Have you ever gone on a “diet” and worked hard to lose 10 pounds, only to gain back 10 or even 15 pounds when you went back to your normal eating routine? Have you ever heard that it’s easy to lose weight but difficult to maintain it? Why is this? Hint: Leptin resistance. Read on to learn what you can do to keep your weight loss lost.

This is a blog post by LifeOmic CEO Dr. Don Brown.

More than 20 years ago, doctors and researchers noticed that people who developed tumors affecting an area of the brain called the hypothalamus were very likely to become obese. For example, a German study found that nearly half of children with craniopharyngioma, a type of benign tumor that starts near the pituitary gland (this gland is connected to the hypothalamus), developed severe obesity. Obese children also had bigger tumors upon diagnosis.

But what was causing this mysterious connection between brain tumors near the hypothalamus and severe obesity?

To understand the connection, we have to understand fat.

We often think of fat cells, called adipose cells, as simple storage depots for triglycerides. However, fat tissue does much more than just hold extra energy for a rainy day. We’re coming to understand that fat is an important endocrine organ. Just like the thyroid and pancreas, adipocytes or fat cells manufacture protein signaling molecules called hormones and secrete them into the bloodstream. Here, these hormones can exert body-wide effects.

One of the main hormones produced by adipocytes is called leptin. Once in the bloodstream, leptin produced by your fat cells travels all the way to your brain where it communicates with (you probably guessed it)… your hypothalamus.

The Hypothalamus (in red). Credit: Life Science Databases (LSDB).
The Hypothalamus (in red). Credit: Life Science Databases (LSDB).

The hypothalamus is an incredible relay between the brain and the rest of the body.  We can think of it like a thermostat – it sets and maintains critical metabolic and physiologic parameters like body temperature. A thermostat works by sensing the temperature in your home. In the winter, it turns on the heat if the temperature drops below a desired level and turns the heat back off when the temperature rises. This sort of control is called negative feedback; its effect is not so different from a reprimand by your boss to stop browsing social media during work time (but this blog doesn’t count!). Negative feedback in biological systems serves to keep a given parameter, like temperature, within a narrow range.

It turns out that there is a negative feedback loop between fat tissue and the brain, specifically the hypothalamus. Fat cells produce leptin – the more fat, the more leptin. This hormone then travels through the bloodstream to the brain. A high level of leptin serves as negative feedback for energy balance; it tells the body to stop eating so much and to move more! For this reason, leptin is often referred to as a satiety hormone.

Since the amount of leptin produced is proportional to total body fat, its activity normally helps prevent the body from accumulating more fat than necessary. Conversely, a low level of leptin in a person who is very lean typically encourages the hypothalamus to take steps to increase appetite and look for food. The overall system looks like this.

Unfortunately, things can go wrong with this system. For example, a tumor that affects the hypothalamus can interfere with the brain’s ability to sense leptin levels.

In this case the hypothalamus doesn’t “see” leptin, even when leptin levels are very high. It continues to generate signals that increase hunger and appetite. This can lead to obesity. A person with an injured or impaired hypothalamus feels like he or she is starving even with an overabundance of fat tissue around.

But a brain tumor is not the only condition that can cause this feedback system to malfunction. In fact, for reasons we don’t fully understand, people with intact and seemingly healthy hypothalami can become leptin-resistant. This means that even though they have plenty of fat and are producing high levels of leptin, their brains are still telling them that they are starving! Why does this happen?

Many negative feedback control systems only operate within a certain “normal” range. For example, your thermostat and heating or AC system may fail  during a particularly extreme winter freeze or summer heat wave. It appears that something similar happens in the human body. Our hunger control system, or the negative feedback loop between our fat and our brain, has evolved over millennia to operate within a normal  range of roughly 10 to 40% body fat. Pushing beyond this range – especially when the change happens relatively quickly – appears to cause a failure in the hypothalamic circuits that sense and respond to leptin.

What this effectively does is increase the set point of our “fat thermostat” to a higher level, thereby creating a new normal in terms of leptin activity required to get our brain to respond by reducing appetite and increasing energy expenditure. The body actively defends its existing leptin/fat set point, even if that point has been raised to a new normal. This is probably a large part of the reason why people find maintaining weight loss so difficult.

Image: Person finished meal and play smartphone.
What if you never really felt full unless you ate way more than your body needed in a meal or in a day? This can happen for leptin-resistant individuals.

