LEPTIN
An often neglected yet extremely important hormone for successful dieting is leptin. Learning how it impacts the human metabolism is crucial in order to understand its importance and how to successfully manipulate it to your benefit.
What Is Leptin?
Leptin is a hormone secreted by white adipose tissue that interacts with the hypothalamus to reduce hunger. Leptin levels in the circulation are directly correlated with the amount of body fat. As the amount of body fat increases, so does the level of leptin, thus suppressing hunger. In contrast, less body fat and lower leptin levels mean hunger is suppressed to a lesser extent.
Leptin is a master-hormone with downstream effects on other hormones related to metabolism (T3/T4, neuropeptide-Y, epinephrine and many others).
Leptin also exerts rapid effects on glucose and lipid metabolism by activating leptin-responsive relays that are initiated in the hypothalamus and transmitted to other tissues via the sympathetic nervous system. The major tissues affected include the pancreas, skeletal muscle, liver, and adipose tissue. Furthermore, leptin receptors are present in tissues other than the hypothalamus, so leptin can exert direct effects on these tissues independent of its role in the hypothalamus. In skeletal muscle, leptin activates AMP-activated protein kinase (AMPK) and thus promotes fatty acid oxidation and utilization for energy. when AMPK is active (phosphorylated), fatty acid oxidation is stimulated and fatty acid synthesis is inhibited. Direct binding of leptin to tissues also regulates glucose metabolism through its effects on insulin. Leptin inhibits the synthesis and secretion of insulin by the pancreas, while insulin signaling is suppressed in the liver and white and brown adipose tissue.
Due to hormonal reasons, women generally have 2-3 times as much leptin as men at any given level of bodyfat. There is also some evidence for gender differences in how leptin responds in women versus men to things like diet and exercise. More importantly, women’s brains may respond to leptin differently than men.
The Discovery Of Leptin
Early research in the 1950’s had established the existence of some type of setpoint (primarily in animal models), making researchers sort of guess what might be going on in terms of regulating body fat levels. The hypothesis was that the brain of the animal must be responding in some form or fashion to a hormone that scaled with body fat levels.
The discovery of leptin as a gene for this hormone in the obesity mouse in this 1994 study was a milestone event in understanding the relationships of appetite control and obesity. The obesity mouse had been studied for decades and was spontaneously overweight with a low resting metabolic rate, low levels of activity, ate a lot, put on fat easily, etc. For many years it was suspected that factors in the bloodstream regulated food intake as well as energy expenditure, and the discovery of leptin provided the first solid evidence.
Superficially, the obesity mouse appeared to be similar to obese humans, and it turned out that it didn’t produce leptin at all, having a gene defect and therefore producing zero leptin. When the mouse was injected with synthetic leptin it lost weight and fat rapidly.
Leptin Levels In Humans
After the aforementioned results on obese mice, researchers measured blood levels of leptin in humans of varying weight expecting obese humans to produce no leptin either. Turns out that obese individuals invariably had very high levels of leptin and it was suggested that, in a similar vein to insulin resistance (where the body no longer responds appropriately to the hormone insulin), the body or brain had become leptin resistant and was not sending the right signal to the brain to turn off appetite and reduce body fat.
A variety of things induce leptin resistance including high blood triglyceride levels.
What Does Leptin Do?
Leptin is controlled primarily by two things:
- Acute energy balance in the short term [1, 2], since a high caloric deficit causes leptin to drop lower than what can be explained by fat loss, and a caloric surplus raises leptin higher than what can be explained by fat gain.
- Total amount of fat mass in the long term [1], since fat cells are factories for leptin production. Not having many factories obviously impairs production and the absolute amount of leptin in circulation.
Essentially leptin tells your brain how much you’re eating and how fat you are. Women’s brains appear to respond more to changes in leptin while men’s respond more to insulin. These effects are probably mediated by differences in hormone levels and it appears that estrogen exerts a leptin like signal in the brain as well.
Leptin levels are also crucially involved in both puberty and fertility. Since a certain level of body fat is required for puberty to hit, achieving critical levels of leptin appears to play a role in allowing puberty to begin and it’s thought that some of the reason children may be hitting puberty sooner is because increasing childhood obesity is causing them to hit that critical level sooner.
Since leptin is a key factor in regulating fertility, this partly explains why dieters that are reaching very low levels of body fat lose both sex drive and the ability to function. In regards to females, loss of menstrual cycle is a well known effect of dieting and intensive training and while it was always thought to be related to body fat levels, it appears that energy availability is a bigger factor. Leptin also acts as an adipometer, a measurement of energy stores that tells the brain whether there are sufficient calories available to spend on bodily functions like bone repair, immune function maintenance among others.
Leptin also directly stimulates fat oxidation in skeletal muscle.
Other Hormones At Play
While leptin absolutely plays a primary role in bodyweight regulation it is far from the only factor involved. Other hormones like Cholecystokinin (CCK), Pancreatic Polypeptide (PP), Glucagon-Like Peptide (GLP)-1, Ghrelin and Oxyntomodulin, can be manipulated to regulate energy balance in humans, and obese subjects retain sensitivity to the actions of gut these hormones.
Cholecystokinin is produced in the small intestine in response to food intake, especially lipids and proteins, goes to the brain, binds to its specific receptor and helps to signal fullness on a meal to meal basis. CCK doesn’t appear to play much of a role in the long-term regulation of bodyweight, its simply a fullness signal in response to meals. Protein, fat and fiber play a primary role in CCK stimulation with carbohydrates having a much smaller effect. This may explain part of the appetite blunting effect of many low-carbohydrate diets (since they are generally high in protein, fat and fiber).
