Written by Dan Gwartney M.D.
14 July 2014

Is Being Fat Stressing You & Your Fat Cells?



A parade of fat-loss products promised rapid weight loss by reducing cortisol, the stress hormone associated with fat accumulation and muscle loss. The classical condition, Cushing’s syndrome, has a distinct appearance: central obesity, “moon” face, “buffalo hump” of fat behind the neck, skinny arms and legs. Other symptoms of Cushing’s include depression, high blood pressure, glucose intolerance, and weakness. However, most overweight/obese people do not have elevated cortisol in the bloodstream, thus the failure of this class of supplement in the market.1

                         Bodybuilders are more familiar with cortisol being the catabolic steroid that causes muscle loss. Cortisol activates processes in the muscle cell that lead to the breakdown of contractile protein to make amino acids available to vital organs in an environment perceived as stressful or threatening. Through the course of evolution/adaptation, stress occurred during wars, droughts, and natural disasters; grueling workouts and long sessions on the treadmill weren’t much of a concern to primitive man.

             Today, most American citizens enjoy relative peace and prosperity compared to primitive man. Yet, the body still responds according to the design that allowed our species to survive hardships; mechanisms that served so well during prolonged starvation are creating harm in the American structure of food excess and sedentary lifestyles. Socio-economic stressors now cause chronic or recurrent periods of anxiety and alarm. Advances made in the last six centuries, particularly the last 50 years, set the stage for pandemic obesity.

             Adrenal glands produce a number of hormones, including corticosteroids— cortisol and cortisone. These two similar-sounding hormones are co-metabolites, meaning each can be generated from or converted into the other. The enzyme responsible for this metabolic doppelgänger effect is called 11-beta hydroxysteroid dehydrogenase (11-HSD). There are two isoforms for 11-HSD, type 1 (oxidoreductase) and type 2 (dehydrogenase). Certain tissues (adipose, liver, pituitary, and brain) have type 1, which generates the metabolically active cortisol from cortisone; others (kidney and colon) contain type 2, which deactivates cortisol to cortisone.2 [To simplify that, there is an enzyme that can turn cortisol on or off, depending upon which type it is].

             One critical point needs to be realized, to understand the value of this article— in healthy individuals, the role of cortisol in fat loss/gain is played within the fat cell. Most obese people have normal circulating cortisol levels.1 Circulating cortisol can be maintained in the normal range by avoiding hypoglycemia (low blood sugar), getting sufficient sleep, sharing healthy social relationships, and avoiding excess physical or emotional stress. Intracellular cortisol concentration is determined by the presence and activity of 11-HSD.

             As a quick aside, low-carbohydrate diets cause a short-term rise in cortisol, and possibly 11-HSD, but the body appears to adapt to the reduced dietary carbohydrate availability, and cortisol levels return to normal.3


The Dreaded ‘Beer Belly’

             Fat cells contain 11-HSD type 1 (11-HSD1), converting cortisone into the active form cortisol, which promotes fat storage, and ironically lipolysis (breakdown of stored fat).2,4,5 Men have higher levels of 11-HSD1 than women— 62 percent higher in lean men than lean women.6 One study reported the effect of testosterone exposure on fat cells of pre-adolescent boys (fat removed during scheduled surgery). After exposure to testosterone, the visceral fat cells displayed a higher content and enzyme activity of 11-HSD1, but the same was not seen in the subcutaneous fat cells.7 This finding partially explains the male pattern of body fat distribution (central obesity or the “beer belly”) as opposed to the female pattern (hips, butt, and legs).

