Introduction to Leptin and Leptin resistance-NOTE: we now have Semaglutide and Tirzepatide!
Leptin and its receptors are essential regulators of body weight and energy homeostasis. Multiple studies show that decreasing leptin’s tissue (or receptor) sensitivity leads to metabolic disorders, including obesity. Physiologic mechanisms underlying the development of leptin resistance include gene mutations that encode leptin and its receptors, proteins involved in the self-regulation of leptin synthesis, and even factors that alter blood-brain barrier permeability. Leptin resistance is a complex pathophysiological phenomenon with multiple “lines of attack” for potential treatment. Why is this important? Leptin resistance is the leading driver of fat gain in humans so let me break down how I’ll discuss this complex topic.
- What is leptin?
- What are normal leptin levels?
- What is leptin resistance?
- Ways to lower leptin and treat leptin resistance
- Raise BDNF (this topic is complex)
- Lower cortisol and stress levels
- Lower inflammation levels
- Improve sleep
- Correct “eating habits”
- Fix SIRT1 enzyme issues
- Miscellaneous tips
What is Leptin?
Leptin is a peptide (short-protein) hormone, originally thought to be secreted solely by fat cells; now known also to be secreted by the kidneys, placenta, salivary glands, and stomach. It’s important to note that leptin levels increase exponentially, not linearly, with fat mass. Leptin receptors are found in their highest concentrations in the brain, specifically in the hypothalamus and hippocampus.
In some clinical studies, chronically-elevated leptin levels correlate with overeating, obesity, and, as mentioned above, metabolic diseases, including diabetes, hypertension, heart disease, and metabolic syndrome.
The exact way “leptin works” is unknown, but the leading theory involves leptin release post-meal, penetration of the blood-brain barrier, and satiety signaling in the hypothalamus. The hypothalamus then signals to the rest of the brain (and probably to fat cells and our microbiome) that we have enough fat stored, we no longer need to continue eating. As a result, caloric burning can continue at a regular rate.
What Are Normal Levels?
We can measure leptin levels with a simple blood test. The results are in ng/mL (nanograms per milliliter).
Normal leptin levels are approximately 4.5 – 23.5 ng/ML and vary slightly between labs. They depend on a person’s BMI, age, gender and tend to get higher throughout the day, towards nighttime when they peak. Degrees of severity are loosely given with “mild” as 15-20 ng/ML and “severe” as 50ng/L or more, but this varies from person to person.
It has been called the “weight loss hormone,” the “satiety hormone,” and even the “starvation hormone.” We know that leptin resistance potentiates the extreme hunger experienced by a high ghrelin state. This (leptin-resistant) physiologic state somehow makes fat cells “think” that they must hang onto fat for dear life. This particular metabolic problem makes weight loss quite tricky unless you deal with the leptin resistance head-on.
Leptin resistance occurs when leptin effectively decreases appetite or increases energy expenditure through basal metabolism or lipolysis in fat cells. As a result, tissues become resistant to even high levels of leptin: a similar phenomenon to insulin resistance with (obviously) different hormonal pathways and different treatments involved.
Clinical studies demonstrate that obese people usually have very high levels of leptin that don’t perform their job correctly. One of the reasons for this is that a leading leptin production site: fat cells, make leptin in proportion to their size.
Although leptin suppresses the appetite when slightly raised, it seems to have the opposite effect when it gets too high. That’s why most researchers feel that leptin resistance leads to increased appetite and decreased energy expenditure.
We can measure leptin levels and speculate on why people become leptin resistant. Theories include leptin entering the brain less effectively, decreasing leptin receptors, or an over-activation of negative feedback loops due to chronically high leptin levels. No matter what causes it, we now have some excellent ways to combat this problem and assist with weight loss. As you’ll see, it’s never a one-size-fits-all (no pun intended) when it comes to effective weight loss strategies. Let’s now get into how we address leptin resistance in the functional medicine world.
How to increase BDNF and therefore lower leptin
General Dietary Improvements
A typical American diet, high in refined sugar and “bad” saturated fat, causes negative structural changes in the brain. Those negative changes occur primarily via neurotrophins (“brain cell fertilizers) such as BDNF. What this means in “real life” is that we see a significant decrease in all neurotrophins if you eat an inflammatory diet. Therefore, it is crucial for brain health and overall good health, and as you are learning now: weight loss, you cut out refined sugar and eat only “good” saturated fats. “Good fats” (such as avocado and coconut) help you lose weight and are suitable for your health. In addition, your testable cognitive performance will improve within months when you consume a healthy diet.
