Leptin and its receptors are key regulators of energy homeostasis and body weight. Studies show that decreasing leptin sensitivity leads to metabolic disorders, including obesity. The development of leptin resistance includes physiologic mechanisms such as gene mutations that encode leptin and its receptors, factors that alter blood-brain barrier permeability, and proteins involved in the self-regulation of leptin synthesis. Leptin resistance is a complex pathophysiological phenomenon with a variety of options for potential treatment.
Leptin resistance is a key driver of fat gain in humans. So, let’s take a deeper look at what happens and what you can do about it.
What is leptin?
Leptin is a peptide (short-protein) hormone that is secreted by the kidneys, placenta, salivary glands, and stomach. Leptin receptors are found in their highest concentrations in the brain, in particular the hippocampus and hypothalamus.
Keep in mind that leptin levels increase exponentially with fat mass. As you gain more fat, leptin levels rise at an increasingly high rate of gain.
Some studies show correlations between chronically-elevated leptin levels and obesity, overeating, and metabolic disorders like hypertension, diabetes, heart disease, and metabolic syndrome.
Scientists are still working to determine how leptin functions exactly. The leading hypothesis involves leptin release after a meal, penetration of the blood-brain barrier, and satiety signaling in the hypothalamus. The hypothalamus subsequently signals the rest of the brain that enough fat is stored and to stop eating. Caloric burning can continue at a regular rate.
What are normal levels?
A simple blood test measures leptin in ng/ml, which is nanograms per milliliter.
Normal leptin levels are approximately 4.5 – 23.5 ng/ML. These levels can vary a bit between lab work, and they can be influenced by your BMI, gender, and age. Levels rise slightly throughout the day peaking at night. Degrees of severity are loosely given with “mild” as 15-20 ng/ML and “severe” as 50 ng/L or more. But each person is a bit different.
Leptin has been called a variety of names like the starvation hormone and the weight loss hormone. Research shows that leptin resistance increases the extreme hunger felt due to increased ghrelin levels. Leptin resistance seems to instruct fat cells to retain the fat no matter what. It’s a metabolic problem that can be difficult to overcome without dealing with leptin resistance directly.
Leptin resistance
Leptin resistance occurs when leptin increases energy expenditure through basal metabolism or lipolysis in fat cells. It may also result in a decreased appetite. As a result, tissues become resistant to even high levels of leptin. It is a similar phenomenon to insulin resistance although through different mechanisms and pathways. Each requires a different treatment.
Studies show that obese people have very high levels of leptin that are malfunctioning. This is because the key leptin producers, fat cells, make leptin in proportion to their size. As they grow, the production of leptin increases as well.
While leptin works as an appetite suppressant when slightly higher than normal, it seems to increase appetite at higher levels. Thus, leptin resistance leads to a higher appetite and lower energy expenditure.
We don’t know for certain why some people become leptin resistant. However, there are some effective methods to combat the issue and assist with weight loss. Each person has individual needs in addressing leptin resistance, so it’s best to work with a functional medicine doctor to tailor the right program.
Increasing BDNF to decrease leptin levels
Intermittent fasting or caloric restriction
Reducing your daily caloric intake or practicing intermittent fasting can increase levels of BDNF. Many studies show the brain health benefits of intermittent fasting and weight management. Restricting your food intake to 8 hours a day (e.g., 11 AM to 7 PM) is ideal, but difficult for many; and doing a 10-hour window has benefits, as does even a 12-hour window; so, do what you are “able” to do and push yourself a day or two per week.
Regular and intense exercise
If you currently do not exercise, any level of body movement will help increase your BDNF levels. This can be taking a neighborhood walk, choosing stairs over the elevator, or parking farther away at the grocery store to walk in. High-intensity interval training (HIIT) will exponentially increase your production of BDNF. You will need to keep a consistent routine. To enjoy the full benefits of increasing your BDNF levels through HIIT, you need to train this way a minimum of once per week.
Doing HIIT 2 to 3 times per week is much better. Studies show that as little as 10 minutes of HIIT will raise BDNF levels.