             Obesity also affects 11-HSD1, with the obese having higher fat cell 11-HSD1 content and activity than lean people— two to seven times as much; this is true in both sexes.6,8,9 This effect creates a self-perpetuating condition, as being obese induces changes that promote fat storage. Additionally, inflammatory cytokines— chemical messengers associated with a number of health risks— also increase 11-HSD1.10 As with obesity, this can be self-perpetuating, as the visceral fat depot is a primary source of these harmful cytokines. Also, obese people tend to have larger individual fat cells, called hypertrophic fat cells that along with the surrounding connective tissue, overproduce inflammatory cytokines— another self-perpetuating mechanism that makes it so difficult for the morbidly obese to really make changes without intensive intervention.11

                         Intensive exercise, particularly resistance training, can increase 11-HSD1 in skeletal muscle.12 This accounts for some of the breakdown in muscle protein that happens with all exercise, but it also serves a physiologic (beneficial) role. Increasing cortisol within the muscle cell helps regulate exercise-related inflammation. However, repeated sessions of severe training, particularly of the same muscle groups, can lead to local (tissue) cortisol excess. This may explain why an elevation in circulating cortisol is not always seen in overtraining, but the (potentially intracellular cortisol-induced) loss of muscle mass and strength still occurs.

             It should not surprise anyone that insulin can increase cortisol via 11-HSD1 in fat.13 It seems this effect requires the co-presence of cortisol in visceral fat and is more pronounced in hypertrophic fat cells, such as is seen in the obese.14 Table sugar (sucrose) also increases 11-HSD1, possibly due to its fructose content.2 Again, it appears that once a person exceeds a certain threshold, fat goes from being a physiologic store of energy to a pathologic source of inflammatory and harmful biochemicals. Ironically, beta-adrenergic drugs (salbutamol, possibly clenbuterol, etc.) increase 11-HSD1; seemingly, this would contradict the known fat-loss effect of such drugs.10 Consider that adrenaline is the first “fight-or-flight” hormone released during immediate threats.

             When 11-HSD1 activity in the liver is elevated, so is the liver’s gluconeogenic activity (converting amino acids to glucose and keeping the blood sugar elevated in the state of insulin resistance), as well as triglyceride (fat) uptake. In animals, inhibiting 11-HSD1 reduces fat uptake by the liver, diverting circulating fat to active tissue (e.g., heart, skeletal muscle) where it is burned to produce energy rather than stored as fat.15

             Endocrine disruptors are environmental agents, often pollutants from industrial sources that affect human or animal physiology. An underappreciated issue, it affects human health— as evidenced by the earlier onset of puberty in girls (breast development as early as age 7) and lower testosterone concentration in adult men. As might be expected, there are also environmental factors that affect the 11-HSD pathway that may influence the growing obesity rate.16


Maximizing Fat-Loss Efforts

             Reducing the activity of 11-HSD1 in fat cells, especially visceral fat cells, would be of great value to the general health of obese Americans. Visceral fat is the “bad fat” more strongly associated with type 2 diabetes, cardiovascular disease, liver abnormalities, and other health conditions. Combining this pathway with other fat-reducing mechanisms (diet, exercise, etc.) would help maximize the efficiency and potency of one’s fat-loss efforts. Reducing the 11-HSD1 activity in the liver would minimize the self-sabotage that occurs during insulin resistance as muscle protein is cannibalized (due to increased 11-HSD1 in the muscle) to make sugar, which perpetuates the need for more insulin. 11-HSD1 promotes the activity of fat-storing and fat-cycling enzymes, and diverts amino acid into sugar production.

             One source of 11-HSD inhibitors has been available on the shelves of nutrition stores for decades. Licorice root extract (not to be confused with candy licorice) contains a number of derivatives, inhibiting both types of 11-HSD. Unfortunately, licorice does not appear to contain a specific 11-HSD1 inhibitor. These derivatives, including glycyrrhetinic acid and carbenoxolone, are not tissue specific, and inhibit both 11-HSD1 and 11-HSD2.17 The downside to inhibiting 11-HSD2, which is present in the kidneys and colon, is that it leads to potassium loss in the urine and can elevate blood pressure to dangerous levels in some people. 11-HSD2 protects organs that are sensitive to aldosterone, a steroid closely related to cortisol, from being inappropriately stimulated by cortisol; 11-HSD2 inhibition leads to sodium retention and holding water. Also, glycyrrhetinic acid appears to directly affect blood vessels, slowing their response to increases in blood pressure.