Let’s say someone accidentally bumps up your home’s thermostat setting to 90 degrees. You don’t know to turn the heater down; you might even assume it or your thermostat is broken. But you notice that it’s cooler outside, so you open all of your windows. This doesn’t work, especially if the outside temperature is already high. You are unknowingly fighting your thermostat because every step you take to reduce the temperature by opening another window is resisted by the thermostat and heater. The heater runs any time the temperature starts to drop. It may even eventually become hotter in your house when you open the windows as your heater goes into overdrive trying to get the temperature of your house up to its set point, especially if your thermostat is situated near a window or downstairs where it senses cool air.

The same thing can happen when you diet and temporarily lose weight, but your leptin/fat “set point” quickly has you back where you started. Nobody can resist food cravings and intense hunger long-term.

Is Your Fat Thermostat Set Too High?

Leptin carries out its effect on the hypothalamus when it binds to a protein receptor on the surface of hypothalamic cells. This binding then activates an intracellular protein called STAT3 that travels to the hypothalamic cell’s nucleus (where DNA is stored) to increase transcription of certain genes. STAT3 affects the expression of genes related to inflammation, immune function and cell survival. It also controls level of the brain chemical POMC that suppresses appetite.

Several factors are known to interfere with the activity of STAT3 and thus block the activity of leptin on the brain:

1. High leptin levels. If leptin goes above the normal range, cells in the hypothalamus begin to ignore it. In effect, the brain becomes desensitized to leptin. A similar phenomenon can be observed in insulin resistance, which can occur when levels of glucose and insulin are too high too much of the time (for example, from a sugary diet).

A protein called SOCS3 increases in activity under chronically high leptin conditions, in an attempt to tap the brakes on what could be a runaway hormone response. But in doing so, SOCS3 reduces the activity of STAT3 and leads to leptin resistance. Increases in SOCS3 are directly linked to weight gain. In fact, mice who can’t produce SOCS3 don’t gain nearly as much weight on a high-fat, high-sugar diet as normal mice, because leptin from their fat still signals their brains to increase their energy expenditure.

2. Inflammation. Inflammation in the body causes the generation of another class of signaling molecules called cytokines. These molecules also activate SOCS3, thereby reducing STAT3 activity and overall response to leptin.

3. High lipid levels. Breakdown products from lipid metabolism also inhibit STAT3 and thus promote leptin resistance.

4. Poor sleep quality. Poor sleep also interferes with STAT3 and leptin signaling, thereby contributing to obesity. This effect occurs via another STAT3 inhibitor called PTP1B.

5. High fat, high carbohydrate diets. The consumption of large amounts of saturated fats and carbohydrates, particularly at the same time, have also been found to raise levels of SOCS3, reducing STAT3 activity and response to leptin.

We already know that a diet high in unhealthy fats (especially saturated animal fats) and simple carbohydrates (sugar, white bread, white rice, potatoes, etc.) is associated with obesity. Now we can begin to understand why. By increasing overall fat deposition, this sort of unhealthy diet increases leptin levels, perhaps pushing them past the normal range to a degree that activates SOCS3, which then inhibits STAT3. In other words, diet or obesity-induced activation of SOCS3 breaks the fat-to-hypothalamus negative feedback loop. High SOCS3 levels render cells in the hypothalamus less able to respond to high leptin levels, leading to hunger even in the presence of excess leptin (and fat).

High intake of saturated fats along with refined carbohydrates also promotes the accumulation of toxic lipid metabolites, again activating SOCS3 and inhibiting STAT3.

“SOCS3 expression is elevated in obesity and it is involved in the inhibition of leptin and insulin signaling, two important hormones involved in the control of energy metabolism. Therefore, increased SOCS3 expression in obese individuals is associated with several metabolic disorders, including reduced energy expenditure, increased food intake and adiposity, and insulin and leptin resistance.” – Pedroso et al., 2018

Perhaps most intriguingly, high levels of saturated fats and sugars* may also create leptin resistance by hurting the “good” bacteria in our guts. These bacteria thrive on the fermentable fiber in plant-based foods and serve to protect the gut lining. When subjected to an unhealthy diet high in animal fats and simple carbohydrates but low in plant material (fruits, vegetables and nuts), these bacteria begin to die off and are replaced by harmful bacteria that attack the gut lining. This leads to permeability of the intestinal barrier, allowing harmful bacteria and their byproducts to leak out of the gut. One of these byproducts called lipopolysaccharide (LPS) is highly inflammatory and activates the innate immune system. Immune cells then spew out the cytokines (inflammatory molecules) mentioned earlier that inhibit STAT3 and thus contribute to leptin insensitivity.

