Hungry, Hungry Hormones – Part I

An overview of Leptin and related hormones. Is It Really That Simple? I wish someone would hand me a shiny US nickel every time I heard some personal trainer or some gym guru respond to an exercise or nutrition related question with “Well, it’s simple really…”

Why am I always doing 3 sets of 10 reps?

Well, it’s simple really…

Why should I eat more protein?

Why am I always doing 3 sets of 10 reps?

Well, it’s simple really…

Why should I eat more protein?

Well, it’s simple really…

Why do I always seem to plateau after a few weeks of dieting?

Well, it’s simple really…

Why won’t the fitness model with the lacy thong respond to my loud grunts and pawing hands?

Well, it’s simple really…

Whenever I see the "Well, it’s simple really…" clowns in action, I wonder how rich I would be if I actually did get those nickels. Next I wonder if anything is really as simple as they make it out to be. Finally I wonder if anyone would miss them if they were buried somewhere in upstate New York.

After all, it seems to me that most exercise and nutrition questions, especially those related to our physiological responses to certain manipulations, are quite complex. Rather than "Well, it’s simple really…" I tend to think that the answer to almost every question relating to exercise and nutrition should start off with "Well, it depends on…"

Feeding and Metabolic Regulation

One of the nutrition answers that has recently gained "Well, it’s simple really…" status is the idea that eating less tends to decrease your metabolic rate while eating more tends to increase your metabolic rate. While most nutrition faithfuls discuss this idea ad nauseum, I wonder if any of them actually understand this phenomenon.

Just how does the body know we’re eating less?

Likewise, how does it know we’re eating more?

Furthermore, how can it adapt the overall metabolic rate to accommodate this knowledge of what’s happening with energy intake?

These are just a few of the questions that need answering if we’re to aspire to better body composition manipulation. After all, if our energy expenditure is intimately linked to our energy intake (see my visual depiction of this below), we need to figure out where the communication is taking place.

By understanding this communication and the integration of intake and expenditure, we can hopefully find ways to dissociate the relationship. For example, if expenditure wasn’t so dependent on intake, we could more easily manipulate our body composition by avoiding that nasty metabolic shutdown that accompanies dieting. Conversely, if expenditure didn’t send such strong signals that impact our urge to eat, many of you miserable dieters wouldn’t feel so hungry when trying to get lean. Of course, with this latter point, we can always just refuse the signals, eating in a way that supports our goals. But that doesn’t make us any friendlier while dieting, now does it?

So Where’s The Communication?

If you’re going around asserting that one’s metabolism increases or decreases based on whether they’re on a hypercaloric or a hypocaloric diet, you’d better hope that there’s some evidence for this hypothesis. You see, if there’s any truth to the theory that the body can "sense" energy intake and respond metabolically, scientists would have to find a metabolic pathway that’s sensitive to changes in some energy metabolite. If they can’t find this, no matter how self-evident they think this idea seems, the "Well, it’s simple really" camp is just vehemently defending an unproven hypothesis.

Fortunately for the "Well, it’s simple" folks, there seems to be a candidate pathway that can explain the fact that our bodies seem to rapidly respond to changes in energy intake. In other words, a pathway has been discovered that can explain how the body knows whether we’re feasting of we’re fasting. This pathway is known as the HBP, or Hexosamine Biosynthetic Pathway.

As many of you know, cells of the body are always metabolizing carbohydrates for energy. This metabolism is accomplished by sending glucose through the anaerobic glycolytic pathway (see below). The metabolites of this pathway usually end up fluxing through the Kreb’s cycle, providing substrates to resynthesize ATP (the cell’s energy currency).

During this normal carbohydrate metabolism, a small amount of the glucose flux (1-3%) is sent through our new friend, the little discussed HBP. This pathway accepts either glucosamine (which is phosphorylated directly) or fructose 6 phosphate (which is phosphorylated by GFAT / glutamine: fructose 6 phosphate amidotransferase) to form glucosamine 6 phosphate. This glucosamine 6 phosphate is then converted to UDP-N-acetylglucosamine and acts as a glycosylation substrate. A glycosylation substrate is one that binds proteins to alter their stability in the cell. This alteration, among other things, influences how the protein interacts with the genetic material. For those "visual learners," a visual depiction of these pathways is provided below.

