Exploring chronic disease
How many times have you been told that you can control your weight simply by adjusting your diet and making time for exercise? The idea that we are able to completely control our weight through willpower and food intake has been seared into our thinking so frequently by friends, family, the media, and even or our doctors, that most people still blame MacDonalds for the country’s weight problems.
Yet, this week another study was published which strongly suggests that our weight is not, by any means, soley governed by what we eat. Rather, it is mediated by factors out of our control, one of them being the balance of chemicals in our bodies.
In a recent paper, published in the Annals of the New York Academy of Sciences, researchers at the Institute of Molecular and Cellular Biosciences Institute at the University of Tokyo in Japan explain two molecular pathways that directly affect the formation of adipocytes, another name for fat cells. At the center of both pathways is the nuclear receptor PPAR-gamma, a receptor that is also at the heart of the immune response.
It turns out that PPAR-gamma plays a fundamental role in determining the fate of undifferentiated bone marrow cells. According to the researchers, bone marrow cells start out as mesenchymal cells – basic cells that under the influence of different chemical signals, can be converted into several different types of cells. If they receive a certain signal, the cells turn into bone cells called osteoblasts. If they receive other signals, they turn into adipocytes, adding to a person’s body weight.
When PPAR-gamma is active, it regulates a set of signals that enhance the formation of adipocytes rather than osteoblasts. This reality has been confirmed by other studies, including some which have shown that diabetes patients given a drug that enhances the activity of PPAR-gamma show a greater rate of adipocyte formation.
What follows is that if the activity of PPAR-gamma is slowed or blocked, mesenchymal cells should follow the opposite course. Rather than turn into adipocytes, more of the cells should remain as osteoblasts, causing a person to loose, rather than gain weight.
The University of Tokyo team was able to elucidate two pathways whose end components block the activity of PPAR-gamma. Interestingly, one of these pathways is mediated by the inflammatory molecules TNF-alpha, IL-1 and Nuclear Factor Kappa B – inflammatory markers that are released by the immune system in response to the Th1 pathogens. In a series of experiments that tested the effects of increased cytokine production on mouse bone marrow stromal cells, the team discovered that a chemical cascade activated by TNF-alpha, IL-1 and Nuclear Kappa Factor B blocks the ability of DNA to bind to PPAR-gamma, thus slowing the activity of the receptor. The result: a decrease in the number of mesenchymal cells converted into adipocytes.
At this point you may be thinking – but a decrease in the number of adipocytes would lead to weight loss. That’s correct. It’s important to keep in mind that many people who develop Th1 disease actually lose weight. This was certainly true in my case. As I started to fall ill with CFS, I lost so much weight, while continuing to eat around the same amount of food, that I was accused of being anorexic or bulemic. Nobody believed me when I tried to communicate that my weight loss seemed to be out of my control.
So, if the above pathway is accurate, then why do many people with Th1 disease gain weight? The reality is the above pathways is probably just one of many yet to be discovered that affects weight regulation. Also, based on gut bacteria studies that I discuss elsewhere on this site, it’s becoming abundantly clear that obesity is, like any other Th1 disease, a bacterial illness. So perhaps those individuals who accumulate enough obesity causing bacteria find that the presence of these pathogens allows for weight gain that offsets any weight loss that might result from the deactivation of PPAR-gamma described above. Other variables that must be factored into the picture, such as the carbohydrate craving frequently experienced by people with Th1 disease that can lead to weight gain. Just like other factors that govern the progression of chronic inflammatory disease, it appears that weight regulation is incredibly complex. As biomedical researcher Trevor Marshall has commented, “at this point the complexity of the body is so imponderable that we must deal with a certain level of uncertainty.” Still, studies like that conducted by the Tokyo researchers have great potential to lead us in the right direction.
The bottom line is that a person’s ability to gain or lose weight, particularly if they have a Th1 disease, is largely out of their control. The above study makes it clear that fat cell production is largely regulated by a complicated chemical pathway, rather than the consumption of a Big Mac. As research in this area continues, the idea that becoming fat or thin is only related to lifestyle choice should become somewhat obsolete. This doesn’t mean that people who ingest huge amounts of food won’t gain weight, or that people who go on strict diets won’t lose weight (at least temporarily), only these factors will become one many other variables to affect body mass.
