You Can Get There From Here

Back in The Real Bathroom Scales, we learned that obesity has less to do with excess consumption than with insufficient energy expenditure, and that energy expenditure is very tightly regulated by our bodies, such that we cannot fool our fat-making machinery with simple changes to diet and exercise. Then, in my most recent post, Through Thick and Thin, we looked at a couple of major physiological determinants of that regulatory process—specifically, the degree of alpha and beta adrenergic stimulation and the amount of insulin our bodies produce. In this post, we’ll continue that discussion by examining a study of several drugs in the so-called “appetite suppressant” class, and look at how they really get the job done. “Back to the Future” Weight Loss TabletsUnless you’ve been living under a rock or aren’t yet 12 years old, you’ve no doubt heard of the infamous “fen-phen” diet drug combination. Fen-phen was short for Fenfluramine and Phentermine, two drugs classified as appetite suppressants, which were at one time heralded as the answer to obesity when used together. Unfortunately, the propensity of Fenfluramine to increase the risk of primary pulmonary hypertension resulted in that drug being removed from the marketplace, but fortunately, Phentermine is still available, and contrary to the mythology of the day, works just as well, if not better, by itself, than in combination with Fen. Some less well-known drugs in this class are Diethylproprion, Mazindol, Sibutramine, and more recently, Bupropion (Wellbutrin), originally intended as a smoking-cessation aid.  All of these drugs have a broadly similar mechanism—they alter the ebb and flow of neurotransmitters in the brain in such a way that thermogenesis is increased, either through direct stimulation of the beta adrenergic receptors or by inhibition of insulin release via the alpha adrenergic receptors. I’ll get further into the mechanics of these actions in another post, but for those of you who are looking for answers now, let’s get down to the brass tacks of what we can expect from drugs in this class. “Back to School” I’d like to review a study that compared the four most common diet drugs of its day (1981). In this study, researchers gave Phentermine, Mazindol, Fenfluramine, and Diethylpropion to four groups of mice, allowing them to eat freely as their respective appetites directed, for a period of 28 days. A group of unmedicated, ad libitum fed mice served as controls, while one other group, also unmedicated, were fed a restricted calorie diet for comparison. Although it is a mouse study and not a human study, I chose this one because of its excellent design, which eliminates the common confounding variables found in most diet drug studies, namely, caloric restriction and added exercise.  Due to the pervasive mythology about the cause of obesity, the vast majority of diet medications are tested in conjunction with a reduced calorie regimen and/or exercise program, which completely obscures the actual effects of the drugs. Since we know that reducing calories and increasing exercise causes both a temporary period of weight loss and a gradual metabolic slowdown, adding these variables into a medication trial is clearly…well, stupid! It makes a fair evaluation of the drug’s effects impossible to tease out. By allowing the subjects in this study to eat and exercise at will, the researchers were able to give a useful assessment of the drugs themselves. Weight Loss Tablets Okay, back to the study. As you can see in these graphs, all of the study treatments resulted in voluntarily reduced intake and some weight loss, but what’s important to note here is the relationship between the reduction in food intake and the amount of weight lost. Notice the bar lengths do not track—the highest intakes, relative to the control group, resulted in the lowest amount of body fat. Phentermine and Mazindol clearly offer a greater bang for the buck than Fenfluramine, Diethylpropion, and the standard caloric restriction. Here are the numbers as percentage reductions from control:
TreatmentIntakeFat WeightRatio
Low Calorie22.3%12.4%0.56
What this is telling us is that for the 22% reduction in calories experienced by the Low-Calorie mice, there was only a 12% drop in fat mass, relative to the controls, while for the lucky mice on Phentermine, there was a mere 6.6% decrease in intake, yet a whopping 15.9% decline in bodyfat, 2.4 times the change in intake.  Looking at the numbers this way, Phentermine and Mazindol are again the clear winners. “Get Your Back into It!” So where do these differences in results come from?  At the risk of charting you to death, let’s look at another interesting and critical statistic from this study:  energy expenditure. Weight Loss Tablets I keep saying that it is innate EE and not intake that ultimately determines our bodily fat content; well, here is more proof of that concept.  If you compare the body fat mass graph (above) with this EE graph, you will see that these bars do track–the drugs which induced the greatest energy expenditure (as measured during the six hours post-medication at four time points) resulted in the least fat mass.  Among these four drugs, again, Phentermine is the obvious star, raising EE by 43% over control. Before I leave this informative study, I would like to point out one more set of measurements the researchers made—body water and lean mass.  At this point, it shouldn’t surprise you to learn that only Phentermine and Mazindol increased both body water and lean mass by a statistically significant amount compared to control.  Good luck getting that result with any old low-calorie diet regimen! If the underlying cause of obesity is actually low energy expenditure and not high calorie intake, then isn’t the obvious solution something that increases EE rather than decreases intake?  From the results of this study, it should seem clear that a good diet medication will be a poor appetite suppressant and a powerful energy enhancer.

