Serotonin's Siren Call

Admit it. Low-carbing is hard. You have to keep a constant eye on what you're eating. And you have to cope with the fact that the people around you are keeping a constant eye on you--trying to figure out why you eat in such a nonconventional way. Wouldn't it be easier just to take a pill to lose weight? Unfortunately, promising weight-loss drugs have a history of regulatory approval followed by withdrawal because of serious side effects.

Fen-Phen
In 1973 fenfluramine, a mixture of two isomers, dexfenfluramine and levofenfluramine, was approved for weight loss by the FDA. In 1996 the dexfenfluramine isomer was approved for long-term weight loss. These compounds produced a small but measurable amount decrease in weight for the patients who took them. When Dr. Michael Weintraub combined fenfluramine with another mildly-effective product called phentermine in a combination popularly called "fen-phen," it produced as much as a 16% weight loss in a four-year clinical trial. Word spread, and thousands of patients began to request prescriptions.

Nonetheless, by 1997 a large number of adverse events had occurred, and the FDA decided to remove both fenfluramine and dexfenfluramine from the market. Up to twenty five percent of users had experienced heart valve hypertrophy, with the degree of pathology tending to correlate with the length of time the product had been taken. Pulmonary arterial hypertension was reported as well. A 1997 article from the New York Times describes the reactions of physicians who had known that the drugs might pose a small risk but felt that it was more than counterbalanced by the public health problem of rising obesity rates.

Serotonin receptor specificity
Because fenfluramine was able to produce anorexia, researchers began to investigate its properties. It was found to work nonselectively on receptors for serotonin, one of the body's most important signaling molecules. Serotonin (also known as 5-HT) has at least seventeen receptor genes that mediate everything from moods to gut motility. As discussed in a review article by Keith J. Miller, the 5-HT1B and 5-HT2C serotonin receptors are known to suppress appetite, and fenfluramine or its metabolite norfenfluramine appear to exert their anorectic effects through these receptors.

Unfortunately, norfenfluramine also acts nonselectively on 5-HT2A and 5-HT2B serotonin receptors which are located in human heart valves. In this location it acts as a growth factor and causes hypertrophy of the valves.

Lorcaserin
In recent years, investigators have attempted to formulate drugs that activate 5-HT2C serotonin receptor but have little or no effect on the 5-HT2A and 5-HT2B serotonin receptors. Lorcaserin was designed to work in this way, and after a year in one trial, patients taking lorcaserin had lost about 4 kg more than those in the placebo group. After two years they had lost an additional two kg and reported reduction in almost all measures of diabetes and cardiovascular risk.

Although lorcaserin did not increase the risk of valvular hypertrophy or pulmonary hypertension, in October 2010, the FDA rejected the new drug application because lorcaserin had increased the incidence of tumors in rats, specifically adenocarcinoma in mammary glands and astrocytoma in the brain. It is possible that growth of these tumors is mediated through one or more of the other 5-HT receptor subtypes, and that lorcaserin nonspecifically stimulates them.

Silbutramine
Silbutramine (Meridia) is not a 5-HT receptor agonist, but it exerts a satiety effect by blocking the reuptake of serotonin by presynaptic nerve terminals. Unlike selective serotonin reuptake inhibitors (SSRIs), silbutramine does not act as an antidepressant. Unlike fenfluramine, it does not produce valvular hypertrophy or pulmonary hypertension. It does have measurable but minimal efficacy for weight loss and was approved for use by the FDA in 1997 for the management of obesity, including weight loss and maintenance of weight loss. Thirteen years later a six-year clinical trial (SCOUT) with approximately 10,000 patients was completed. In the silbutramine group, there was a 16% increase in the risk of a set of serious events, including non-fatal heart attack and stroke, compared with the placebo group. On October 8, 2010, the FDA asked Abbott Laboratories to voluntarily withdraw silbutramine from the U.S. market.

No magic bullets
Orlistat (Xenical/Alli) is still available as a pharmacologic treatment for weight loss. It does have side effects with social significance, particularly for those who are trying to live a low-carb lifestyle. On the positive side, as of this writing it does not appear to increase morbidity or mortality when used as directed. Unfortunately that doesn't seem to be the case for anti-obesity drugs that have serotonergic actions.

