Hungry, Hungry Hormones

by John Berardi

from http://www.johnberardi.com/articles/hormones/hungry.htm
First published at www.t-mag.com, May 2 2003.

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?

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.

Express Yourself

As discussed in Part I, Leptin is a hormone produced when the OB (obesity) gene is expressed. While I've already discussed one mechanism to induce OB gene expression and Leptin production, the three main cellular signals involved are:

• Increased energy/carbohydrate flux through the HBP.
• Increased triacylglycerol (triglyceride) metabolites. These include diacylglycerols and/or free fatty acids.
• Increased tension in adipose tissue due to cellular stretching (increases in adipose size).

As you can see, these three phenomena provide response mechanisms whereby both acute and chronic overfeeding or underfeeding will influence OB gene expression and Leptin production. If overfeeding, more carbohydrates will flux through HBP, more triglycerides will be metabolized, and adipose tissue sizes will increase. This leads to more Leptin production. Conversely, if underfeeding, carbohydrate and triglyceride availability will be decreased, as will adipose tissue size. Of course, this means less Leptin.

Since we now know why Leptin is formed, how about discussing where it's formed? In adult humans, most of the body's leptin is formed in white adipose tissue. This should be self-evident from the signals discussed above. However, Leptin has also been found in the following tissues, making it relatively ubiquitous.

• Brown adipose tissue
• Gastric epithelium
• Placenta
• Skeletal muscle
• Mammary gland

Of Rat and Fat

When Leptin was originally discovered, scientists found that rats that had mutations in the OB gene (and couldn't produce Leptin) became insanely obese. Now when I say obese, I'm not talking a little overweight here. I'm talking so obese that members of NAAFA actually pointed and laughed. In the obese rats, the extreme obesity was caused by mutations in the Ob gene. In these animals, there was simply too little Leptin. Interestingly, when administered Leptin, these tubby rats saw big increases in metabolic rate and lost massive amounts of body fat.

As a result of these findings, researchers speculated that Leptin might be a magical fat loss hormone. Unfortunately for the pharmaceutical companies who immediately jumped all over the rights to sell recombinant Leptin, this hypothesis didn't pan out. You see, another model of rat was discovered, a model that was as obese as the Leptin deficient rats but had adequate Leptin concentrations in the blood. These rats, instead of a Leptin deficiency, had problems with their Leptin receptor. Therefore the Leptin that was present couldn't do its job.

In addition to this new rodent data, thwarting the potential billions to be gained from Leptin sales, new human data also showed that Leptin was unlikely to help the obese drop those few hundred unwanted pounds. Research had clearly demonstrated that:

a) Very few obese humans actually suffer from Ob gene mutations
b) Very few obese humans actually suffer from Leptin receptor mutations
c) Obese humans often have very high concentrations of leptin in the plasma

Since obese humans often have so much Leptin, research has been directed toward how these individuals can have so much Leptin, yet fail to respond with a reduction in body weight, as did our furry rodent friends. One hypothesis that has gained popularity suggests that a Leptin resistance causes human obesity. In other words, the very obese got this way because they were somehow intolerant to rising Leptin. As one researcher put it, "Leptin resistance is not well defined, however this term is usually used to mean that leptin does not perform its central and peripheral functions."

At this point, there is some evidence for the Leptin resistance hypothesis. Since Leptin seems to have central effects, the saturable blood brain barrier transport system for leptin may be linked to obesity. Since obese humans have a CSF (cerebrospinal fluid) to plasma ratio that is much lower than normal-sized humans, it appears that only so much Leptin can get across the BBB into the brain. In addition, in rats, dietary induced obesity (DIO) is accompanied by high plasma leptin concentrations. This leptin doesn't seem to prevent the obesity. However, when administered intracerebroventricular leptin (leptin into the brain), they lose weight, indicating a potential BBB transport limit.

Although these data offer support to the idea that there is a limit to amount of leptin allowed into the brain and therefore a type of Leptin "resistance" exists at the higher levels of Leptin production, some authors believe that leptin resistance is actually a misnomer. These researchers are of the opinion that since leptin may not be designed to function in such high concentrations as seen in obesity, Leptin may be more important in its absence than its presence (i.e. may be more important in calorie restriction and not in calorie excess, as is often seen with obesity). In other words, it's not that the obese are "improperly" responding to their leptin. Instead, these authors are suggesting that the obese aren't "supposed" to have so much leptin and therefore don't respond to it's elevation above a certain point.