Through Thick and Thin

kindle helpIn The Real Bathroom Scales, we verified two important facts. First, we confirmed that the body responds to alterations in calorie balance with a combination of adjustments to energy storage (body mass) and to energy usage, the latter being mostly via changes to TEF and NEAT. Second, we saw that there was a wide variance between individuals in their rate and degree of adaption via the energy expenditure variables. In fact, in the Mayo Clinic NEAT study, the change in expenditure in response to an added 1,000 calories per day ranged from a low of +107 cals to a high of +917 cals, a nine-fold difference!1 So what drives these vast differences in our ability to adapt to changes in intake, such that some of us pile on the pounds, while others never seem to gain an ounce? While there are myriad biological abnormalities that can lead to obesity, most of them are uncommon, such as leptin deficiency, adrenal tumors, or genetic diseases such as Prader-Willi Syndrome. Most common obesities, on the other hand, can be directly linked to poor function or signaling of the sympathetic nervous system. The SNS is a primary regulator of many of the body’s homeostatic mechanisms, not the least of which is energy balance. The effects of the SNS on energy balance are achieved through the binding of catecholamines (adrenaline and noradrenaline) to a series of receptors known as the adrenergic receptors. “Greek Alphabet Soup” There are two basic types of adrenergic receptors, the alphas and the betas, and while both play a role in the management of body fat, the beta adrenergic receptors have been much more extensively studied with regard to energy balance, so we’ll start there. There are three beta receptors, and all are involved in the automatic regulation of energy expenditure, with some ability of each to compensate for the others. When these receptors are sufficiently stimulated by endogenous catecholamines or pharmacologic substitutes, the body is relatively resistant to weight gain. High levels of beta adrenergic stimulation probably underlie the “lean ‘n hungry” phenotype referred to in The Calculus of Calorie Counting. Without that stimulation, eating the same amount of food and doing the same amount of exercise, you will simply burn less of it as heat and energy and store more of it as fat. Like the patient in the Mayo Clinic NEAT study who only increased his energy expenditure by 107 calories per day, you would have what researchers call “defective thermogenesis”. Although the concept of thermogenesis has been around for at least half a century, the definitive proof that the beta-adrenergic receptors mediate thermogenesis took some time to develop.
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Adapted from “beta-AR Signaling Required for Diet-Induced Thermogenesis and Obesity Resistance” by Bachman, E.S., et. al. Science, August 2, 2002; 297(5582): 843 – 845.

In a revealing study of mice specially bred to lack all three beta receptors, researchers at Harvard Medical School showed how profoundly the beta receptors effect our ability to dispense with our caloric intake. In two separate experiments, these beta-null mice were compared with normals under free-feeding situations with first, ordinary lab chow, and second, with more palatable high-fat chow. All the mice consumed more calories with the more palatable chow, however, in both situations, beta-nulls ate exactly the same amount as normal mice and engaged in similar amounts of activity. The difference in the outcomes, however, was startling. The beta-nulls had consistently lower energy expenditure, and as the graph shows, consistently higher weight gain; on lab chow, it was about 70% higher, and on the palatable diet, it was three times higher! Now, while the beta adrenergic receptors are clearly important to fat-burning, the alpha adrenergics should not be ignored.  The alpha adrenergics are often described as being anti-lipolytic, because the alpha-2 adrenoreceptors reduce levels of cyclic adenosine monophosphate, an important second messenger in the thermogenic process.  This characterization is somewhat lopsided, however, as the alpha-2’s also have a generally inhibitory effect on the pituitary hormones, putting the brakes on excessive levels of insulin, prolactin, cortisol2, and thyroid.  These are not hormones that we necessarily want to inhibit, but neither do we benefit from excess; all of these hormones have optimal levels, and too much is just as problematic as too little.  With regard to controlling our weight, we particularly need to keep our levels of insulin in check. “Insulination” Recall from Dr. Segal’s research in Calculus, how the presence of insulin resistance dramatically reduces the thermic effect of feeding (TEF), in both the lean and the obese.3 Besides just impacting TEF, however, insulin reduces the overall fat-burning ability of the body. In fact, insulin reduces the effect of beta-adrenergic stimulation in a dose-dependent manner; in one study, the calorigenic effect of norepinephrine was decreased by the presence of elevated insulin levels by as much as 50%.4 Just how powerfully does insulin sensitivity impact our ability to burn fat? Consider this interesting study: a group of researchers in Canada bred a strain of mice with a mutation in their insulin receptors, such that the same amount of insulin would keep the receptor active longer, thereby reducing the amount of insulin needed to return blood sugar to basal levels. In other words, these mutant mice were exquisitely insulin-sensitive. The researchers then placed the mutants and a control group of wild-type mice on a high-calorie diet designed to cause weight gain. Weight Loss Tablets While on the diet, the mutant mice maintained slightly lower blood glucose levels, despite secreting approximately half the amount of insulin as the controls. Because of the reduction in insulin, weight gain was significantly lower, too. After 10 weeks on the diet, the mutants had added 27% to their weight, while the wild-types gained 50%–all while eating and exercising in a similar fashion. So here we have two common physiologic aberrations–insulin resistance and decreased adrenergc stimulation–that lead to decreased energy expenditure without any difference in diet or exercise patterns. For those who have any degree of either or both of these conditions, fat will tend to accumulate easily and be difficult to lose, while those on the other end of the spectrum, our (annoying) “lean ‘n hungry” friends, can’t gain weight to save their lives. Now, the important thing is, is there anything we can do about this? Well, it just so happens there is. If nature left a little something out of your gene pool, you can get it back. In my next post, You Can Get There From Here, I’ll start showing you which products, both prescription and OTC, can truly change your metabolism.
  1. Levine, J.A., et. al. Role of Nonexercise Activity Thermogenesis. Science 1999; 283(5399): 212–214.
  2. Price, L.H., et. al. Alpha 2-adrenergic receptor function in depression. The cortisol response to yohimbine. Arch Gen Psychiatry 1986 Sep; 43(9): 849-58
  3. Segal, K.R., et al. Independent Effects of Obesity and Insulin Resistance on Postprandial Thermogenesis in men. J Clin Invest 1992; 89:824-833.
  4. Marette, A. and Bukowiecki, L. J. Stimulation of glucose transport by insulin and norepinephrine in isolated rat brown adipocytes. Am J Physiol Cell Physiol 1989; 257: C714-C721.