Pharmaceutical companies have a powerful motivation to develop drugs that will help with weight loss. However, if history is any guide, there is a high probability that drugs with initial promise will turn out to have serious adverse effects in the long run. In the meantime, there is growing evidence that the low-carb lifestyle offers us a non-drug way to lose weight and to maintain that loss. People have been doing low-carb safely since Dr. Atkins came out with his Diet Revolution in 1972. For those who prefer a non-anecdotal approach, more and more articles are being published that show an actual health advantage for the low-carb lifestyle.

Low-carb is not easy. But it isn't impossible either. Until scientists come out with a magic pill for weight loss, we can rejoice that we have found a way to cope with our own personal version of the obesity epidemic.

Can You Be Fat and Not Know It?

The short answer is yes, you can be fat and and not realize that you're fat.

A recent article in the Archives of Internal Medicine used data from the 2000-2002 Dallas Heart Study to describe this phenomenon. The full article (Body Size Misperception: A Novel Determinant in the Obesity Epidemic) is not yet available, but news descriptions of it are here, here and here. The authors have presented the data in powerpoint form here.

Misperception of body size
Researchers asked 2056 obese men and women to look at line drawings like those pictured above. The study participants were asked to choose the figure that looked the most like them. Although all of the participants met criteria for obesity, eight percent of them (14% of blacks, 11% of Hispanics and 2% of whites) did not consider themselves to be obese.

Definitions
Let's take a moment to define our terms. Study patients did not have the benefit of the BMI values that are printed underneath each series of pictures. I've added those because I suspected that readers would like to take the test themselves and see (1) which figure they would choose and (2) which figure actually corresponds to their body size. (You can click on the pictures to enlarge them, if necessary.) If you don't know your BMI, it can be calculated here.

As obesity grows more common, it also becomes harder to pick out which figures are thin, normal and fat. Here are the definitions according to BMI:

• Underweight = BMI less than 18.5
  
• Normal weight = 18.5–24.9
  
• Overweight = 25–29.9
  
• Obese = BMI of 30 or greater

In the figures above, the only underweight figure is women's drawing 1. The overweight figures are drawings 5 & 6 of both sexes. The obese figures are drawings 7, 8 & 9 of both sexes. (Note that, in this context, "overweight" and "obese" have very specific definitions.)

Behavioral associations
Back to the Dallas Heart Study. Among the eight percent of obese study participants who misperceived their body size, 66% believed they were at low risk for obesity, even though they were already obese. Although those with and without body size misperception had equal probabilities of developing diabetes, heart disease and high blood pressure, those with body size misperception were significantly less aware of their risks for these conditions.

In practical terms, this meant that fifty six percent of obese subjects with body size misperception had seen a doctor in the past year. Of those, only 38-45% had discussed diet/habits, exercise or weight loss with their physician. By contrast, among the obese patients with accurate body size perception, 74% had seen a doctor in the past year and 64-68% had discussed such lifestyle issues with their physician. This suggests that obese people who do not realize their condition will get poorer medical care as a result of their misperceptions.

BMI and health risks
Not all causes of mortality can be related to obesity. A 2007 article in JAMA did an extensive analysis of the association of BMI with particular causes of death for the year 2004 in the United States. Researchers found that obesity was not related to increased deaths from cancer, respiratory disease or injuries. However, obesity was associated with increased mortality from cardiovascular disease and from diabetes and kidney disease. When all causes of mortality are considered, the graphs look like this (source article here):


Interestingly, these graphs show that a BMI of about 25 (between normal weight and overweight) seems to be the healthiest for long-term survival, and being underweight is actually unhealthy. However, the graphs do show that as obesity (BMI=30.0 or more) increases, all-cause mortality risk increases. For that reason, it pays to have an accurate idea of our body size, and to be willing to recognize that dealing with obesity could have a beneficial effect on our personal lifespan.