             Another factor discouraging the use of licorice-based supplements for fat loss in male athletes is the negative effect glycyrrhetennic acid and carbenoxolone have on testosterone production. Licorice consumption and animal studies using carbenoxolone, as well as a synthetic 11-HSD1 inhibitor, is associated with lowering natural testosterone production.18 For the drug-using athlete who uses anabolic steroids, a potassium-sparing diuretic, and possibly an ACE inhibitor, this may not be an issue. However, this has never been studied— and certainly is not a recommendation.

             There are 11-HSD1-specific inhibitors being developed by pharmaceutical corporations in the hopes of treating obesity or the metabolic syndrome. There are encouraging results being reported, but at this time, none are scheduled to be available in the near future.

             Logically, certain drugs used by bodybuilders are able to inhibit 11-HSD1. A little-mentioned drug uncommonly used by bodybuilders is adrenocorticotropic hormone (ACTH). A pituitary hormone, much like growth hormone (GH), ACTH’s traditional role is to stimulate the adrenal glands to increase circulating cortisol production. Ironically, fat cells exposed to ACTH reduce 11-HSD1.10 GH stimulates the liver, and to a lesser degree skeletal muscle, to produce a secondary messenger called IGF-1. It is IGF-1 but not GH that inhibits 11-HSD1 in both the liver and fat cells, reducing cortisol in these tissues.19

             It has been mentioned that many of the benefits of GH treatment, or signs of GH deficiency, may be related to the concentration of tissue cortisol affected by IGF-1. Interestingly, neither GH nor IGF-1 appear to affect 11-HSD2, supporting the role GH or IGF-1 therapy may have in many conditions. Note: it may take one month or longer for the effects to be evident through blood analysis, or subjectively.

             Certain drugs used to treat high cholesterol or type 2 diabetes inhibit 11-HSD1, specifically the PPAR-alpha and PPAR-gamma agonists.20 However, the effect of these drugs at the doses used clinically is very modest at the level of the fat cell. This is consistent with the lack of significant fat loss reported with these drugs.

             11-HSD1 also exists in the brain; elevated concentrations of cortisol in the appetite control regions of the brain result in greater hunger and weight gain. This appears to involve a system called NPY.21 The antagonist to this in the brain, as well as fat cells elsewhere in the body, is the melanocortin system. It is conceivable that sun exposure or the use of melanotan-like drugs may aid in reducing cortisol’s presence in fat and the brain.

             In summary, the stress hormone cortisol not only depletes muscle of protein as athletes have learned, but also encourages fat cells to accumulate fat, release fat to be stored in unhealthy locations such as the liver or blood vessels, and increases the state of inflammation that’s associated with a number of health consequences. It is not the cortisol in the bloodstream that is the culprit in most people— rather, cortisol created in fat cells through the enzyme 11-HSD1. 11-HSD1 is higher in men, accounting for the “beer-belly” pattern of fat in men, and increases with obesity or with high insulin concentrations. 11-HSD1 can be reduced by chemicals in licorice root, but the chemicals are not specific and affect a related enzyme called 11-HSD2, which protects against hypertension and other effects of cortisol.

             IGF-1 is possibly the most potent inhibitor of 11-HSD1, and may account for much of the lipolytic effect of GH. Certain drugs used to treat high cholesterol or diabetes are called PPAR-alpha and PPAR-gamma agonists, but their effect is modest at best. Melanotan-II and similar drugs are said to improve weight loss, and any benefits may be the inhibitory or counter-regulatory effect of the melanocortin system on 11-HSD1.

             This field will hopefully grow, as pharmaceutical companies are looking to exploit the pathway in treating or preventing obesity.



             1. Staab CA, Maser E. 11beta-Hydroxysteroid dehydrogenase type 1 is an important regulator at the interface of obesity and inflammation. J Steroid Biochem Mol Biol, 2010 Mar;119(1-2):56-72.


            2. London E, Castonguay TW. Diet and the role of 11beta-hydroxysteroid dehydrogenase-1 on obesity. J Nutr Biochem, 2009 Jul;20(7):485-93.


            3. Volek JS, Sharman MJ, et al. Body composition and hormonal responses to a carbohydrate-restricted diet. Metabolism, 2002 Jul;51(7):864-70.


