic steatohepatitis: Selected practical issues in their evaluation and management. Hepatology 2009 Jan;49(1):306-17.
4. Clark JM. The epidemiology of nonalcoholic fatty liver disease in adults. J Clin Gastroenterol. 2006 Mar;40 Suppl 1:S5-10.
5. Angulo, P.  Non-alcoholic fatty liver disease.  N Engl J Med 2002 April 18; 346(16).
6. Bermudez-Silva FJ1, Viveros MP, McPartland JM, Rodriguez de Fonseca F.The endocannabinoid system, eating behavior and energy homeostasis: the end or a new beginning? Pharmacol Biochem Behav 2010 Jun;95(4):375-82.
7. Pagotto U, Marsicano G, Cota D, Lutz B, Pasquali R.The emerging role of the endocannabinoid system in endocrine regulation and energy balance. Endocr. Rev. Feb;27(1):73-100.
8. Alvheim AR1, Malde MK, Osei-Hyiaman D, Lin YH, Pawlosky RJ, Madsen L, Kristiansen K, Frøyland L, Hibbeln JR. Dietary linoleic acid elevates endogenous 2-AG and anandamide and induces obesity. Obesity 2012 Oct;20(10):1984-94.
9. Mallat A, Lotersztain S. Endocannabinoids and their role in fatty liver disease. Dig Dis. 2010;28(1):261-6.
10. Westerbacka J, Kotronen A, Fielding BA, Wahren J, Hodson L, Perttilä J, Seppänen-Laakso T, Suortti T, Arola J, Hultcrantz R, Castillo S, Olkkonen VM, Frayn KN, Orešič M, Yki-Järvinen H. Splanchnic balance of free fatty acids, endocannabinoids, and lipids in subjects with nonalcoholic fatty liver disease. Gastroenterol. 2010 Dec;139(6):1961-1971.
11. Blüher M, Engeli S, Klöting N, Berndt J, Fasshauer M, Bátkai S, Pacher P, Schön MR, Jordan J, Stumvoll M. Dysregulation of the peripheral and adipose tissue endocannabinoid system in human abdominal obesity.Diabetes  2006 Nov;55(11):3053-60.
12. Côté M, Matias I, Lemieux I, Petrosino S, Alméras N, Després JP, Di Marzo V. Circulating endocannabinoid levels, abdominal adiposity and related cardiometabolic risk factors in obese men. Int J Obes  2007 Apr;31(4):692-9.
13. Akbas F, Gasteyger C, Sjödin A, Astrup A, Larsen TM. A critical review of the cannabinoid receptor as a drug target for obesity management. Obes Rev. 2009 Jan;10(1):58-67.
14. Batetta B, Griinari M, Carta G, Murru E, Ligresti A, Cordeddu L, Giordano E, Sanna F, Bisogno T, Uda S, Collu M, Bruheim I, Di Marzo V, Banni S. Endocannabinoids may mediate the ability of (n-3) fatty acids to reduce ectopic fat and inflammatory mediators in obese Zucker rats. J Nutr. 2009 Aug;139(8):1495-501.
15. Jourdan T, Djaouti L, Demizieux L, Gresti J, Vergès B, Degrace P.CB1 antagonism exerts specific molecular effects on visceral and subcutaneous fat and reverses liver steatosis in diet-induced obese mice. Diabetes 2010 Apr;59(4):926-34.
16. Oya J, Nakagami T, Sasaki S, Jimba S, Murakami K, Kasahara T, Wasada T, Sekiguchi H, Hasegawa M, Endo Y, Iwamoto Y. Intake of n-3 polyunsaturated fatty acids and non-alcoholic fatty liver disease: a cross-sectional study in Japanese men and women. Eur J Clin Nutr. 2010 Oct;64(10):1179-85.
17. Masterton GS, Plevris JN, Hayes PC. Review article: omega-3 fatty acids – a promising novel therapy for non-alcoholic fatty liver disease. Aliment Pharmacol Ther. 2010 Apr;31(7):679-92.
18. Banni S, Carta G, Murru E, Cordeddu L, Giordano E, Sirigu AR, Berge K, Vik H, Maki KC, Di Marzo V, Griinari M. Krill oil significantly decreases 2-arachidonoylglycerol plasma levels in obese subjects. Nutr Metab (Lond). 2011 Jan 30;8(1):7.
19. Ulven SM, Kirkhus B, Lamglait A, Basu S, Elind E, Haider T, Berge K, Vik H, Pedersen JI. Metabolic effects of krill oil are essentially similar to those of fish oil but at lower dose of EPA and DHA, in healthy volunteers.Lipids. 2011 Jan;46(1):37-46.
20. Haugaard SB, Vaag A, Mu H, Madsbad S. Skeletal muscle structural lipids improve during weight-maintenance after a very low calorie dietary intervention. Lipid Health Dis 2009 Aug 13;8:34.
21. Vladimir Badmaev, Yoshitaka Hatakeyama, Noriyuki Yamazaki, Akira Noro, Faizal Mohamed, Chi-Tang Ho, Min-Hsiung Pan,. Preclinical and clinical effects of Coleus forskohlii, Salacia reticulata and Sesamum indicum modifying pancreatic lipase inhibition in vitro and reducing total body fat. Journal of Functional Foods 2015; 15: 44–51.