Cold Temperatures, Adaptive Thermogenesis and Obesity

Winter is on its way. Leaves are changing color; daylight is diminishing. Another sign of impending winter is the temperature change, with coats and sweaters coming out of storage to accommodate the colder weather. But have you noticed that some people need sweaters in chilly weather while others don't?

Besides adding layers of clothing, people respond to cold by decreasing internal body temperature (hypothermia), by decreasing peripheral body temperature (insulation) and by increasing energy expenditure (adaptive thermogenesis). Thanks to modern conveniences, exposure to extreme cold is uncommon. However, people still have many opportunities to experience mild cold exposure, as can happen when they move from a heated house to a cooler situation outdoors, or from a hot outdoor environment into an over-air-conditioned building. In the context of weight loss, it is interesting to note that these temperature transitions may be made more easily by those who are lean than by those who are overweight.

Heat Production Higher in Lean Subjects
A 2006 article by Claessens-van Ooijen et al. compared the effect of mild cooling and rewarming on healthy men who were lean (average BMI=21) and overweight (average BMI=29). The men wore standardized clothing and spent an hour sitting in 59°F air while covered by a duvet. Under baseline conditions there was no significant difference in energy expenditure between the two groups. In order to produce cooling, the duvets were removed for an hour. During this time both groups showed an increase in heat production, but the increase in the lean group was significantly greater. (Possible shivering was monitored and did not occur.) When the duvets were replaced, after an hour heat production returned to baseline in the overweight group but remained significantly higher than baseline in the lean group. In other words, the overweight men showed less adaptive thermogenesis in response to a mild exposure to cold.

Thermogenesis by Mitochondrial Uncoupling
One mechanism for adaptive thermogenesis was proposed by Wijers et al. in 2008. Eleven lean male subjects spent 34 hours in a respiration chamber at a baseline of 72°F and subsequently spent 82 hours in the respiration chamber without shivering under mild cold conditions of 61°F. Although the activity of the subjects decreased about 20% under mild cold conditions, their total daily energy expenditure increased by 2.8%. Muscle biopsies were taken at the end of the baseline and mild cold conditions. Analysis of the tissue showed that the cold-induced increase in total daily energy expenditure of each subject was significantly related to the amount of mitochondrial uncoupling that had occurred in his skeletal muscle. It is possible that during cold conditions, adaptive thermogenesis occurs when muscle mitochondria bypass some of their ATP synthesis in favor of dissipating energy as heat.

Brown Fat Activity Higher in Lean Subjects
Another possible mechanism for adaptive thermogenesis is the action of brown fat, also called brown adipose tissue. Unlike white adipose tissue, brown adipose tissue has small lipid droplets and many more iron-containing mitochondria, which makes it brown. Normally it functions to provide body heat to newborn humans and to hibernating animals. However, it is still present to some extent in adult humans.

In a 2009 article in the New England Journal of Medicine, van Marken Lichtenbelt et al. studied 24 healthy men, 10 lean (average BMI=22) and 14 overweight (average BMI=30). They rested in a supine position for one hour at 72°F and then for two hours at 61°F. The activity of their brown adipose tissue was assessed by PET-CT scanning that measured the uptake of a glucose isotope, ¹⁸F-fluorodeoxygluxose (¹⁸F-FDG). Example scans are shown below.

Under the thermoneutral condition of 72°F, very little of the ¹⁸F-FDG was taken up by brown fat, as shown by the lean subject on the far left. However, when the temperature was decreased to 61°, brown fat activity was significantly increased in the lean subject (center picture). It was also increased in the overweight subject seen on the right, but not as much. For the entire group, the activity of the brown adipose tissue was greater in the lean subjects than it was in the overweight ones. There was a a positive correlation between brown adipose activity and resting metabolic activity and a positive correlation with brown adipose activity and the core temperature under thermoneutral conditions. Overall, the study found that inreased BMI, but not increased age, was significantly associated with a decrease in brown adipose tissue activity.

