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Leptin and Leptin Resistance: Everything You Need to Know

Many people falsely believe that weight gain (and loss) is all about calories and willpower.

However, modern obesity research disagrees… and scientists are increasingly pointing their fingers at a hormone called leptin (1).

Being resistant to this hormone’s effects (called leptin resistance) is now believed to be the leading driver of fat gain in humans (2).

In the video above, Dr. Stephan Guyenet, an obesity researcher and blogger, explains everything you need to know about leptin and how it is implicated in obesity.

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Meet Leptin – The “Master” Hormone That Regulates Body Weight

Woman Standing on The Scale, Frustrated

Leptin is a hormone that is produced by the body’s fat cells (3).

It is often referred to as the “satiety hormone” or the “starvation hormone.”

Leptin’s primary target is in the brain, particularly an area called the hypothalamus.

Leptin is supposed to tell the brain that we have enough fat stored, that we don’t need to eat, and that we can burn calories at a normal rate (4).

It also has many other functions related to fertility, immunity, brain function and others (5).

However, leptin’s main role is long-term regulation of energy balance… the amount of calories we eat and expend, and how much fat we store on our bodies (6).

The leptin system evolved to keep us from starving or overeating, both of which would have made us less likely to survive in the natural environment.

These days, leptin is very effective at keeping us from starving. But something is broken in the mechanism that is supposed to prevent us from overeating.

Bottom Line: Leptin is a hormone that is produced by the fat cells in the body. Its main role is regulating how many calories we eat and burn, as well as how much fat we carry on our bodies.

Leptin is Supposed to Tell The Brain That We Don’t Need to Eat

The way leptin works is relatively simple…

This hormone is produced by the body’s fat cells. The more body fat they carry, the more leptin they produce (7).

Leptin is carried by the bloodstream and into the brain, where it sends a signal to the hypothalamus… the brain area that controls when and how much we eat (8).

The fat cells use leptin to “tell” the brain how much body fat they carry. Lots of leptin tells the brain that we have plenty of fat stored, while low levels of leptin tell the brain that fat stores are low and that we are at risk of starvation (9).

This schematic shows how leptin is supposed to work:

Leptin Function Diagram

We eat –> body fat goes up –> leptin goes up –> we eat less and burn more.

Or…

We don’t eat –> body fat goes down –> leptin goes down –> we eat more and burn less.

This kind of system is known as a negative feedback loop and is similar to the control mechanisms for many different physiological functions… such as breathing, body temperature, blood pressure and others.

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Bottom Line: The main function of leptin is sending a signal to the brain, “telling” it how much fat is stored in the body’s fat cells.

Leptin Resistance May be The Main Biological Abnormality in Obesity

People who are obese have a lot of body fat in their fat cells.

Because fat cells produce leptin in proportion to their size, obese people also have very high levels of leptin (10).

Given the way leptin is supposed to work, these people shouldn’t be eating… their brain should know that they have plenty of energy stored.

Obese vs Thin Woman

However… the problem is that the leptin signal isn’t working. There’s a whole ton of leptin floating around, but the brain doesn’t “see” that it is there (11).

This condition is known as leptin resistance. It is now believed to be the main biological abnormality in human obesity (12).

When the brain doesn’t receive the leptin signal, it erroneously thinks that the body is starving, even though it has more than enough energy stored.

This makes the brain change our physiology and behavior in order to regain the fat that the brain thinks we’re missing (13, 14, 15):

  • Eating More: The brain thinks that we MUST eat so that we don’t starve to death.
  • Reduced Energy Expenditure: The brain thinks we need to conserve energy, so it makes us feel lazier and makes us burn fewer calories at rest.

In this way… eating more and exercising less is not the cause of weight gain, it is the consequence of leptin resistance, a hormonal defect (16).

For the great majority of people, trying to exert cognitive inhibition (willpower) over the leptin-driven starvation signal is next to impossible.

Bottom Line: People who are obese have high levels of leptin, but the leptin signal isn’t working due to a condition known as leptin resistance. Leptin resistance can cause hunger and reduced energy expenditure.

