Paper #1: Leptin levels are associated with multiple sclerosis risk
Martin Biström , Johan Hultdin , Oluf Andersen et al
Multiple sclerosis; 2021, Feb.; 27(1):19-27
Paper #2: Obesity and the risk of Multiple Sclerosis. The role of Leptin
Marrodan, M., Farez, M. F., Balbuena Aguirre, M. E., Correale, J.
Ann Clin Transl Neurol; 2021; 8(2:406-424
Paper #3: Metabolic consequences of obesity and type 2 diabetes: Balancing genes and environment for personalized care
Pillon, N. J., Loos, R. J. F., Marshall, S. M. and Zierath, J. R.
Cell; 2021; 184(6):1530-1544
While we don’t know the cause of MS we do know that certain characteristics affect susceptibility to the disease. One of these is a person’s weight. Increased weight, especially in adolescence, is associated with an increased susceptibility to MS. In adulthood overweight and obesity can increase MS-related disability and predisposes to other illnesses such as Type 2 diabetes and vascular disease. We don’t know exactly why being overweight and obese increases susceptibility to MS, but new evidence presented in the above papers sheds light on possible mechanisms. One major component is the effect of the appetite controlling hormone, leptin, on immune function.
It’s very difficult to lose weight and not regain it. This may be even more difficult for persons with MS with physical disabilities. Understanding some of the factors leading to overweight and obesity, how to manage them, and even better, how to prevent overweight and obesity, could result in significant benefit to persons with MS. These issues are discussed below.
1. Multiple factors determine what a person weighs. One of the most important is one’s genes. There are about 700 of such genes and they determine between 30%-70% of a person’s body mass index. What we don’t know is how these genes affect body weight, either negatively or positively.
2. Genes alone are not sufficient to determine a person’s weight. A person’s environment (hot climate versus cold climate; rural versus urban), the quality and quantity of food intake, and the level of regular activity are also major determinants of a person’s body weight.
3. The picture becomes even more complex in that there are different patterns of obesity, varying with where the fat is deposited (e.g., liver versus under the skin). Many patterns are associated with an increased risk of developing Type 2 diabetes, high blood pressure and heart disease, while other persons with obesity are metabolically normal.
4. While one’s genes play an important role in determining one’s weight, it is possible to modify the activity of these genes with changes in nutrients and physical activity. Other important factors are when one eats, how calories are distributed throughout the day, and when one exercises.
5. Multiple studies have demonstrated an increased susceptibility to MS in overweight or obese adolescents.
6. How obesity effects susceptibility to MS is not known, but multiple factors may contribute. For example, immune cells infiltrate fat cells, resulting in low grade chronic inflammation. Increased concentrations of fatty acids in the blood also affect circulating immune cells, resulting in activation of these cells and release of toxic cytokines. As discussed below, exercise and changes in diet can reduce these changes.
7. An important contributing factor to becoming overweight or obese is the appetite-controlling hormone leptin. Leptin is a hormone secreted into the blood by fat cells. The more fat cells a person has, the more leptin is secreted. Leptin binds to receptors in the brain and reduces appetite and feelings of hunger. However, this response is blunted in overweight and obese individuals, resulting in decreased appetite suppression even with high levels of leptin.
8. Each person’s body adapts to a particular leptin level and tries to keep that level stable. If leptin levels fall below that person’s “thermostatically” set level, the person feels hungry. Once sufficient leptin binds to brain receptors that person’s hunger abates. Leptin is but one of several factors controlling appetite. These are reviewed in more detail in the “Discussion” section below.
9. Crash diets can reduce levels of leptin by reducing numbers of fat cells. If levels fall below a person’s “thermostatically” set level, that person will experience feelings of hunger and “starvation.” Once a diet is stopped, and feelings of hunger persist, persons may experience a need to overeat in an effort to restore their leptin levels to their prior “normal” level. As a result lost weight is often rapidly regained.
10. The best way to avoid such weight “yo-yo-ing” is with a gradual and sustained reduction in daily calories in association with a regular program of exercise suited to one’s individual abilities. This more gradual approach can result in “resetting” a person’s perceived normal leptin levels, with weight loss being sustained. Paper #3 provides an excellent review of these issues.
11. Studies of leptin levels in persons with MS are controversial. The scientists of Paper #1 measured both leptin and insulin levels in 649 persons with MS up to 8 years before being diagnosed with relapsing forms of multiple sclerosis. Results were compared to matched, control individuals without MS. Leptin levels were 5x higher in women of both groups (those with MS and in controls) compared to men.
12. When the two groups, persons with MS and controls, were compared as a whole, levels of insulin and leptin were the same and did not correlate with subsequent development of MS. When groups were divided by age, persons with MS younger than 20 years did have higher levels of leptin with a 40% increased risk of developing MS compared to controls. A similar increase in leptin levels with increased risk for developing MS was noted for males, regardless of age. In older women with MS (30-39 years) higher leptin levels were associated with a 26% lower risk of developing MS. These observations suggest that leptin and fat-related inflammatory processes are different in adolescents than in pre-adolescents or older individuals that develop MS.
