A quick recap of part one of this series:

Leptin is the hormone produced in your adipose (fat) tissue that tells your body whether you have enough food. It controls appetite and metabolic rate.

If you are low in leptin, your brain urges you to find food and it also turns down metabolic processes. If you are low in leptin (e.g. in a time of famine), your brain also puts the brakes on the reproductive hormones, signaling that it isn’t a good time to get pregnant.

If all is going well with your leptin signaling, when you have enough fat mass, your brain tells you that you don’t need to eat quite so much (no longer hungry) and signals to the hormones needed for reproduction.

In this article, you will learn the details on what happens when that leptin signalling goes wrong.

Leptin resistance, weight gain, and infertility

If you are overweight, you have probably wondered at some point – why can’t I just stop being hungry?  Most other animals seem to eat just the right amount. What is wrong with us humans?

Leptin is the signaling hormone that communicates with the hypothalamus, a region in your brain, to say that you don’t need to eat any more.

It does this in two ways:

1. reduce the amount of appetite increasing peptides (neuropeptide-Y) and
2. increase the appetite suppressing peptides (POMC, CART).

Rabbit trail for you — CART stands for cocaine and amphetamine-regulated transcript.  There is a reason that coke and meth addicts are usually skinny. This controls both appetite and dopamine (reward) activation in the brain. (study)

If we have such a great system to control appetite and metabolism, why are so many people overweight these days?

Adipose (fat) tissues isn’t just a storage spot for excess fat. It is actually an endocrine organ that is secreting hormones. Leptin is just one of many hormones secreted by adipose tissue.

Leptin is considered both a hormone and a cytokine.  As a hormone, it regulates signals to other tissues for a response. As a cytokine, it is also a pro-inflammatory cell-signaling molecule.

In general, people who are overweight produce plenty of leptin to tell the brain that there is sufficient fuel reserve available.

Researchers think that leptin resistance is the cause of overweight/obesity. The leptin signal is not being received in the brain and thus the control system for weight is out of balance. (study)  To put it simply, it’s as if the leptin is making the phone call to the brain to stop eating but the brain is ignoring the call.

People and animals who either don’t produce leptin or don’t produce the leptin receptor also don’t produce the reproductive hormones needed for menstruation and pregnancy. (study)

Defining overweight and obesity:

A quick timeout here to define a couple of terms…

Almost all studies that are referenced consider women to be overweight if their BMI is between 25 and 30 kg/m².

Women with a BMI over 30 are considered obese. Women with a BMI over 40 are considered to be severely obese (sometimes called class III obesity or morbid obesity).

Use this calculator to know your BMI.

How leptin works in the brain to control appetite and hormones

Back to how leptin controls weight and reproductive hormones…

Within the brain, there is a small region called the hypothalamus that controls appetite, circadian rhythm, body temperature, and reproductive hormone production. Yes- these are the most basic things needed for survival of the species!

Leptin is a large molecule that must pass through the blood brain barrier to reach the hypothalamus.  The blood brain barrier (BBB) is there to filter out the larger molecules, such as bacteria, that can damage the brain. So for the leptin signal to get through to the hypothalamus, it needs to be actively transported across the BBB.

Once leptin reaches the hypothalamus, it binds to leptin receptors on the surface of different groups of neurons.  Some of those neurons are responsible for the control of appetite and metabolism.

Another group of neurons in the hypothalamus is responsible for the initial signal to the pituitary to release reproductive hormones (luteinizing hormone and follicle-stimulating hormone).  (study)

When leptin binds to the leptin receptor in the hypothalamus, it starts a cascade of reactions within the cell to cause the correct response. This is a complex pathway, involving multiple molecules and feedback loops to regulate everything.

What is Leptin Resistance?

There are several ways that researchers think that leptin resistance occurs.(study)

The first way is that there can be reduced transport across the BBB.  Transport could be downregulated due to too much leptin, or there could be another cause that is decreasing the signal into the brain.

The second way that leptin resistance occurs is when the leptin receptor function is impaired in the hypothalamus.  This could be due to inflammation in the hypothalamus. (study)

Another possibility is that high triglyceride levels could cause the dysfunction in the hypothalamus. One study showed that triglycerides pass through the blood brain barrier into the brain and induce leptin resistance there. (study)  More on how high triglycerides tie into diet in the lifestyle section below.

Reproductive hormones:

The hormones needed for ovulation, menstruation, and pregnancy are controlled by what is known as the hypothalamic-pituitary-gonadal axis. This means the signal comes from the hypothalamus to the pituitary saying that it is time to release the reproductive hormones, luteinizing hormone and follicle-stimulating hormone.

If the leptin signal doesn’t reach the hypothalamus — or if there is dysfunction with the leptin receptors in the neurons of the hypothalamus — the signal for your reproductive hormones is going to be altered. Specifically, the amount of luteinizing and follicle-stimulating hormones can be altered.

