Adipose, or fat tissue, is considered an endocrine organ. This tissue releases hormones into the blood that exert effects on the entire endocrine system. One such hormone, leptin, is now the center of ME/CFS research thanks to new insight from researcher Jarred Younger.

Younger and his team have shown that high leptin levels are correlated with symptom severity in ME/CFS patients. In a well-designed study, he monitored blood leptin levels on 25 consecutive days in conjunction with a symptom severity questionnaire. In addition to leptin, several other markers were evaluated including cytokines and other inflammatory mediators. Leptin alone was the only statistically significant correlate in patients’ symptoms (1). More studies are now underway using larger cohorts and methods to determine causation.

Leptin is classically known as an appetite suppressor. Higher levels are released after a meal to give the feeling of satiety. Leptin has long been the target of obesity research, with high levels associated with obesity and insulin sensitivity (2).

White, Beige, Brown

Leptin stimulates the storage of dietary fat as triglycerides in white fat cells. To burn this stored energy, the nervous system communicates with white fat cells turning them beige, then brown. Brown fat cells are considered superior to white fat cells as they promote the burning of stored fat. White fat cells produce leptin excessively and are associated with obesity (3). The best-studied stimulator of brown fat cells is exposure to cold. In animal and human studies, cold exposure results in the recruitment of brown fat cells. It has also been speculated that lower risks of obesity and diabetes exist among people who live in cold climates (4).

Complex Roles

Leptin is unique in that it is released from other types of cells other than fat cells. This suggests a far more complex function than just regulating food intake. Studies have indicated that leptin is a pro-inflammatory cell signaler. High levels are associated with chronic inflammatory diseases such as hypertension, cardiovascular disease, and metabolic syndrome (3,4).

More research is needed to explore the complex role of leptin. Likely, it is closely linked to other key hormones including insulin, ghrelin, and adiponectin.

Receptors for leptin are found on key sites such as the hypothalamus, signifying close communication between both endocrine and autonomic functions. Leptin can cross the blood-brain barrier to allow for quick feedback to these control centers. Since it has pro-inflammatory properties, leptin in the central nervous system can provoke microglia—resulting in neuroinflammation (1).

All about Eve

The incidence of both fibromyalgia and ME/CFS is far more common in females, yet the reason for this is still unknown. With the new finding of leptin in these groups, plausible explanations begin to emerge.

The level of leptin is 3 times higher in women than men. This due to the fact that estrogen stimulates leptin production, while testosterone lowers it. Leptin also has been found to be higher during the premenstrual phase, especially in women with PMS (5). Might this explain why many female patients experience a worsening of pain and fatigue prior to the onset of their cycles?

Modulating Leptin

In his webinar, Younger stated that chronic leptin suppression through medications or other means is likely not indicated. There are still many unknown mechanisms to discover, but given the multi-system role of leptin, chronic suppression may result in throwing off the homeostatic balance of other pathways.

However, modulating leptin to manage ME/CFS or Fibro symptoms may be indicated. Younger mentioned several leptin antagonists that are already commonly used by many patients with good effect:

• Low-dose Naltrexone

• Curcumin

• Resveratrol

• Panax Ginseng

• Boswellia

• Berberine

While these may provide benefits, the leptin findings also suggest a role in dietary modification to down-regulate leptin release. Low carbohydrate diets are known to reduce leptin levels and stimulate the browning of adipose tissue (6). Low carbohydrate diets can safely be implemented by patients and may improve symptom severity as well as other markers of health.

The issue of nutritional fasting arises again to modulate the effects of leptin. While Dr. Younger advised against it, if done correctly, intermittent fasting may be indicated. Without caloric intake, leptin levels remain low, which might reduce the pro-inflammatory effect and hasten the microglia activation (6). A small study in men showed that 24-72 hour fasts results in decreased leptin levels (7). Far more research is needed, but this could be yet another mechanism in which fasting improves outcomes in CFS and fibro.

References

1  Stringer EA, et al. Daily cytokine fluctuations, driven by leptin, are associated with fatigue severity in chronic fatigue syndrome: evidence of inflammatory pathology. J Transl Med. 2013 Apr 9;11:93. http://www.ncbi.nlm.nih.gov/pubmed/23570606

2  Grant RW, Dixit VD. Adipose tissue as an immunological organ. Obesity (Silver Spring). 2015 Jan 22. http://www.ncbi.nlm.nih.gov/pubmed/25612251

3  Park A, Kim WK, Bae KH. Distinction of white, beige and brown adipocytes derived from mesenchymal stem cells. World J Stem Cells. 2014 Jan 26;6(1):33-42. http://www.ncbi.nlm.nih.gov/pubmed/24567786

4  G. Dodd et al., Leptin and insulin act on POMC neurons to promote the browning of white fat. Cell, 2015 Jan 15;160(1-2):88-104. http://www.ncbi.nlm.nih.gov/pubmed/25594176

5  Anim-Nyame N , et al. Plasma leptin concentrations are increased in women with premenstrual syndrome. Hum Reprod. 2000 Nov;15(11):2329-32. http://www.ncbi.nlm.nih.gov/pubmed/11056127

6  Ahima RS, et al. Role of leptin in the neuroendocrine response to fasting. Nature. 1996 Jul 18;382(6588):250-2. http://www.ncbi.nlm.nih.gov/pubmed/8717038/

7  Chan JL, et al. The role of falling leptin levels in the neuroendocrine and metabolic adaptation to short-term starvation in healthy men. J Clin Invest. May 1, 2003; 111(9): 1409–1421. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC154448/