13. Paper #2 provides even greater insight into immune abnormalities in persons with MS that are overweight or obese. They studied immune changes and leptin levels in 147 overweight or obese persons with relapsing forms of multiple sclerosis and compared them with results from 162 persons with MS of normal or underweight and with 322 persons without MS whose weight ranged from underweight to obese. Being overweight at age 15 or being obese at age 20 doubled and almost quadrupled the risk of developing MS in these two age groups respectively. Leptin levels were also higher both in persons with MS and controls that were overweight or obese compared to normal or underweight persons with MS and controls.
14. The scientists produced lines of immune cells from overweight and obese persons with MS and controls. These cell lines responded specifically to central nervous system myelin proteins. They then measured responses of these immune cells to their stimulating myelin proteins when leptin was added to the tissue cultures.
15. Addition of leptin to cell lines from overweight and obese persons with MS resulted in the cells becoming even more activated and releasing increased levels of inflammatory chemicals called cytokines. Addition of leptin to a different population of immune cells that have the ability to regulate immune responses (called regulatory T cells or Tregs) resulted in a loss of their regulatory abilities.
16. Finally, the scientists measured the extent of death of myelin reactive cells when steroids were added to the cultures, a phenomenon called “apoptosis.” They noted that addition of leptin to myelin reactive cells protected these autoreactive cells from apoptosis or death if cells were from overweight or obese persons with MS, but not if cells were from persons of normal weight.
17. The observations made by the above scientists provide important insights into how excess weight early in life increases the risk of developing MS and how being overweight or obese later in life can contribute to worsened disease. As difficult as losing weight is, benefits of such efforts to persons with MS may be considerable.
Overweight and obesity are reaching epidemic proportions, even in countries that did not have such issues in the past. The causes are multiple, from abandoning local diets and changing to “western” diets, to decreased levels of exercise, failure to maintain regular or circadian body rhythms, and to an increasingly aging population. Paper #3 provides an excellent review of these issues.
While the consequences of overweight and obesity in terms of risks for developing Type 2 diabetes, vascular disease and autoimmune disease such as rheumatoid arthritis and systemic lupus are well known, the effects of increased weight in persons with MS is less well defined. What is known is that overweight and obesity in adolescence increases susceptibility to developing MS. Overweight and obesity can also contribute to MS-related disability. There are several pathways for these changes to occur. The above papers provide new insights into such pathways.
Overweight and obesity leads to significant changes in immune function. Immune cells enter fat cells and become activated. This leads to a release of inflammatory chemicals called cytokines. As a result, a low grade, chronic level of inflammation occurs in the body. This also leads to the release of chemicals called “adipokines.” One of the most important adipokines released from fat cells is the hormone leptin. It is released into the blood and the more fat a person has, the higher the levels of leptin. Leptin affects many parts of the body including the immune system, but one of its main roles is to control appetite and energy expenditure. Leptin binds to receptors in the brain and in so doing “tells” the brain that sufficient food has been eaten. It thus suppresses appetite. Regulation of appetite is quite complex, varying with multiple factors such as blood sugar levels, times of day, and levels of other hormones (e.g. ghrelin and orexin). Leptin levels, however, are a major regulator of appetite.
Over time each person’s body adapts to a certain level of leptin. It is difficult to change this “thermostatic” level over the short term. This explains why persons who try to lose weight by suddenly changing their diet will often fail. Diet may result in loss of fat, resulting in lower levels of leptin. Since that person’s leptin “thermostat” is set at a higher level, that person’s brain will signal that the body it is being “starved.” As a result, once a diet is stopped it becomes very difficult to control increased appetite and prevent regaining lost weight. These issues are that much more difficult in overweight and obese individuals. In overweight and obese persons the brain’s responsiveness to leptin is reduced, so that even with higher levels of this hormone, appetite is not well suppressed. Changing one’s leptin “thermostat” requires a gradual and sustained reduction in calories eaten, combined with a program of gradually initiated, but regular exercise.
As discussed in the above papers the immune system is significantly affected by leptin in a setting of overweight and obesity. This hormone preferentially activates autoimmune cells and prevents their death (“apoptosis”). It also decreases numbers of regulatory T cells (Treg), cells that play an important role in controlling the intensity and duration of immune responses. These profound effects on the immune system may play an important role in why overweight and obesity increases susceptibility to MS and worsens MS disability.
Understanding the mechanisms underlying these effects could lead to new, personalized approaches of treatment, such as finding ways of increasing the responsiveness of the brain to leptin. Even more important is understanding the importance of weight gain on the course of MS and making best efforts to prevent it.