Improve your diet
Our typical American diet, which is high in refined sugar and “bad” saturated fat, causes negative structural changes in the brain. These negative effects happen through neurotrophins such as BDNF. An inflammatory diet results in a significant decrease in all neurotrophins. For greater brain health, weight loss, and overall well-being, you need to change your diet. Eliminate refined sugar and eat only “good” saturated fats like avocado oil or coconut oi.
Weight loss
It seems obvious, but necessary to point this out. Your body and brain undergo metabolic changes when you are overweight. BDNF decreases when your fat levels are high. When you reduce your weight, you improve your overall health and increase your BDNF levels and help your brain perform its functions better.
Certain medications and BDNF levels
Some medications can raise BDNF levels. Short term, they are probably safe, but their long-term use is unclear. SSRIs (Selective-serotonin reuptake inhibitors such as Prozac) will increase levels of BDNF when used to treat depression. These drugs elevate the levels of the neurotransmitter; serotonin. However, it is unclear how these drugs affect our brains with long-term use. A no-risk way to increase serotonin is to take the building block, 5-OH tryptophan, which is perfectly safe if you are not taking other antidepressants and not bipolar.
Peptides that increase BDNF
Peptides are small sequences of amino acids that make up specific proteins. They act as messengers, signaling specific glands and other proteins into performing or improving particular tasks. These tasks often have no relation to their usual function. These bioidentical substances have been isolated and replicated for use by compounding pharmacies. Since they are bioidentical, there are no side effects. They are a fantastic addition to the arsenal of treatments, and there happen to be two that are quite useful for enhancing BDNF levels. A third peptide called Selank also increases BDNF levels but is more commonly used for anxiety and cortisol issues.
Supplements that increase BDNF
Some supplements will help but are typically not as effective as the peptides discussed below. These supplements are frequently helpful with other issues and include green tea extract, curcumin, acetyl-l-carnitine, omega-3 fish oils, resveratrol, and vitamin D.
Peptides to increase BDNF
Dihexa
Dihexa is a peptide derived from angiotensin IV, a metabolite of the naturally occurring vasoconstrictor angiotensin II. Angiotensin IV enhances memory acquisition, hippocampal consolidation, and recall in animals. In addition, Dihexa is seven times more potent than BDNF.
Dihexa is an oral compound that penetrates the blood-brain barrier to increase BDNF significantly. As a result, it improves memory consolidation, retrieval, neural processing speed, and concentration. In addition, it helps lower leptin levels.
Heptapeptide semax
Semax is a “nootropic” peptide due to its ability to increase BDNF: the most potent stimulator of neurogenesis. Several studies show its ability to cause the brain to release both serotonin and dopamine, enhancing feelings of well-being and improving depression.
The heptapeptide Semax is an analog of the N-terminal fragment (4-10) of ACTH (adrenocorticotropic hormone) but lacks any hormonal activity. However, after intranasal application, it stimulates memory and attention in rodents and humans. It is useful for adult ADHD.
Heptapeptide selank
Clinical studies show that Selank has strong anti-anxiety and cortisol lowering effects. The clinical impact of Selank is similar to those of anti-anxiety medications such as Xanax or Valium-benzodiazepine drugs, which increase the activity of the calming brain chemical GABA. Selank is non-addictive and has the ability to increase BDNF.
DSIP
This highly effective peptide is useful for insomnia of all types; sleep interruptions, re-sleeping issues, and sleep induction problems-all, with enormous success. It is also effective for people with circadian rhythm issues; again, quite successfully. Although there have been no clinical studies looking at the use of DSIP in people trying to shed pounds, I have personally seen quite a correlation in my clinical practice. Of course, this is “anecdotal,” so take that with a grain of salt.
Inflammation and high leptin levels
Chronic, low-grade inflammation is associated with various metabolic disorders, including obesity. Many complex physiologic pathways responsible for this phenomenon are currently under investigation for pharmacological intervention. However, much more research is necessary to draw precise conclusions.
Instead, let’s take a look at chronic inflammation and how to address it.