Losing Weight Reduces Leptin, so The Brain Tries to Gain The Weight Back

Frustrated Woman Eating Red Bell Pepper

Most “diets” don’t provide good long-term results. This is a well known problem in weight loss studies.

Diets are so ineffective that whenever someone goes from obese to thin, it is seen as newsworthy material.

The truth is… when it comes to losing weight, long-term success is the exception, NOT the rule.

There are many possible reasons for this, but the research is showing that leptin may have a lot to do with it (17, 18).

Losing weight reduces fat mass, which leads to a significant reduction in leptin levels, but the brain doesn’t necessarily reverse its leptin resistance.

When leptin goes down, this leads to hunger, increased appetite, reduced motivation to exercise and decreased amount of calories burned at rest (19, 20).

Basically, the reduced leptin makes the brain think it is starving… so it initiates all sorts of powerful mechanisms to regain that lost body fat, erroneously thinking that it is protecting us from starvation.

In other words, the brain actively defends the higher amount of fat mass, using strong biochemical forces that compel us to eat back the lost weight.

The majority of dieters will be familiar with this… weight loss is often easy in the beginning, especially when motivation is high, but very soon hunger, cravings and a reduced desire for exercise set in.

This is the main reason so many people “yo-yo” diet… they lose a significant amount of weight, only to gain it back (and then some).

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Bottom Line: When people lose fat, leptin levels decrease significantly. The brain interprets this as a starvation signal, changing our biology and behavior to make us regain the lost fat.

What Causes Leptin Resistance?

Obese Woman Eating Junk Food

According to Dr. Guyenet, several cellular mechanisms behind leptin resistance have been identified.

These include (21, 22):

  1. Inflammation: Inflammatory signalling in the hypothalamus is likely an important cause of leptin resistance in both animals and humans.
  2. Free Fatty Acids: Having elevated free fatty acids in the bloodstream may increase fat metabolites in the brain and interfere with leptin signalling.
  3. Having high leptin: Having elevated levels of leptin in the first place seems to cause leptin resistance.

Pretty much all of these factors are increased in obesity… so this may form a vicious cycle where people get fatter and increasingly more leptin resistant over time.

Bottom Line: Potential causes of leptin resistance include inflammation, elevated free fatty acids and high leptin levels. All three are increased in obesity.

What Science Knows About Reversing Leptin Resistance

Obese Man on a Scale, Smaller

The best way to know if you are leptin resistant, is to look in the mirror.

If you have a lot of body fat, especially in the belly area, then you are almost certainly leptin resistant.

A key to preventing (or reversing) leptin resistance, is reducing diet-induced inflammation.

There are several things you can do:

  • Avoid processed food: Highly processed foods may compromise the integrity of the gut and drive inflammation (23).
  • Eat Soluble Fiber: Eating soluble fiber can help improve gut health and may protect against obesity (24).
  • Exercise: Physical activity may help to reverse leptin resistance (25).
  • Sleep: Poor sleep has been implicated in problems with leptin (26).
  • Lower your triglycerides: Having high blood triglycerides can prevent the transport of leptin from blood and into the brain (27). The best way to lower triglycerides is to reduce carbohydrate intake (28).
  • Eat Protein: Eating plenty of protein can cause automatic weight loss. There are many reason for that, one of them may be an improvement in leptin sensitivity (29).

Any of these look familiar? These happen to be many of the same things we generally associate with good health.

Unfortunately, there is no simple way to do this. Eating real food, maintaining a healthy gut, exercising, sleeping well, etc… these are all lifelong endeavours that require a drastic shift in lifestyle.

Take Home Message

Obesity is not caused by greed, laziness or a lack of willpower.

There are strong biochemical forces at play… which are mostly driven by changes in the environment, and particularly the Western diet.

The truth is… everywhere this diet goes, obesity and chronic disease follows.

Not because this diet turns people into gluttons and sloths, but because it alters our biology in a way that changes our behavior.

Although the causes of obesity are complicated and diverse, leptin resistance is the main reason people gain weight and have such a hard time losing it.

Leptin is the “master hormone” of body fat regulation.