Leptin is supposed to be the initial check point in the hypothalamus that says you have enough fuel in reserve, thus it is a good time to reproduce. (study)

Additionally, leptin in the ovarian follicles needs to be in the right amount also. Too high of leptin levels in the follicles is linked to decreased fertility. (study)

PCOS and Leptin:

Polycystic ovarian syndrome is a common problem affecting many women today.  It is characterized by cysts in the ovaries and increased androgen hormone levels. Women with PCOS are more likely to have insulin resistance, problems with weight gain, and may have increased facial and body hair due to the high androgen levels.

Women with PCOS often deal with infertility, due to lack of ovulation during some menstrual cycles. In fact, PCOS is one of the leading causes of infertility and thought to be the cause for about 45% of infertile women. (study)

About 60% of women with PCOS are overweight or obese. So it makes sense that they would also have higher leptin levels.

Because leptin levels often correlate with insulin levels, the two conditions of insulin resistance and leptin resistance commonly overlap. This can make it difficult for researchers to know which one is causing the problem – or if it is due to both.

However, reviewing the research on lean or normal weight women who have PCOS can help to show whether leptin resistance is a causative problem for PCOS and infertility.

A study of lean women with PCOS compared with a control group of lean women of similar age found that the women with PCOS had significantly higher leptin levels. (study)

Another study examined women with PCOS and found that leptin levels were higher in patients independent of the effects of BMI. (study)

Not all studies give the same result, possibly due to different methods of measuring leptin. Timing is also important when measuring leptin because levels fluctuate by about 30% overnight.

A large meta-analysis took into consideration the differences in studies and combined the data from 19 different studies on leptin levels in women with PCOS. The compiled results showed that leptin levels were elevated by 62% in women with PCOS when compared with women of the same BMI and age without PCOS. (study)

Animal models are often used to dig deeper into the mechanisms that cause a disease. Animal models of PCOS show that there is “a state of chronic low-grade inflammation in the hypothalamus” which researcher think is the mechanism for leptin resistance in PCOS. [ref]

Keep in mind that when researchers measure leptin levels in people, they are measuring it using blood samples. Researchers aren’t tapping into people’s brains to measure the leptin levels within the hypothalamus.

The high serum leptin levels in PCOS don’t tell us for sure whether the signal is being properly received in the hypothalamus. The problems with ovulation in PCOS indicate that there is a problem with the HPG axis – which then leads to the conclusion that women with PCOS are likely to have leptin resistance.

Solutions for PCOS, leptin resistance, and infertility:

The higher serum leptin levels in women with PCOS (both lean and overweight) may mean that leptin is acting as an inflammatory cytokine in the ovaries or acting within the hypothalamus to alter hormone levels. Decreasing your leptin levels may be the key.

If you are overweight:

For anyone who is overweight, decreasing fat mass — i.e. losing weight — is the sure fire way to lower leptin levels.

Weight loss needs to be done carefully when you are TTC. This is not a time to go on a crash diet or use unregulated diet pills.

Sticking to a diet that is high in whole foods such as vegetables and meats while eliminating processed foods is a great way to maintain your nutrient balance while losing some weight.

Getting regular, moderate exercise is important, but this is also not the time to go overboard with exercising too much.

If you are not overweight:

For women who are not overweight and have PCOS, you want to make sure that you are getting enough quality nutrition each day and are not over-exercising. Follow the dietary interventions below for reversing leptin resistance.

Dietary interventions for leptin resistance:

High fructose consumption has been linked to leptin resistance. So eliminating high fructose corn syrup from your diet is a must. (study)(study)

High triglyceride levels have been linked in several studies to leptin resistance. (study)(study)

You can get a simple, inexpensive blood test done to check your triglyceride levels.

Excessive carbohydrate consumption is one cause of high triglycerides, so eating a lower or more moderate amount of carbohydrates can help to lower your triglycerides. (study)(study) High fructose consumption also elevates triglyceride levels for some people, so avoid foods with added fructose. (study)

Getting enough sleep is important for a number of reasons – including reversing leptin resistance. Seriously, invest in your sleep.  Get to bed at a reasonable time each night, and put away the electronic devices an hour or two before bed. (study)(study)

Putting away the electronics will reduce the amount of blue light hitting your eyes at night. Blue light at night halts the production of melatonin, which your body naturally produces at high levels when it is dark.

Why is this so important for leptin, a hunger hormone?  Melatonin has recently been shown to be important in the production and regulation of leptin. An animal study found that removing the melatonin receptor caused leptin resistance. Adding in extra melatonin reversed the leptin problems and restored fertility to the animals.(study)

Finally, studies show that a protein in wheat and in legumes can bind to the leptin receptor, blocking it from receiving the leptin signal. (study) While the research isn’t conclusive on this being a big component of leptin resistance, trying a wheat and legume-free diet is a good idea. Instead of breads and pasta, substitute extra servings of organic vegetables.

Let me sum this up in a list of five things you can do today to increase your sensitivity to leptin:

1. Reduce your triglyceride levels if they are high. Lowering your carbohydrates and specifically avoiding high fructose corn syrup may help to lower triglycerides.
2. If you are overweight, try losing weight through a nutrient dense diet that includes organic meats and vegetables.
3. Exercise in moderation.
4. Sleep well and avoid blue light for two hours before bed.
5. Try eliminating wheat and legumes from your diet.