What's Leptin Do?

The hormone Leptin seems to affect nearly every system of the body. Since there are Leptin receptors in the brain and throughout the body, we can discuss the effects of Leptin as central or peripheral.

Since Leptin is released (mostly) by adipose tissues, adipose tissue seems to be a peripheral static indicator of the chronic energy balance of the body. Once released into the blood, under normal conditions, Leptin travels across the blood brain barrier and is sensed by the Leptin receptors in the hypothalamus. Since these receptors have some idea of what's a "normal" Leptin signal, changes in Leptin binding initiates the release of a series of anabolic (orexigenic or meal stimulating) and catabolic (anorexigenic or meal preventing) hormones/neurotransmitters. An increase in leptin leads to the expression of several anorexigenic (catabolic) hormones and neurotransmitters including áMSH and CART. These chemicals decrease hunger and meal size.

Conversely, a decrease in leptin leads to the expression of several orexigenic (anabolic) hormones and neurotransmitters including NPY and AgRP. These compounds increase hunger and meal size. This is a rather nice way for the body to deal with energy surplus or energy deficit. If there's a surplus, Leptin increases, signaling the hypothalamus to tell the body to stop eating. Conversely, if there's a deficit, Leptin decreases, signaling the hypothalamus to make us really hungry. For you visual learners, here's a visual depiction of what happens when Leptin concentrations increase in the hypothalamus.

Although I only mentioned a couple key orexigenic and anorexigenic hormones/neurotransmitters, there are many others that can interact with Leptin or the same signaling systems as Leptin. These are listed below:

Orexigenic (stimulate food intake) — May act in the lateral hypothalamic neurons

Anorexigenic (reduce food intake) —May act on the ventral & dorsal medial hypothalamus

Neuropeptide Y (NPY)— is the most potent orexiant known; may respond to aberrant leptin signaling; antagonism may reduce hunger and fat mass Agouti Related Peptide (AgRP) — potent orexiant; may respond to absent leptin; antagonism may reduce hunger and fat mass Melanin Concentrating Hormone (MCH) — receives signals from NPY to increase food intake Orexin — increases arousal and food intake Ghrelin — a potent GH releasing hormone released from the stomach, pituitary, and hypothalamus; increases food intake and body weight; may compete with leptin

Pro-Opiomelanocortin (POMC) — precursor to áMSH Melanocyte Stimulating Hormone (áMSH) — decreases food intake; may respond to increased leptin; antagonism increases appetite and food Melanocortin 4 receptor (MC4R) — áMSH receptor; binding of agonist reduces food intake Cocaine Amphetamine Related Transcript (CART) — decreases food intake; may respond to increased leptin CCK — gastric released peptide; increases satiety; reduces food intake (single feeding and meal frequency) Corticotropin releasing factor (CRF) — regulates adrenal hormones and ACTH; decreases food intake, increases energy expenditure Insulin — increasing concentrations of insulin decrease appetite

While these energy regulating hormones and neurotransmitters may be relatively new to you, the important message here is that they are responsible for sensing a starvation response (with decreased Leptin). In response to these decreases in Leptin concentrations, these chemicals are responsible for promoting the following effects:

a. Increased food intake
b. Decreased skeletal muscle growth
c. Decreased energy expenditure
d. Decreased body temperature
e. Decreased reproductive function
f. Increased adrenal production of stress hormones
g. Increased parasympathetic tone

Conversely, these energy regulating hormones and neurotransmitters are responsible for sensing an energy surplus (with increased Leptin). Therefore, when Leptin concentrations increase, the following effects are promoted:

a. Decreased food intake
b. Increased energy expenditure
c. Increased sympathetic tone

Again, for you visual kids, here's a schematic. Remember, Leptin is regulated in response to acute feeding as well as chronic energy balance (as measured by adipose mass). Therefore, while you'll see weight gain and weight loss as regulators below, you could replace these terms with underfeeding and overfeeding.

Notice that the main discussion today has centered on the central effects of Leptin (in the hypothalamus). However, Leptin, as discussed earlier, also has a number of peripheral effects. The peripheral effects include the following.