An acute inflammatory response is healing. It responds to a threat with swelling, heat, redness, and pain. The symptoms resolve as the healing takes place. Think of your immune system fighting off bacteria or viruses. Or it could be a response to a splinter in your finger.
Chronic inflammation is very different. Healing does not occur. Inflammation is silent and continual. It can make you feel fatigued or contribute to a host of other health problems.
Here are the principal causes of chronic inflammation.
Excessive omega-6 intake: Omega-6 fats form the building blocks for inflammatory eicosanoids, a vital part of the inflammatory response. High omega-6 status translates to excessive production of inflammatory eicosanoids and an exaggerated inflammatory response to normal stimuli. Cut down on your omega-6 intake by reducing your intake of meat and dairy products. Lowering omega-6 intake has been demonstrated to lower leptin levels.
Insufficient omega-3 intake: Conversely, omega-3 fats are the precursors for anti-inflammatory eicosanoids. Poor omega-3 status means inadequate anti-inflammatory eicosanoids, which blunts the anti-inflammatory reaction to normal stimuli. Eat omega-3-rich fish such as salmon or sardines and take good omega-3 fish oil supplements. Leptin levels will decrease with an appropriate Omega 3 to Omega 6 ratio.: I know I sound like a broken record with this mantra, but it is imperative to
Poor diet: Commonly consumed foods considered” inflammatory” are highly-processed carbohydrates, sugary foods, high-industrial fat, and seed oils, high gluten, and quite frankly, all overly processed and fast foods. Furthermore, this eating pattern causes oxidative stress, which worsens inflammation.
Leaky gut: This is another pervasive American problem due to eating habits, consumption of pharmaceuticals (especially antibiotics), high cortisol levels, and the increase of mycotoxin illness. It is easily treated, usually with a gut-specific peptide such as BPC-157. Typically, leaky gut is the root cause of all autoimmune disease. Address this problem first.
Excess weight: The more fat cells you have and the bigger they are, the more inflammation they cause for your entire body. The risk of chronic inflammation is very high if you are obese or even just overweight. Obese and overweight people have higher levels of inflammatory blood markers than people of the same age who are not overweight or obese. According to numerous clinical studies, inflammatory markers decrease when men and women lose weight.
Chronic stress: Cortisol is an independent risk factor for elevated leptin levels. Your body will have a physiological, inflammatory response to emotional stress, which, as you now know, translates to a high cortisol level.
Toxins: Heavy metals such as mercury and lead, as well as biotoxins such as mycotoxins and Lyme toxins, can cause chronic inflammation.
Lack of movement: A lack of activity causes systemic, low-grade inflammation. The pandemic has worsened this problem. Get your body moving even for short periods. It will help. Recent data regarding exercise reveals that short bursts of exercise are great for your health. It can be as little as 1,2, or 3 minutes of activity. Doing it just three times a day is demonstrated to be good for your health.
Poor recovery and overtraining: Some people move too much- over-exercising, with too little rest and recovery. Overtraining causes chronic inflammation. Obviously, this is a potential issue for elite athletes, but even casual bikers, swimmers, and runners can overtrain. Over-exertion to the point of daily fatigue can cause inflammation, as well as elevated cortisol levels and disrupted sleep.
Lack of outdoor time: We all spend too much time cooped up in offices or, more likely “now,” in our home offices, doing those blasted zoom calls. We just don’t spend enough time in nature. Believe it or not, this lack of time out in nature can indeed cause low-grade inflammation.
Poor sleep increases leptin
Both “regular” sleep patterns and circadian rhythms modulate daily metabolic shifts. Various sleep deficiencies associated with short sleep duration, insufficient sleep schedules, narcolepsy, sleep apnea, circadian misalignment (including shift work), and even sleep-related eating disorders contribute to metabolic dysregulation. Sleep deficiencies or circadian disruption, which cause or contribute to metabolic dysregulation, will contribute to weight gain and obesity by disrupting energy balance, causing inflammation, impairing glucose tolerance and insulin sensitivity, and raising leptin levels.