Pancreatic Polypeptide (PP) is synthesized primarily in the pancreas and secreted in response to food intake. Its mechanisms of action are not well understood, although PP receptors are present in the hypothalamus and binding appears to down-regulate NPY mRNA expression, thus decreasing hunger.
Glucagon-Like Peptide (GLP)-1’s production occurs along the entire length of the intestine in proportion to caloric intake. GLP-1 release is delayed in obese individuals, who also have lower circulating GLP-1 levels. GLP-1 stimulates the pancreas to secrete insulin while inhibiting secretion of glucagon. It also reduces gastric emptying and intestinal motility, the latter causing signals to be sent via the vagus nerve to the brain, resulting in decreased hunger.
Peptide YY (PYY) is produced in the small and large intestine and like CCK, PYY decreases hunger and appetite although it may do so for longer periods. Infusion of PYY blunts hunger in humans for up to 24 hours. PYY increases within 15 minutes of eating and may stay elevated for up to 5 hours. Obese individuals have been found to have lower basal PYY levels and less of an increase with meals. PYY also appears to be related primarily to the energy content of the meal although work suggests that dietary fat has the biggest impact on PYY. The appetite supressing effect of protein along with fiber appear to be related to increased PYY levels.
Ghrelin is released primarily from the stomach, going towards its specific receptor in the brain. Ghrelin raises levels of growth hormone, stimulates hunger, and appears to be a key hormone in initiating the hunger that goes along with meals.
Ghrelin levels are also “entrained” to meal time schedule. This is precisely the reason why you become hungry at the time you’re used to have a meal. When changing meal frequency, for example when you start doing Intermittent Fasting, you might feel hungry at the times you used to have your meals. This is going to last for a few days or even weeks until ghrelin re-entrains itself to the new frequency. Leptin appears to restrain both grhelin release from the gut and its stimulation of hunger. Similarly to leptin, carbohydrates appear to play a primary role in regulating ghrelin levels with dietary fat having less of an impact, the effect of protein is currently unclear. In one study, a high carbohydrate/low-fat diet generated weight loss without the normal increase in ghrelin levels. Low-sodium intakes increase ghrelin levels, which is another reason why reducing sodium excessively while dieting is a mistake.
Diet, Energy Availability & Leptin Levels
When dieting, the body undergoes an overall adaptation that attempts to slow fat/weight loss via reductions in metabolic rate and activity. These adaptations become stronger the leaner you become. Impaired conversion of T4 to T3 in the liver is also a well known effect of dieting.
Like mentioned previously, leptin doesn’t only scale with body fat percentage, but is also related heavily to food intake, specifically carbohydrate metabolism in the fat cell, and in response to both over- and under-feeding, leptin changes quite rapidly.
Even with short-term overfeeding, leptin can come up far more quickly than body fat is gained. This latter fact is part of the basic premise behind refeeding and cyclical dieting. Short-term very high carbohydrate/caloric intakes can raise leptin without causing significant fat gain. In the short-term, only carbohydrate intake affects leptin levels, while fat overfeeding has no effect. Additionally, changes in fat mass don’t regulate leptin in the short-term(less than 48 hours).
That means that high carbohydrate, high calorie refeeds of varying lengths (anywhere from 5 hours to 3 days) is the best way to raise leptin while dieting. As you become leaner, leptin drops more and more, refeeds need to become larger and/or more frequent.
Not only does this provide a “reset” to the metabolic adaptations that occur with dieting, but it also provides a psychological break from the grind of continuous dieting, making it crucial for long-term success.
Zinc, Vitamin E , fish oil and exercise appear to regulate leptin production and improve leptin sensitivity.
Practical Applications
Utilizing strategically planned and regular high carb refeeds is the best way to raise leptin while dieting, as well as making diet adherence a lot easier. My preferred method to achieve the aforementioned is macronutrient and calorie cycling.
On lifting days, eating at or slightly above maintenance will provide with ample room for high carbohydrate intakes, with the following results:
- raise in leptin levels,
- improved conversion of T4 to T3,
- raise in blood glucose and insulin,
- reverse the binding of testosterone to SHBG,
- decreased cortisol,
- increased both liver and muscle glycogen,
- improved protein synthesis,
- increased insulin and testosterone,
- decrease in blood fatty acid concentrations which in turn improves insulin sensitivity
- long-term diet adherence will become much much easier
On rest days, the calorie intake will differ from lifting days. Depending on your goals, you may tailor the calories to either fat loss or weight gain.
Summary
Tldr; Leptin is a hormone secreted by white adipose tissue that interacts with the hypothalamus to reduce hunger. Leptin levels in the circulation are directly correlated with the amount of body fat.
Leptin is a master-hormone with downstream effects on other hormones related to metabolism (T3/T4, neuropeptide-Y, epinephrine and many others).
Leptin resistance occurs to obese individuals.
Leptin is controlled primarily by two things: Acute energy balance in the short term, since a high caloric deficit causes leptin to drop lower than what can be explained by fat loss, and a caloric surplus raises leptin higher than what can be explained by fat gain. Total amount of fat mass in the long term.
Leptin changes quite rapidly in response to both over- and under-feeding. Short-term very high carbohydrate/caloric intakes can raise leptin without causing significant fat gain. In the short-term, only carbohydrate intake affects leptin levels, while fat overfeeding has no effect. Additionally, changes in fat mass don’t regulate leptin in the short-term.
As you become leaner, leptin drops more and more, refeeds need to become larger and/or more frequent.
Utilizing strategically planned and regular high carb refeeds is the best way to raise leptin while dieting, as well as making diet adherence a lot easier.
If you’re tired of getting no results in the weight room and you’re ready to level up your life you can work directly with me. For any questions shoot me a DM on Telegram or via the contact page.