• In skeletal muscle, leptin increases fat oxidation and insulin sensitivity, explaining part of its effect on weight reduction.
• Leptin may act in concert with the immune system since leptin deficient animals have reduced immunity. This may explain part of the effect of dieting on weakened immune function.
• Leptin may play a permissive role in female menarche since there is an inverse relationship between Leptin concentrations and age of first menstruation. This means girls with more body fat (and higher Leptin concentrations) may have first menstruation sooner than leaner girls.
• Leptin concentrations and Testosterone concentrations are inversely proportional through the normal range of Testosterone. This means that as Leptin goes up, Testosterone down. Conversely, as Leptin goes down, Testosterone goes up. This should be no surprise as very overweight men are often hypogonadal. However, you should wonder why those who are extremely lean are often hypogonadal as well.
• The paradox of this relationship is that leptin is partly responsible for increasing GnRH secretion as well as LH, FSH, and Testosterone secretion. Therefore, at very low concentrations there would be an occurrence of hypogonadism. But very high concentrations, Leptin directly inhibits Testosterone release (leptin decreases T secretion from testis, even in spite of increased GnRH activity), again causing hypogonadism. Therefore the best Leptin concentrations would be at the low normal range. Not coincidentally, this usually occurs in those lean individuals who are well fed.

In addition to these peripheral effects, Leptin has shown the following interactions with other hormones:

• Leptin increases GnRH at hypothalamus
• Leptin decreases Testosterone at testis
• Glucocorticoids increase plasma leptin
• SNS activity (epinephrine) decreases plasma leptin
• Testosterone decreases plasma leptin
• Insulin acts with leptin by stimulating the same neuronal populations
• Insulin increases Ob gene expression
• Ghrelin competes with leptin centrally, with opposite actions as leptin
• Leptin and insulin sensitize the hindbrain to the anorexigenic hormone CCK

The following adipocytokines (hormones released from adipose) may also interact with leptin:

• Resistin adipocytokine that may regulate insulin sensitivity
• Adiponectin enhances insulin function increases with insulin and decreases with obesity
• increases UCP2 in muscle
• increases fatty acid transporter protein
• increases acyl CoA oxidase
• decreases triglyceride content in liver and muscle
• Adipsin is found in proportion to adiposity
• is required for the synthesis of ASP (acylation stimulating protein — is involved in the uptake and esterification of TAG and FA)
• stimulates TAG synthesis more than insulin

What's that sound? Oh, that's the bell! Quickly I'd like to recap this week's lesson. First of all, Leptin is released from many peripheral tissues but the biggest player is white adipose. Once released, Leptin has all kinds of divergent effects on the peripheral systems of the body, many of which are just coming to light. These peripheral effects include interactions with many hormones of the body as well as interactions with the skeletal muscle, the immune system, and the reproductive system. Also, Leptin acts centrally in order to stir up a neurotransmitter soup of meal stimulating and meal reducing chemicals. These central and peripheral effects are important to understand as they are ultimately responsible for metabolic changes with feeding as well as weight gain and loss.

So class is now dismissed for this week. But don't miss out on next week's lecture. I'll be reviewing some of the important feeding studies and discussing some recent data showing how recombinant Leptin injections may actually help prevent the metabolic decline associated with dieting.

Fasted and Fed — Why Leptin Matters

As discussed in Part II, Leptin concentrations are very closely correlated with body fat mass. The fatter you are, the more Leptin you make. This relationship highlights the role of Leptin as a static indicator of chronic energy balance in the body. If you lose fat, Leptin goes down. If you gain fat, Leptin goes up.

To complicate the matter, however, it’s important to note that Leptin concentrations also reflect acute energy status and change very rapidly in response to feeding and fasting, as demonstrated below.

When fasting, the decline in Leptin concentrations would be associated with a ravenous hunger, a reduction in metabolic rate, and a decrease in voluntary activity. Since Leptin concentrations play an integral role in these changes at the muscle, fat, and hypothalamic tissues, a critical body composition target would be the maintenance of Leptin concentrations while dieting. At this point, let’s review some feeding research to highlight what exactly happens when dieting (and overfeeding).

Study #1 - (Coleman et al, Diabetologia 42: 636-646, 1999)

During a 52-96 hour fast, subjects experienced a 4% loss in body mass, accompanied by a 54-72% decline in Leptin concentrations.

