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Hungry, Hungry Hormones - Part III
An overview of Leptin and related hormones

By Dr. John M Berardi, Ph.D.
First published at www.t-mag.com, May 16 2003.

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Fasted and Fed — Why Leptin Matters

As discussed in Part II earlier, 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.

In the scenario graphically illustrated above, 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…"