*As a quick aside – artificial sweeteners also “feed” microbes in the gut that cause inflammation, with implications for insulin resistance and leptin resistance

Obesity itself is associated with inflammation that can activate SOCS3, inhibit STAT3 and cut off the leptin negative feedback loop. Innate immune cells called macrophages infiltrate adipose tissue and secrete inflammatory cytokines. Fat cells themselves also seem to produce inflammatory cytokines.

How can you be successful with your weight loss program? Incorporate exercise, adequate sleep and increased fruit and veggie intake. Image: Curvy woman celebrating during a training session.
How can you be successful with your weight loss program? Incorporate exercise, adequate sleep and increased fruit and veggie intake.

Why IS it So Hard to Keep The Weight Off, and What Can You Do?

Most obese people who lose weight regain it within a relatively short period of time. This observation isn’t just anecdotal – it has been reported consistently in many studies.

There is a frustrating asymmetry at play here. If it was so easy to gain the weight, why isn’t it easy to lose, too? The short answer is that the set point of the body’s “thermostat” for fat increased with the original weight gain. Carrying a lot of fat becomes the new normal that the body works hard to maintain. As discussed above, the extra fat mass itself reduces the brain’s responsiveness to leptin. So does the inflammation caused by an unhealthy diet along with breakdown products of excess fatty acids and triglycerides (which are three fatty acids linked to a glycerol molecule for convenient storage). The poor sleep quality common in our modern world just exacerbates the problem.

Fight leptin resistance by increasing your fruit and veggie intake. Yes, MORE of these foods may help you lose weight and maintain it. Image: Composition of vegetables and ingredients on wooden table
Fight leptin resistance by increasing your fruit and veggie intake. Yes, MORE of these foods may help you lose weight and maintain it.

It’s easy to see that simply reducing calories may not be enough to restore the previous set point. An unhealthy diet will continue to cause inflammation and leptin resistance. Poor sleep will further impair leptin signaling. Even more troubling is the observation that obesity may lead to epigenetic or “on top of the genome” changes – silencing of certain genes via methylation – that further lock in the new set point for adiposity or fat mass.

This is why maintaining weight loss requires a series of long-term changes in lifestyle Here’s what you can do to prevent leptin resistance and maintain weight loss:

1. Adopt a healthy diet high in fermentable plant fiber in order to encourage growth of bacteria that will protect your intestinal lining and fight inflammation. In one American Diabetes Association study, healthy people who ate even just one high-fat, high-carbohydrate meal had significantly raised levels of inflammation and SOCS3 expression following the meal, while people who enjoyed a meal rich in fiber and fruit had no such increases.

2. Increase your energy expenditure through exercise. When paired with caloric deficit (such as through intermittent fasting), this will gradually reduce your body fat and increase your insulin and leptin sensitivity.

3. Get high quality sleep, and enough of it. To improve your sleep, minimize alcohol consumption and avoid consuming caffeine and food at least 2-3 hours before bedtime.

Although not mentioned above, insulin also affects leptin sensing. Persistently high insulin levels can lead to overly active leptin sensing. You might remember from earlier that a chronically high level of leptin, or overactive leptin sensing, eventually upregulates SOCS3 and encourages leptin resistance. Just like in the story of the Boy Who Cried Wolf, a continued alarm starts to be ignored after a while. So, in addition to the lifestyle changes listed above, people looking to maintain weight loss need to reduce their intake of refined carbohydrates, which will decrease insulin levels. Intermittent fasting is another lifestyle intervention that can dial back insulin signaling.

Based on findings from animal studies, intermittent fasting may also temporarily bring down high leptin levels and reduce leptin resistance!

Because of the epigenetic changes caused by obesity, these lifestyle modifications must be adopted for long periods of time, not as fad diets or health “bootcamps.” Eventually, the body develops a new normal similar to the one that existed before the development of obesity.

Change is hard. But the cellular changes that occur with obesity, especially leptin resistance, are especially hard to undo. Still, it should be encouraging that it is possible to lose weight and maintain it. Even better, the lifestyle changes required to maintain weight loss also reduce the risk of diabetes, heart disease, cancer and other disorders. An improved diet rich in fruits and vegetables, more activity and better sleep are key components of the solution.



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