Yes, I know this header got a bit of an eye-roll from you. However, I’m just giving you the scientific facts, so know that your body and brain undergo metabolic changes when you are overweight. BDNF will decrease when you are over-fat, with high body weight. When you reduce your weight, you improve your overall health and increase your BDNF levels and help your brain perform its functions better.
Intermittent Fasting or Caloric Restriction
Reducing your daily caloric intake or practicing various proven ways to do intermittent fasting can increase levels of BDNF. There is so much data coming in on the brain health benefits of intermittent fasting and the benefits for weight management and overall health that, at a minimum, timed eating intervals should be a part of your life: 5 days per week. 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 especially Intense Exercise
If you are currently a couch potato, you have nowhere to go but up when it comes to BDNF levels. Any exercise at all will boost your BDNF levels. Whether you are walking your dogs, going up stairs, walking from your parked car to the store-anything-will help. However, high-intensity interval training (HIIT) that super-boosts your heart rate will exponentially increase your production of BDNF. Consistency is essential: one intense exercise session once in a while will not make any difference. To reap the full benefits of increasing your BDNF levels through HIIT, you need to train this way a minimum of only once per week.
Of course, doing it three times per week is even better. Studies show that as little as 10 minutes of HIIT will raise BDNF levels. Start by simply jumping rope, running on a treadmill, or doing jumping jacks or burpees for 30 seconds to a minute. Do one of these activities until you feel short of breath, then walk slowly to catch your breath. Perform this sequence three times, working up to 6 times while gradually and comfortably increasing the active intervals.
A “Rich” Social Life
Of course, I’m going to discuss social connections, not money. Social enrichment (e.g., more meaningful and numerous interactions) for adults increases levels of BDNF. In addition, studies show that children exposed to socially enriched environments experience long-lasting cognitive and behavioral benefits.
A socially enriched environment is also beneficial for animals too. Rodents, for example, have been shown to have a lifelong increase in BDNF levels, as well as positive social behaviors and reduced risk of depression when raised in a stimulating and “rich” social environment.
Some drugs can raise BDNF levels. Short term, they are probably safe, but their long-term use is entirely unclear. I will only discuss one of the classes of drugs here as I do not recommend the use of pharmaceuticals to raise BDNF. Instead, I will explain the mechanism of this one class of medication below only because there is a healthy alternative. And as you will see “in a bit,” there is another bioidentical class of substances that work better than pharmaceuticals.
SSRIs (Selective-serotonin reuptake inhibitors such as Prozac) will increase levels of BDNF when used to treat depression. These drugs do this by elevating 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 anti-depressants and not bipolar.
Supplements that increase BDNF
Some supplements will “help the cause” but are nowhere near as strong as the peptides I’ll discuss next in terms of increasing BDNF. However, they are not used only to increase BDNF. Many of these supplements (integratives) are pretty helpful for a myriad of other reasons outside this particular article’s scope. They include green tea extract, curcumin, acetyl-l-carnitine, omega-3 fish oils, resveratrol, and vitamin D, something everyone should be taking. Now for the “seriously good stuff.”
Peptides that increase BDNF
If you’re my patient, you are probably using the intra-nasal peptide Semax or the oral peptide, Dihexa which both far exceed the power of the just-named supplements to increase BDNF. If you are not familiar with peptides as a class of medications (not drugs), here is a description.
Peptides are small sequences of amino acids that make up specific proteins. I’m talking about tiny proteins that have been isolated from human secretions and have many natural target functions. They have been studied and re-purposed for use throughout the body. 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 our 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 which I’ll discuss in the next section.
Heptapeptide Semax: (Amino acid sequence: Met-Glu-His-Phe-Pro-Gly-Pro)
Semax is a “nootropic” peptide due to its ability to increase BDNF: the most potent stimulator of neurogenesis. In addition, several studies demonstrate 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. Therefore, let me just mention that it’s also useful for Adult ADHD.
Dihexa: (Endogenous hexapeptide angiotensin IV)
Dihexa “rules” when it comes to increasing BDNF. It’s 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 itself!