In some subjects, once Leptin declined, the authors administered a glucose infusion (5% solution totaling 338 kcal/day), causing Leptin to increase by 80%, relative to that large depression. This demonstrates that a small carbohydrate load can almost normalize depressed Leptin concentrations. It's important to note that this small addition of carbohydrate is only associated with an increase in Leptin concentrations during a fast. During a normal diet phase, I doubt a small carb increase will increase Leptin concentrations.

In other subjects, after the 4-day fast, only 12 hours of "refeeding" returned Leptin to baseline, demonstrating that acute feeding is an important regulator of Leptin concentrations.

Study #2 - (Kolaczynski et al Diabetes 45: 1511-1515, 1996)

During the first part of this study, researchers found that after 36h of fasting, Leptin decreased by 77% while after 60h of fasting, Leptin decreased by 82%.

During the second part of the study (the data plotted above), authors found that Leptin decreased by 20% after 12h and 65% after 36h of fasting. However after 12 h of refeeding, Leptin increased to 62% of normal and after 24h refeeding, leptin increased to 100% of normal. These data indicate that 12h fasting is sufficient to reduce serum leptin dramatically — this is concomitant with decreased insulin and increased glucagon, cortisol, catecholamines, and GH. They also indicate that a normal single meal has negligible impact on leptin — it takes prolonged feedings to impact Leptin concentrations.

Finally, in this study the authors demonstrated that after an overnight fast with a small amount of glucose infusion, Leptin doesn’t drop at all.

Study #3 - (Kolaczynski et al J Clin Endocrinol Metab 81 4162-4165, 1996)

In Part 1, subjects were ridiculously overfed as follows: over 12 hours, subjects ate 120kcal/kg (about 12000kcal for a 100kg individual).

During the 5th to 10th hour of overfeeding, there was a 40% increase in Leptin that persisted through the morning and continued beyond. Unfortunately, the researchers only measured out Leptin levels until the morning. We don’t know how long the Leptin remained elevated. These data indicate that with very big, "Victor Richards type" overfeedings, elevations in Leptin concentrations may persist even after an overnight fast.

In Part 2, subjects ate 25kcal/kg (2500kcal for a 100kg individual) above normal intake until they gained an additional 10% body mass. During this study, fasting Leptin tripled in response to weight gain (there was a varied response, though: in subjects that gained the most fat, Leptin increased the most).

Study #4 - (Dallongeville et al Int J Obesity 22, 728-733, 1998)

Leptin increased by 27% over an 8h post meal period while it decreased by 29% during a similar fasted period (these results were obtained during daytime feeding/fasting). These data weren’t simply circadian due to the fact that similar changes were seen during nighttime feeding/fasting where Leptin increased by 37% over 8h when fed, and decreased by 27% over 8h when fasting. These data indicate that meal feeding during a normal circadian cycle increases Leptin concentrations while fasting decreases them.

Studies #5 - #7 - (Evans et al Clin Sci London 100(5) 493-498, 2001; Coppack et al Proc Nutr Soc 57 461-470; Dirlewanger et al Int J Obes Relat Metab Disord 11 1413-1418, 2000)

These studies show that CHO are necessary to induce postprandial Leptin increases, as fat alone doesn’t increase Leptin after meals. They also demonstrate that mixed meals are sufficient to induce Leptin increases. Fat doesn’t have to be avoided.

From Research to Hypotheses

From these data, a number of individuals, including fellow T-mag contributor Joel Marion, have speculated that prolonged (8-12 hour) carbohydrate refeeds can help a struggling dieter’s metabolism. His argument is that while dieting, Leptin declines to a modest extent and, as a result, the metabolism slows, cravings increase, progress slows, and the diet begins to seem futile. He reasons that if carb feeding increases Leptin concentrations (which it will), the metabolic rate will kick up again and fat burning will resume.

While I applaud these speculations of my colleagues, I can’t totally agree with this hypothesis. As the research above has illustrated, Leptin kicks up and down very rapidly as energy intake fluctuates. Therefore, while Leptin may kick up with a 10-hour carbohydrate reefed, it’s likely to drop back down just as rapidly after the reefed is over and another 10 hours of dieting are accomplished. Therefore, a dieter may just end up with a bigger positive energy balance during those 24hours of refeeding and subsequent return to dieting.

