I’ve written a comprehensive post about Leptin before. This post is about leptin resistance. Sensitivity to leptin may result in significant weight loss and lower inflammation.
Leptin resistance is common in cases of obesity, because it doesn’t decrease appetite. Learn about the causes & how you can increase sensitivity.
What is Leptin Resistance?
Leptin resistance is when leptin doesn’t work as well to decrease appetite or increase energy expenditure.
Leptin resistance is now believed to be the leading driver of fat gain in humans .
Leptin resistance leads to increased appetite and decreased energy expenditure.
What Are The Mechanisms of Leptin Resistance?
In obese subjects with very high leptin, leptin levels in the cerebrospinal fluid only increase slightly . This shows that leptin is not getting into the brain much, and this is part of the problem.
A second issue might be from fewer leptin receptors .
Tips to Increase Leptin Sensitivity
1) Keep to a Circadian Rhythm
One significant underlying cause of leptin resistance is Circadian Rhythm Disruptions.
Night-shift workers, who must be awake, active, and eating during the night are at a higher risk for obesity and metabolic diseases .
Chronic jet lag is sufficient to disrupt the clock in fat cells and also induce Leptin resistance in the brain in mice (11).
While you may not travel across time zones much, most people don’t get enough light in the day and get too much light at night, which disrupts our natural biological rhythm.
It is hypothesized that eating during the ‘wrong’ circadian time contributes to circadian desynchronization and increased weight gain.
One mechanism by which obesity can result from eating at the wrong time (night) is by not burning off the calories as much.
In humans, eating identical meals (~544 kcals; 15% protein, 35% fat, 50% carbohydrate) results in less generation of heat in the nighttime vs the daytime .
Similarly, studies in free-living healthy adults have shown that meal satiety also varies with time of day and that food intake during the night is less satiating and leads to greater daily caloric intake compared to food consumed in the morning hours [16, 17].
For the natural course of mammalian history, we’ve eaten for about 12 hours in the day and fasted for 12 hours at night.
So for weight loss, when you eat might be more important than what you eat – and maybe even how much you eat to a degree.
2) Eat Less – especially at night
Chronically high levels of leptin cause leptin resistance, as a means to stay in homeostasis .
The act of overeating leads to chronically high levels of leptin, causing leptin resistance. At that point, it’s harder to lose weight because you’ve moved yourself to a new homeostasis.
Many people don’t care about their weight until they are already overweight, and so they diet to lose the weight, but at that point, it’s harder than if they always ate a normal amount.
This might not be a problem if people stop eating for 12 hours and give their system time for leptin to become more sensitive again.
Also, eating too many calories can also increase inflammation and fatty acids, which can cause leptin resistance as well.
3) Cut Out Sugar
Eating too much fat and carbs can also increase fatty acids in the blood.
Reducing carbs decreases triglycerides , which was one mechanism that inhibited leptin transport to the brain.
4) Reduce Inflammation
Low-grade, chronic hypothalamic inflammation is closely associated with various metabolic disorders including obesity .
If you’re Th2 dominant, you might increase SOCS3, which will cause leptin resistance.
Besides burning calories, exercise improves hypothalamic leptin sensitivity at least in part through suppressing hypothalamic inflammation and inhibiting Endoplasmic Reticulum stress in rodents .
Exercise also increases BDNF and can likely help in lowering triglycerides.
6) Eat More Protein and Fewer Carbs
An increase in dietary protein from 15% to 30% of caloric intake (at a constant carbohydrate intake) produces a sustained decrease in caloric intake that may be mediated by increased leptin sensitivity in the brain and results in significant weight loss. This appetite-reducing effect of protein may contribute to the weight loss produced by low-carbohydrate diets .
Also reducing carbs can lower triglycerides .
7) Take a Cold Shower and Lower the Thermostat
Therefore, cold can make you more leptin sensitive.
8) Chill Out
There are many other mechanisms by which stress can cause weight gain, so it’s a good idea in many ways if you’re interested in weight loss .
9) Sleep More/Increase Autophagy
Autophagy is a process by which cells remove and recycle junk proteins.
Autophagy is important for leptin sensitivity .
Saunas and sleeping are two simple ways to increase autophagy.
10) Try to Avoid Lectins
Lectins bind to sugar structures on the receptors of cells and can mimic or block the effects of that receptor .
The leptin receptor has these sugar molecules that lectins bind .
Thus, lectin avoidance could possibly bind to the leptin receptor and affect its function.
11) Make Sure Estrogen Levels Are Adequate
12) Increase BDNF
Leptin works, in large part, through BDNF .
My post on BDNF delves into all of the ways to increase BDNF, but suffice it to say that a generally healthy lifestyle will increase BDNF.
Overview of the Causes of Leptin Resistance:
- Inflammation in the hypothalamus 
- Triglycerides and Free Fatty Acids in the blood [8, 9] – this can be from eating too many carbs or fat, or from mitochondria that are not able to burn it for fuel well enough. Triglycerides block leptin from entering the brain and are an important cause of leptin resistance and this may have evolved to increase hunger during starvation .
- Lectins 
- Emotional Stress and cortisol 
- Insulin resistance
- Inadequate autophagy 
- Lower SIRT1 
- Lower STAT3 and JAK2: Ketogenic diets inhibit STAT3 and cause leptin resistance .
- Low BDNF 
- Higher SOCS3, caused by inflammation [37, 38].
- Higher PTP1B  – Deletion of this protein increased leptin and insulin sensitivity, preventing body weight gain in a diet-induced obesity animal model [40, 41]
- Endoplasmic reticulum stress 
- Estrogen deficiency causes leptin insensitivity in the brain and increased hypothalamic neuropeptide Y .