Leptin Resistance & Weight Loss

If you have been struggling with weight gain or inability to lose weight, leptin may be the solution.

What is leptin?

Leptin is a hormone made by fat cells. It tells the brain the relative amount fat stores. More fat stores means more leptin. The brain does a lot with this information:

  • adjusts food intake & appetite
  • adjusts energy expenditure & metabolism
  • influences feeling of fullness
  • modulates hormone levels (thyroid, sex hormones, cortisol)
Leptin | Leptin Resistance | BioAdaptive Medicine | Naturopathic Medicine | Functional Medicine

The basic model of leptin's role in weight is through leptin's effects on appetite and metabolism as shown in the diagram. Ideally, this would result in a weight homeostasis. Depending on what and how much you ate at your last meal, your body would modulate your appetite and metabolism to influence your next meal. The net effect would be no weight loss and no weight gain.

Based on this simple model, the solution seems clear. Can't we just supplement with leptin to suppress appetite, increase metabolism and lose weight? The short answer is no. Because leptin levels are not the problem. Leptin signaling is. When leptin signaling goes wrong, the brain stops listening to leptin. It just tunes it out. This is known as leptin resistance. 

What is leptin resistance?

Leptin resistance is basically when the brain stops listening to leptin. It doesn't matter how much leptin your fat cells make, your brain just doesn't register it, so you don't get the modulation of your appetite and metabolism. In this basic model of leptin resistance, you would experience hunger and cravings even after eating a meal, leading you to overeat. 

Factors that increase leptin

  • inflammation
  • insulin 
  • glucose
  • high cortisol
  • estrogen excess
  • increased adiposity (fat tissue)
  • overeating

In this basic model of leptin resistance, the idea is that increased leptin levels (hyperleptinemia) lead to leptin resistance. This may be from desensitization of leptin receptors or downregulation of leptin receptors (meaning the cells make less leptin receptors).

But in this model, weight gain caused by a poor (high fat, high sugar) diet would essentially be the cause of the leptin resistance. The leptin resistance would then exacerbate the weight gain. 

This is true for some people but not all people.

Most of the women I diagnose with leptin resistance do not fit this model. Most started struggling with weight in their 40s or 50s. They tried all the diets, all the programs, all the supplements, all the things, mostly focused on cutting calories. They did all the "right things" for weight loss and yet, they either couldn't lose the weight or they continued to slowly gain weight. 

For these women, the leptin resistance came first and caused the weight gain. This is a theory that is backed up by research. In rat models, researchers have demonstrated the a pre-existing reduction in leptin sensitivity is what caused diet induced weight gain.

So the question is what is the cause of the pre-existing leptin resistance? We don't really know, but research poses some possible causes or contributing factors.

potential causes/contributing factors of leptin resistance

  • inability of leptin to cross the blood-brain barrier
  • issues with the leptin receptor and its associated proteins (may be genetic)
  • inflammation in the hypothalamus (part of the brain)
  • overload of proteins in the endoplasmic reticulum of the hypothalamus (aka ER stress)

We do not fully understand these mechanisms and how they develop. We need to ask why can leptin not cross the blood-brain barrier? Is it a result of some form of inflammation or immune imbalance? If so, what is the cause of the inflammation/immune imbalance? Why is the hypothalamus inflamed? Is it due to a leaky blood brain barrier, gastrointestinal inflammation, intestinal infections, chronic viral infections, or a toxin? Those are the questions we need to ask and the answers we need to find to truly heal leptin resistance.

Diagnosing leptin resistance

We currently have no direct way of assessing the sensitivity of leptin receptor or the functionality of leptin signaling. So we indirectly diagnose by measuring fasting leptin levels. If you have not eaten for 10-12 hours, your leptin levels should be low. This is normal fasting biochemistry. If your leptin levels are high, we infer that their is something wrong with the leptin pathway and assume leptin resistance.

Measuring your leptin levels just takes a simple blood test done in the morning before breakfast. You want your leptin levels to be below 12. I typically see leptin levels in the 30s or 40s in women who have normal blood sugar markers and have a moderate struggle with their weight. 

treating leptin resistance

Since we don't fully understand leptin resistance, we don't have targeted therapies. We have a few strategies to address some of the potential contributing factors and causes.

The primary focus so far has been on treating leptin resistance caused by high leptin levels (hyperleptinemia). We can use nutrition as a biochemical intervention to lower leptin levels and allow the leptin receptors to recalibrate, so to speak. This strategy works fairly well for most people.

Nutrition guidelines

1. Eat enough calories

Many women have damaged their metabolism and biochemistry through chronic calorie restriction. This leads to oxidative stress, impaired cellular communication, and hormonal imbalances that shut down your metabolism. So the first step is to start nourishing your body with enough calories. How much is enough will be vastly dependent on you, your body, and your lifestyle. With that said, most women "should" be eating around 1800-2000 calories a day. If you rapidly increased your calorie consumption, you may initially experience a little bit of weight gain but don't worry. That is just part of your metabolism recalibrating.

2. Balance your macronutrients

The next part of the nutrition guidelines is to follow a very specific balance in fat, proteins, and carbs in order to modulate our biochemistry. You will need to eat 60% of your calories from fat, 20% from protein, and 20% from carbs. On an 1800 calorie diet, this is 120 grams fat, 90 grams of protein, and 90 grams of carbs. This is NOT a ketogenic diet, which is much more restrictive in carbohydrates, which most women do not do well with long term.

additional notes on the nutrition guidelines

  • You will initially lose water weight due to the changes in biochemistry. Your body doesn't need as many water molecules to burn fat as it does to burn carbs for fuel.
  • You may lose electrolytes with the water weight causing dizziness. Just supplement with electrolytes until the dizziness resolves.
  • You may experience nausea if you have trouble digesting fat, which many women over 50 do because of hormonal changes. Use a digestive enzyme specific for fat digestions (usually contains lipase and ox bile).
  • Most women report 1-2 lb weight loss per week, which is a healthy pace.
  • You will notice changes in your body measurements before you notice changes in the scale.
  • If hyperleptinemia is the primary cause of leptin resistance, you may only need to follow these guidelines for 4-6 months before resuming a balanced and healthy diet that is lower in fat. If that is not the cause of your leptin resistance and the root cause had not been corrected, you may need to remain on the diet indefinitely or until you identify and treat the causes to maintain your new healthy weight.

getting started 

If you think leptin resistance may be the key to your weight struggles, the first step is to get tested. So many people want to jump straight into treatment, but I have witnessed people waste a lot of time and a lot of money by skipping the clinical workup. Test, don't guess.

You may be thinking that it would be safe to assume you are leptin resistant, but I have definitely seem people who struggle with their weight have healthy leptin levels. So do the test first.

If you do have leptin resistance, the next step is to start the diet. You can't do this gradually and get results. You need to dive right into and strictly follow the guidelines. That means you have to meal plan, calculate and meal plan some more. You CANNOT wing it. You have to do the calculations. This can be incredibly daunting for many people. 

That is why I have done all the work for you. I have a 4 week leptin diet meal plan that has everything planned out to the letter. All you have to do is buy the items on the grocery list and cook the meals as scheduled. No thinking, no calculating, no worrying, no wondering. Just cooking and eating. Click here to learn more.


  • https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2829242/
  • https://www.ncbi.nlm.nih.gov/pubmed/29789721
  • https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4069066/