Since there is no data, one way or the other, illustrating what happens in dieting weight lifters when refeeding, there's only speculation. Of course, Leptin itself aside, if there were some prolonged increase in Leptin, we should be able to measure the effects of this Leptin increase by observing increases in metabolic rate the day after the refeed. Unfortunately, metabolic increases as a result of acute overfeeding aren’t observed a day after the overfeed (or refeed). But no matter, I don’t want to make a big deal about either of these points. As I’ve indicated in previous columns, I do see other good reasons (i.e. a psychological break from dieting, increased adherence, better glycogen status, more intense workouts) for refeeding besides the Leptin issue.

Another interesting hypothesis is that fish oil can positively impact Leptin concentrations and Leptin action. While all of the current data is in rats, it appears that dietary fish oil can acutely increase plasma Leptin concentrations, increasing metabolic rate and decreasing hunger. If this were to occur during dieting, it would be beneficial in preventing metabolic decline. However, due to the fact that fish oil feeding prevents fat gain or reduces body fat in rats after a high saturated fat diet, chronic Leptin concentrations should be reduced (as Leptin is correlated with body fat stores). Regardless of what the rat data say, currently I know a grad student who is measuring the effects of fish oil supplementation of plasma Leptin concentrations. Once these data are collected I’ll be sharing them here.

Leptin Injections While Dieting?

Theoretical issues shelved, the last study I want to address today is one demonstrating just what does happen when Leptin is "replaced" (exogenously) during a dieting situation.

Study #8 - (Rosenbaum et al J Clin Endo Metab 87(5) 2391-2394 , 2002)

In this study, subjects were fed a diet until they became weight stable for 2 weeks. Then subjects were fed a diet designed to help them lose 10% of their body mass. After this was achieved, calories were then adjusted up to achieve weight stability for 2 weeks.

At this reduced weight, Leptin was decreased (30%), as was T3 (9%), T4 (13%), total mass (10% or 8.6kg), lean mass (5% or 2.5kg) and fat mass (18% or 6.2kg), and total daily energy expenditure.

At this point, Leptin injections were then given to the subjects for 5 weeks as they consumed the amount of calories required to keep weight stable. The amount of Leptin given was just enough to return Leptin back to their baseline (pre-diet concentrations).

The 5 weeks of Leptin administration led to normalizations in Leptin concentrations, T3, T4, and total daily energy expenditure while leading to further losses in body mass (an extra 1.5kg), fat mass (an extra 1kg), and a small loss of lean mass (an extra 0.6kg).

This study demonstrates that Leptin replacement during a maintenance diet (with a depressed metabolism due to prior dieting) can facilitate a greater rate of fat loss due to the effects of Leptin on normalizing the thermogenic environment of the body.

Body Weight Regulation

As this article has repeatedly stressed, body weight is regulated by short term and long-term signals. The short-term signals include altered meal patterns and individual meal consumption. The long-term signals include the balance of energy expenditure with energy intake.

While, for disciplined dieters, the meal consumption factor is held constant (despite an ever increasing appetite), another problem arises. Dieting efforts can be foiled by metabolic and hormonal adaptations such as decreased metabolic rate, decreased voluntary energy expenditure (exercise), reduced immune function, decreased reproductive function, and decreased anabolic hormonal output (GhRH and GH, GRH and Testosterone, TSH and Thyroid hormones), all the while increasing CRH and adrenal hormones. It appears that Leptin is a big player in these adaptations.

While I don’t have any easy answers as to how we can recruit Leptin to fight the good fight — to help out with our fat loss efforts—Leptin research is coming at us at an alarming rate. As a result, I have no doubt that in the near future, in response to questions about how Leptin operates, some trainer or nutritionist will be starting their answer off with "Well, it’s simple really…"

About the Author

John M Berardi is one of the world's foremost experts in the field of human performance and nutrition. His company, Science Link, provides unique and highly effective training, nutrition, and supplementation programs for high level athletes as well as recreational exercisers. John is a prolific author and a sought after speaker and consultant. Visit www.johnberardi.com for more information about John and his team. Also, check out his new DVD entitled No Nonsense Nutrition:

Tags: fat-loss hormones