The important point here is that when you eat more, more glucose is available and there will be more flux through the HBP. Conversely, if you eat less, less glucose is available for flux through the HBP. This means that the HBP can directly "sense" what’s happening with the energy in side of the energy balance equation.

At this point, if you’re wondering why this matters, I’d like to draw your attention to the effects of increased flux through the HBP (or, a habitual increase in energy intake):

• Decreased glucose uptake
• Reduced insulin sensitivity
• Increased insulin secretion
• Increased fatty acid synthesis in the liver

Now, obviously reduced insulin sensitivity and glucose uptake aren’t what weight trainers are striving for. But keep in mind that these reductions occur relative to what’s happening on a lower calorie diet. Therefore, these changes would be expected. If you’re overfeeding, the cells will be stuffed full of carbohydrate and will obviously have to work harder to get any new carbohydrates in. But keep in mind that if you have excellent insulin sensitivity, overfeeding may reduce this sensitivity (as shown above) a bit. That certainly doesn’t mean, though, that you need to immediately get on diabetic meds.

What it does mean is that we now have a candidate mechanism by which acute and chronic food intake can be "sensed" by the body (i.e. through glucose flux). In addition, we also have a mechanism by which the "sensing" can cause a cellular response (glycosylation of proteins by UDP N-acetyl glucosamine).

For you budding physiologists out there, you may be wondering what happens when proteins are glycosylated by UDP N-acetyl glucosamine. Well, scientists aren’t completely clear on that one just yet. However, what scientists have done is link HBP flux with the expression of the OB (obesity) gene. And this, my friends, is the hormonal segway you’ve been looking for. By altering expression of the OB gene, the HPB is directly linked to the expression of the hungry, hungry hormone — Leptin.

As alluded to, Leptin (a term derived from the Greek leptos – meaning slim) is a 16-Kd (this indicates it’s size) hormone produced in the translation of the genetic information contained on the Ob (obesity gene). Upon stimulation of the Ob gene, cellular translation initiates the formation of a leptin precursor protein (Leptin mRNA). This Leptin mRNA is then transcribed into the hormone leptin without any significant post-transcriptional regulation (i.e. most all of the Leptin mRNA ends up becoming Leptin).

At this point, I’m gonna give you a week to think about what you’ve learned with respect to how the body senses energy intake. Now that you have this background, next week we can dive right into Leptin, covering how this hormone helps to regulate feeding, energy balance, and body composition.

Of course, if you want a complete guide to doing this yourself, I strongly recommend you pick up a copy of Precision Nutrition, where I’ll show you in great detail exactly what to do.

About the Author Dr. John M. Berardi PhD, CSCS

Dr. Berardi’s philosophy is simple: people from all walks of life, from soccerstars to soccer coaches to soccer moms, should have access to the most recentdevelopments in health, exercise, and nutrient science. Dr. Berardi and his company,Precision Nutrition, Inc. have one purpose: to take the latest in advanced nutritionresearch and teach it to others in a way that doesn’t take an advanced degree tofigure out. Dr. Berardi has earned a doctoral degree from the University of WesternOntario (2005) with a specialization in the area of exercise biology and nutrientbiochemistry. Prior to his doctoral studies, Dr. Berardi studied Exercise Scienceat Eastern Michigan University (Masters program; 1999) as well as Health Science,Psychology, and Philosophy at Lock Haven University (Undergraduate program; 1997).Currently, Dr. Berardi is an adjunct professor of Exercise Science at the Universityof Texas at Austin. Through his company, Precision Nutrition, Inc., Dr. Berardi hasworked in the exercise and nutrition arena for over a decade, working with individualsfrom all walks of life, from the sedentary to athletes at the highest level of