            4. Morton NM, Seckl JR. 11beta-hydroxysteroid dehydrogenase type 1 and obesity. Front Horm Res, 2008;36:146-64.


            5. Tomlinson JW, Sherlock M, et al. Inhibition of 11beta-hydroxysteroid dehydrogenase type 1 activity in vivo limits glucocorticoid exposure to human adipose tissue and decreases lipolysis. J Clin Endocrinol Metab, 2007 Mar;92(3):857-64.


            6. Paulsen SK, Pedersen SB, et al. 11Beta-HSD type 1 expression in human adipose tissue: impact of gender, obesity, and fat localization. Obesity (Silver Spring), 2007 Aug;15(8):1954-60.


            7. Zhu L, Hou M, et al. Testosterone stimulates adipose tissue 11beta-hydroxysteroid dehydrogenase type 1 expression in a depot-specific manner in children. J Clin Endocrinol Metab, 2010 Jul;95(7):3300-8.


            8. Desbriere R, Vuaroqueaux V, et al. 11beta-hydroxysteroid dehydrogenase type 1 mRNA is increased in both visceral and subcutaneous adipose tissue of obese patients. Obesity (Silver Spring), 2006 May;14(5):794-8.


            9. Engeli S, Böhnke J, et al. Regulation of 11beta-HSD genes in human adipose tissue: influence of central obesity and weight loss. Obes Res, 2004 Jan;12(1):9-17.


            10. Friedberg M, Zoumakis E, et al. Modulation of 11 beta-hydroxysteroid dehydrogenase type 1 in mature human subcutaneous adipocytes by hypothalamic messengers. J Clin Endocrinol Metab, 2003 Jan;88(1):385-93.


            11. Fain JN. Release of inflammatory mediators by human adipose tissue is enhanced in obesity and primarily by the nonfat cells: a review. Mediators Inflamm, 2010. Epub 2010 May 23.


            12. Dovio A, Roveda E, et al. Intense physical exercise increases systemic 11beta-hydroxysteroid dehydrogenase type 1 activity in healthy adult subjects. Eur J Appl Physiol, 2010 Mar;108(4):681-7.


            13. Purnell JQ, Kahn SE, et al. Enhanced cortisol production rates, free cortisol, and 11beta-HSD-1 expression correlate with visceral fat and insulin resistance in men: effect of weight loss. Am J Physiol Endocrinol Metab, 2009 Feb;296(2):E351-7.


            14. Lee MJ, Fried SK, et al. Depot-specific regulation of the conversion of cortisone to cortisol in human adipose tissue. Obesity (Silver Spring), 2008 Jun;16(6):1178-85.


            15. Berthiaume M, Laplante M, et al. 11beta-HSD1 inhibition improves triglyceridemia through reduced liver VLDL secretion and partitions lipids toward oxidative tissues. Am J Physiol Endocrinol Metab, 2007 Oct;293(4):E1045-52.


            16. Odermatt A, Gumy C, et al. Disruption of glucocorticoid action by environmental chemicals: potential mechanisms and relevance. J Steroid Biochem Mol Biol, 2006 Dec;102(1-5):222-31.


            17. Marandici A, Monder C. Inhibition by glycyrrhetinic acid of rat tissue 11 beta-hydroxysteroid dehydrogenase in vivo. Steroids, 1993 Apr;58(4):153-6.


            18. Armanini D, Bonanni G, et al. Licorice consumption and serum testosterone in healthy man. Exp Clin Endocrinol Diabetes, 2003 Sep;111(6):341-3.


            19. Agha A, Monson JP. Modulation of glucocorticoid metabolism by the growth hormone - IGF-1 axis. Clin Endocrinol (Oxf), 2007 Apr;66(4):459-65.


            20. Wake DJ, Stimson RH, et al. Effects of peroxisome proliferator-activated receptor-alpha and -gamma agonists on 11beta-hydroxysteroid dehydrogenase type 1 in subcutaneous adipose tissue in men. J Clin Endocrinol Metab, 2007 May;92(5):1848-56.


            21. Asensio C, Muzzin P, et al. Role of glucocorticoids in the physiopathology of excessive fat deposition and insulin resistance. Int J Obes Relat Metab Disord, 2004 Dec;28 Suppl 4:S45-52.




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