The University of Tokyo study is also of interest when one considers that the statins and the sartans (two classes of drugs) bind PPAR-gamma. Olmesartan, also called Benicar, is the sartan taken several times a day by patients on the Marshall Protocol. Olmesartan has a high affinity for PPAR-gamma, and very likely acts as an antagonist of the receptor (slows it’s activity). Thus, Olmesartan should technically make it a little easier for a person to maintain a healthy weight since by blocking PPAR-gamma, it should slow the formation of adipocytes. Indeed, some patients on the Marshall Protocol find that Benicar helps their weight to stabilize.
Other sartans such as Telmisartan and Ibersartan also bind PPAR-gamma with a high affinity (and are also likely antagonists). Among the statins, Simvastatin, Lovastatin, and Atorvastatin have similar properties. The fact that these drugs may affect fat cell formation is certainly also food for thought.
Several months ago, I reported on two studies published in the medical journal Nature by Jeff Gordon, a Washington University Scientist intent on investigating correlations between gut bacteria and weight.
Among Gordon’s findings was the fact that his obese and lean volunteers had substantially different compositions of bacteria in their guts. Obese volunteers had 20 percent more of a bacterial species called firmicutes in their gut, but harbored almost 90 percent less of another bacterial species called bacteroidetes than lean volunteers.
Interestingly, when obese subjects were put on a low-carb, low-fat diet, the composition of the bacteria in their guts started to adjust to more closely resemble the ratios of bacteria seen in their lean counterparts.
Similarly, the team found that mice injected with gut bacteria from other obese mice gained about twice as much weight as mice injected with bacteria taken from the stomachs of lean mice, strongly suggesting a direct relationship between the relative abundance of certain bacteria in the gut and the tendency of an individual to gain weight.
This week, a new study revealed similar findings, demonstrating that the mix of bacteria in a baby’s gut may predict whether the infant will become overweight or obese later in life.
In a study published in the March issue of The American Journal of Clinical Nutrition, researchers at the University of Turku in Finloand reported that babies with high numbers of the bacterial species Bifidobacteria and low numbers of the bacterial species Staphylococcus aureus may be protected from excess weight gain.
The Finnish team selected 49 children from a larger long-term study aimed at evaluating the effect of probiotics on allergic disease. The babies had been evaluated at birth, five more times before age 2, and then again at ages 4 and 7. The researchers in the original study had also tested for intestinal microbes in fecal samples collected at 6 months and 12 months.
Of the 49 subjects selected from the larger study, 25 were overweight or obese at age 7, while 24 subjects of the same age were of normal weight.
When the Finnish team examined the fecal samples taken from the children earlier in life, the average bacterial counts of Bifidobacteria taken at 6 months and 12 months were twice as high in those children who were at a healthy weight as in those who had become obese.
Those who stayed at a healthy weight also had lower fecal S. aureus levels at 6 months and 12 months than did those who got heavy.
The researchers speculated that S. aureus may trigger low-grade inflammation that also contributes to developing obesity, a statement which supports biomedical researcher Trevor Marshall’s view that obesity is not a cause for other diseases such as heart disease and stroke, but is an inflammatory disease in its own right. As with other chronic diseases, it is directly related to a patient’s bacterial load.
Since Bifidobacteria are prevalent in the guts of breast-fed babies, the Finnish team also suggested that their findings may help explain why breastfed babies have been found to be at lower risk for later obesity. Other studies have repeatedly found that breastfed babies have a 13 to 22 percent reduced risk of excess weight or obesity in childhood.
“The finding that the lean children harbored higher levels of Bifidobacteria at younger ages is very intriguing,” commented Ruth Ley, a research assistant professor at Washington University School of Medicine in St. Louis. According to Ley, the Finnish study is unique, because it collected information over several years, making it possible to look for differences in gut microflora.
Someday, the Finnish researchers speculated, tinkering with gut flora may help prevent or treat obesity. Little do they know (at least we presume so) that patients on the Marshall Protocol are already doing much more then simply tinkering with the pathogens in their guts. By using a combination of low-dose antibiotics and Benicar they are able to gradually wear away at pathogenic species in the gut, allowing their GI tracts to re-establish an optimal composition of gut flora after several years of therapy.
Amy Proal graduated from Georgetown University in 2005 with a degree in biology. While at Georgetown, she wrote her senior thesis on Chronic Fatigue Syndrome and the Marshall Protocol.