Pure Speculation
None of these studies establishes the idea that being overweight reduces the ability of our bodies to cope with a mild exposure to cold, or that having a reduced ability to do adaptive thermogenesis makes us obese. On the other hand, they do raise the interesting possibilities that (1) losing weight might help us increase our ability to do adaptive thermogenesis, or (2) perhaps forcing our bodies to do adaptive thermogenesis might increase our ability to lose weight. As scientists love to say at the end of articles, more study is needed.

Insulin Sensitivity Affects Weight Loss

Last time we looked at the possibility that genetics may determine whether a person is able to lose more weight on a low-carb diet or on a low-fat diet. The jury is still out on that.

However, two articles from 2005 suggest that insulin sensitivity may play an important role in whether low-carb diets or low-fat diets work better for weight loss for particular people. The first of these, Insulin sensitivity determines the effectiveness of dietary macronutrient composition on weight loss in obese women, was published in Obesity Research. The second, A low-glycemic load diet facilitates greater weight loss in overweight adults with high insulin secretion but not in overweight adults with low insulin secretion in the CALERIE trial was published in Diabetes Care. Both articles were short, sweet and to the point. And both concluded that if you're insulin-sensitive, you will probably do better on a low-fat calorie-restricted diet, but if you are insulin-resistant, you can expect better weight loss on a low-carb calorie-restricted diet.

Experimental Design
The two studies were quite similar to each other, as outlined in the table above. Subjects were randomized into high-carb/low-fat (HC/LF) and low-carb/high-fat (LC/HF) diet groups. In both cases, high-carb was defined as 60% of calories, while low-carb was defined as 40% of calories. Not a dramatic difference, but because all the food was provided for the participants, it was possible to be fairly certain of what the subjects had consumed. (The amount of study food eaten plus any additional food eaten was taken into account.) In all cases, participants received a restricted number of calories.

Insulin Resistance
The variable of interest in these studies was insulin resistance. In the Obesity Research study, insulin resistance was determined by measuring fasting insulin levels. Insulin-sensitive (IS) individuals were defined as those with a fasting insulin below 10 mU/L and insulin-resistant (IR) subjects were defined as those with a fasting insulin above 15 mU/L. Subjects with a fasting insulin between those two values were excluded from the study. In the Diabetes Care study, insulin resistance was determined by administration of a 75 gram oral glucose tolerance test. The subjects whose plasma insulin at 30 minutes post-glucose was less than 66 mU/L were termed low insulin secreters and those whose plasma insulin at 30 minutes was above 66 mU/L were termed high insulin secreters.

Results
As expected, all groups lost a significant amount of weight. The findings are summarized in the two figures below. (I have modified both figures from their original forms to make it easier to compare them.)


The Obesity Research article stated that they expected a loss of approximately 1 kilogram of body weight for every 7300 deficit in calories. Therefore, their 16 week study should have produced a weight loss of at least of 6.1 kilograms, and this was indeed the case.

What was surprising was that two of the groups lost almost twice that amount of weight: the insulin-sensitive (IS) subjects who ate high-carb/low-fat (HC/LF) and the insulin-resistant (IR) subjects who ate low-carb/high-fat (LC/HF). A similar result is seen in the Diabetes Care article. All of those subjects lost an average 6 kilograms or more of body weight, but among the high insulin secreters, significantly more weight was lost when they followed a low-carb/high fat diet as compared with a high-carb/low-fat diet. Among low insulin secreters, there was a tendency to lose more weight with a high-carb/low-fat diet, but in this case the difference was not statistically significant.

Take-Home Lessons
It pains me to say it, but a low-carb/high-fat diet may not be the best weight loss diet for everybody. From these two studies, a person who is still insulin-sensitive could well find that a low-carb diet might actually be their worst choice. It would still work, but not as well as a low-fat/high-carb/calorie-restricted diet. On the other hand, for a person who is insulin-resistant (and if you're not insulin-resistant when you're young, you tend to get that way as you get older), a low-carb/high-fat/calorie-restricted diet appears to work the best. For whatever reason, if you follow the diet indicated by your insulin sensitivity, chances are good that you will not only lose the amount of weight predicted by the decrease in your caloric intake, but a few extra kilograms as well.