Dihexa is a first-in-class oral compound that penetrates the blood-brain barrier to increase BDNF significantly. As a result, it improves memory consolidation and retrieval and neural processing speed and concentration. The bonus is that it helps drive down leptin levels quite nicely too.
Lower leptin by lowering Stress and cortisol levels
In the hours or even days after the experience of an ongoing stressful event, glucocorticoids (e.g., cortisol and similar substances)increase in the bloodstream. This phenomenon is important when considering what cortisol does to accumulate and store body fat. Glucocorticoids enhance the activity of the enzyme lipoprotein lipase in adipose (fat) tissue, leading to an increase in fat storage. This fat storage occurs even moreso in visceral (deep) fat, where lipoprotein lipase activity is higher. Therefore, chronically elevated cortisol levels contribute to visceral fat accumulation.
High cortisol can trigger sugar cravings for reasons which are not clear. It is one of the principal “drivers” of menopausal belly fat. If you are trying to build muscle, it inhibits that by being catabolic. It not only can decrease muscle mass, but it also reduces bone mass and can slow your metabolic rate by reducing adrenal and, therefore, thyroid functioning. Finally, it can trigger leaky gut syndrome, which causes systemic inflammation, another cause of leptin resistance.
And finally, glucocorticoids influence the function of leptin, whose usual role, as you recall- is to signal satiety and therefore suppress appetite. Although glucocorticoids stimulate leptin release from fatty tissue, they also reduce the brain’s sensitivity to leptin, contributing to leptin resistance.
In functional medicine, we strive to maintain a normal fasting cortisol level in our patients. Therefore, I often re-set the adrenals with adrenal adaptogens and adrenal glandulars. Sometimes I use integratives such as a magnolia bark derivative. Sometimes I will prescribe pure liposomal GABA. Often, I’ll rely on another BDNF-enhancing intra-nasal peptide called Selank.
Heptapeptide Selank: (Thr-Lys-Pro-Arg-Pro-Gly-Pro)
Numerous clinical studies have shown that Selank has strong anti-anxiety and, therefore, 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. We see this similarity of effect in several clinical trials, with the advantage of using Selank being its non-addictive properties and its ability to increase BDNF.
Inflammation-another cause of High Leptin
Chronic, low-grade inflammation is innately associated with various metabolic disorders, including obesity. Many complex physiologic pathways responsible for this phenomenon are currently under investigation regarding therapeutic, pharmacological intervention. Unfortunately, the discussion of the possibilities is far too premature for this article, which focuses on alleviating leptin resistance. So, let me make sure you know what chronic inflammation is, and then let’s go into how to take care of this particular issue.
What exactly Is inflammation?: Let me clarify the concept of “acute inflammation.” Think about getting a splinter in your finger. If you don’t remove it, the area turns red and gets puffy. That’s acute inflammation- a good thing, as it’s your body responding appropriately to the situation. It’s also your immune system flooding the area to fight off any viruses or bacteria that might have come in with the splinter. If you leave the spot alone with a physical injury, the swelling will go down, and everything will go back to normal. The signs of acute inflammation are swelling, heat, redness, and pain. The symptoms of inflammation will all resolve as healing occurs.
However, if you don’t remove the splinter and instead keep poking at the same spot, you will maintain high levels of inflammation. That’s what happens with chronic internal inflammation, but you can’t feel the splinter or the poking. The inflammatory response is short and precise. When it’s chronic, inflammation can be “silent,” make you feel fatigued or contribute to many other health problems. It can even make you look older! Here are the principal causes of chronic inflammation.
Unhealthy diets: I know I sound like a broken record with this mantra, but it is imperative to eat a healthy 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. Unfortunately, this just so happens to be the typical U.S. diet. And a big reason why just about everyone who is not “taking this seriously” is chronically inflamed. Furthermore, this eating pattern causes oxidative stress, which worsens inflammation.
Gut hyperpermeability AKA “leaky gut”: This is another pervasive American problem due to eating habits, consumption of pharmaceuticals (especially antibiotics), high cortisol levels (especially since the COVID pandemic), and the increase of mycotoxin illness. It is easily treated (usually with a gut-specific peptide such as BPC-157). Still, first, you need to recognize that you might have no symptoms or minor symptoms such as gastrointestinal bloating or mild constipation. Since this is the root cause of all autoimmune disease, it’s always a good idea to treat this problem, no matter what.