Disruption of sleep and circadian rhythms is increasingly evident as a contributing factor to impaired physiological function, especially concerning metabolic dysregulation, overweight and obese conditions. Ongoing research regarding regulating circadian rhythm with melatonin implicates melatonin as a possible way to improve leptin resistance.
Poor eating habits and leptin
Omega-3/6 content in the protein we consume: Whether due to a decrease in inflammation, or other factors, when we increase our Omega 3 fatty acid intake via supplements or fatty fish, and we decrease our Omega 6 fatty acid consumption by substituting plant-based eating for meat and dairy, we see reduced leptin levels.
Specific foods: We discussed the concept of inflammatory foods, but it doesn’t stop there. Unhealthy, fast-food-type diets reportedly induce a different inflammatory response in the hypothalamus in animals. This hypothalamic response subsequently promotes the development of brain leptin resistance and then- obesity.
Over-eating: Independent of metabolic changes and weight gain, consistently “eating too much” in one sitting appears to raise leptin levels. Based on epidemiologic data, no one should consume much more than 500 calories in a single meal consistently. In addition, hedonically-loaded foods (the seriously fatty-sugary-tasty stuff) interrupt the inhibitory actions of leptin on orexin (satiety) neurons in the brain and interfere with the homeostatic control of feeding.
Protein consumption: In a few small studies, increasing dietary protein intake from 15% to 30% of calories (with a constant carbohydrate intake) produced statistically significant decreases in caloric intake, so those study participants lost weight. The mechanism by which this occurred is unknown, although the theory is that it somehow causes increased brain leptin sensitivity.
SIRT1 enzyme dysfunction raises leptin
SIRT1 is a NAD(+)-dependent protein deacetylase enzyme. If you have SIRTT1 dysfunction, you typically have issues with glucose and cholesterol. You also usually have some degree of fatigue caused by decreased NAD(+) levels due to decreased mitochondrial function. In addition, SIRT1 activity improves both leptin sensitivity and insulin sensitivity; conversely, a SIRT1 deficit will impair these pathways. NAD(+) is necessary to transfer energy from cell to cell and help carry out numerous metabolic functions.
Overall, SIRT1 in the hypothalamus improves energy (NAD+ levels), glucose control, and leptin and insulin sensitivity. Both SIRT1 and NAD(+) levels decrease with age in the brain’s temperature regulation center- the hypothalamus. Increased hypothalamic SIRT1 levels prevent age-associated weight gain and improve leptin sensitivity in mice. Therefore, avoiding the age-dependent (as well as disease-dependent and toxin-dependent) loss of SIRT1 and NAD+ function in the hypothalamus could potentially improve leptin sensitivity.
Exciting studies that look quite promising involve improving SIRT1 and, therefore, leptin sensitivity with IV NAD+, intra-nasal NAD+ or oral nicotinamide ribonucleotide (NMN). I use these modalities in my practice currently with (again anecdotally) notable success.
Additional issues impacting leptin levels
High triglyceride levels will contribute to leptin resistance. Most doctors know that high triglycerides are an independent cardiac risk factor and treat it accordingly.
Autophagy is a process by which cells remove and recycle junk proteins, and some studies link it to leptin resistance. Medications to enhance autophagy may improve leptin levels. Hormones can impact leptin levels, and estrogen deficiency may cause leptin insensitivity in the brain.
More research shows that what we consume impacts leptin levels. Some theories suggest that lectins (e.g., gluten, beans, grains, dairy, nightshades) bind to surface receptors of cells–including leptin receptors–and mimic or block the effects of that receptor. This theory posits that lectins could interfere with the function of leptin, exacerbating leptin resistance.
Even cold therapy is showing some positive results in leptin regulation. One last note, if you are trying to lose weight and have leptin resistance, a ketogenic diet is inappropriate. Keto is effective for insulin resistance but not leptin resistance.
Talk to your functional medicine doctor about normalizing cortisol, sleep, NMN, dihexa, and eating and exercise plans. When leptin is low enough, the peptide, AOD-9604, will help accelerate lipolysis and weight loss.