Your weight: Fat cells are little inflammation-producing factories. The more you have and the bigger they are, the more inflammation they cause for your entire body. The risk of chronic inflammation is a guarantee if you are obese or even just overweight. Obese and overweight women and men have higher levels of inflammatory blood markers than men and women of the same age who are not overweight or obese. According to numerous clinical studies, inflammatory markers decrease when men and women lose weight.
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 (especially when combined with poor omega-3 levels) 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. It’s easy to get good blood levels: eat omega-3-rich fish such as salmon or sardines and take good omega-3 fish oil supplements. Let me mention that leptin also responds to flipping your Omega 3 to Omega 6 ratio.
Lack of sleep: Poor sleep causes elevated blood inflammatory markers in and of itself. Disordered sleep is a chronic problem in the U.S. We go to bed too late, wake up too early, don’t get enough hours of sleep, or we use too many electronics late at night and disrupt the sleep quality we get. I’ll get more into the topic of sleep in this article, as disordered sleep in many forms will raise leptin levels, and I definitely need to address this issue.
Chronic stress: I know we discussed cortisol earlier as an independent risk factor for elevated leptin levels. But I’d be remiss if I didn’t discuss the relationship to inflammation (independent of causing leaky gut, too!). 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. We often sit for hours and then don’t make time for regular exercise. We need to get out of the Zoom room and make time to move more. Get up on your feet for two to three minutes each hour you’re sitting. Better yet, do some burpees, jumping jacks, or push-ups. And you may not even have to do “this much” to get positive health benefits. Recent data regarding exercise reveals that “exercise snacks” are great for your health. An exercise snack is as little as 1,2, or 3 minutes of activity. Use your imagination-it can be any sort of movement at all. Doing it just three times a day is demonstrated to be good for your health, even if you aren’t doing anything else that day that “counts” as exercise.
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 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. I’m certainly not discouraging regular exercise, but over-exertion to the point of daily fatigue can cause inflammation, as well as elevated cortisol levels and disrupted sleep. Speaking of sleep, I’d like to focus a bit on this near-epidemic problem.
Poor sleep raises 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. Once again, what dominates the literature is a “sleep peptide” called DSIP (delta sleep-inducing peptide).
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.
Poor Eating Habits and Leptin
Yes, I know we discussed weight loss, intermittent fasting and have touched on food choices; but now I’d like to get more in-depth about eating habits in general.
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.
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.
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.
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.
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.
Odds and Ends
I didn’t mention that high triglyceride levels will contribute to leptin resistance. In this day and age, all primary care doctors know that high triglycerides are an independent cardiac risk factor and, therefore; treated accordingly. So, there’s that. I also didn’t discuss metformin as a viable treatment for leptin resistance, even though doctors routinely use it to treat metabolic issues in women with PCOS (polycystic ovary syndrome).
The reason for that is not due to any inherent danger of metformin use-in fact-it is a pretty safe drug; it just doesn’t work all that well for leptin resistance. Now, let me get into the “mentions” of things that didn’t quite make the cut for having enough data, but they are things that make sense to me (given the data we have), or the emerging data is super-promising. Here they are.
Autophagy is a term that you will be hearing about more and more as a contributor to disease and aging. It’s a process by which cells remove and recycle junk proteins, and some studies link it to leptin resistance. No matter what, we are starting to recommend “meds” to enhance autophagy even now. Next, let’s discuss hormones, many having positive effects on aging, disease, and metabolic issues, including excess fat. In particular, estrogen deficiency is likely to cause leptin insensitivity in the brain based on good animal data.
And believe it or not, there is more research about how what we eat might impact leptin. 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. To “cover all bases,” I advise my moderate to severely leptin-resistant patients to avoid lectins.
New data is evolving consistently regarding the use of cold therapy, whether that be cold showers, ice baths, or even cold weather. Of course, cold might play a role in leptin regulation, so stay tuned for more data on this. But, at least we know that cold is excellent for your mitochondria and, therefore, your energy levels, so why not?. One last and critical note- if you are trying to lose weight and have leptin resistance, don’t do a ketogenic diet, or it will worsen the leptin problem; seriously! (Use keto for insulin resistance).
In my clinical practice, I find that adjusting eating and exercise plans, normalizing cortisol, sleep (often using DSIP), and prescribing NMN and dihexa do the trick every time. The “weight loss peptide” AOD-9604 then “kicks in” when leptin is low enough to allow it to accelerate lipolysis. Bon appetit!
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