Leptin is a hormone that is well known in the weight-loss-dogma / diet-guru arena. The hormone, discovered in 1994, is produced by fat cells and signals to the hypothalamus in the brain that you have enough stored energy.
When you go on a low-calorie diet to lose weight, leptin increases to tell your brain that you are in starvation and need to conserve energy, thus lowering your metabolic rate. One thing your body naturally does is stimulate the vagus nerve in an effort to get you to store more fat and restore your leptin levels to where they were before you started dieting.
Leptin resistance, often written about in regards to weight loss, is when your brain stops getting the signal that you are at the right level of stored energy. So in obesity, it is usually not the case that a person doesn’t produce enough leptin, but rather that the leptin signal is not being received. Since leptin is made in fat cells, it is not a matter of lack of leptin, and obese people usually produce more of it than lean people. (There are, of course, a small percentage of people who are overweight because they don’t produce enough leptin, but that is a fairly rare phenomenon.) [ref]
A good article to learn more about leptin and leptin resistance is on the Authority Nutrition website: Leptin and Leptin Resistance: Everything You Need to Know.
Of course, leptin resistance is a theory, and there have been several recent studies that contradict that model. Last year, a study from the University of Cincinnati found: “In the UC study, funded by the National Institutes of Health, the team headed by Perez-Tilve took a different approach. They blocked leptin action in both lean and obese mice. The results were that both sets of mice ate more and gained weight to the same extent, proving that “leptin action was not impaired in the obese mouse.”[ref] Another recent genome-wide survey found that even when factoring in obesity, leptin levels vary among individuals based on genetic polymorphisms unrelated to obesity. [ref]
Genetics components of leptin:
The first thing to look at genetically in the leptin signaling to the brain is the leptin receptor coded for by the LEPR gene. (There is a lot more to do with leptin that will be discussed in future blog posts)
Leptin receptors are a transmembrane-domain receptor, and deficiencies in leptin receptors are associated with obesity. In fact, the obese mice called db/db that are used in studies for obesity, diabetes, and dyslipidemia are bred to have a mutation in the leptin receptor causing the deficiency.
There are leptin receptors found in the hypothalamus as well as a short-form that is found in the pancreas and other peripheral tissue. [ref]
Most of the variants below are very common with half or more of some populations carrying the minor allele. So while leptin receptors may play a role in obesity, if genetics were totally to blame, half the population would be obese. But wait, that is pretty much the case! In the US, 68% of the population is now considered overweight or obese. [ref] And no, I don’t really think that it all can be blamed on the leptin receptor polymorphisms. This is just one piece of a huge puzzle.
rs1137101 (G is the minor allele, also known as 668 A>G and Q223R and Gln223Arg in studies)
- Associated with higher risk of obesity in many populations.
- risk of type-2 diabetes. [ref]
- In a study looking at the response to resistance training, “adults with the LEPR 668 G allele gained greater arm muscle volume … and subcutaneous fat volume… than adults with the LEPR 668 AA genotype, respectively.” [ref]
- Increased risk of thyroid cancer for those with AG or GG (OR=3.7, OR=5.4) [ref]
- Associated with total parathyroid size in patients with hyperparathyroidism [ref]; obesity in Pacific Islanders [ref]; risk of nonalcoholic fatty liver disease [ref]; lower risk of breast cancer [ref]
rs1137100 (G is the minor allele, also known as K109R, Lys109Arg and 326 A>G)
- Note that this is a common variant and in some populations it homozygous in the majority of the people.
- Associated with the risk of obesity in many populations.
- Lower risk of breast and gastric cancers [ref]; higher odds of severe preeclampsia [ref]; risk of nonalcoholic fatty liver disease, but lower fibrosis score [ref]; obesity in Indian children [ref]; lower risk of breast cancer [ref]
- Not associated with obesity in Pacific Islanders [ref]
rs6700896 (C is the minor allele, very common variant )
- Minor allele is associated with higher leptin levels, insulin resistance and with more severe nonalcoholic fatty liver disease [ref]
- CRP levels (an inflammatory marker) were almost 15% lower in those with the minor allele. This was found as part of a huge study and replication study of over 50,000 individuals, and the conclusion of the study found that CRP levels don’t have a causal association with heart disease. [ref]
rs37904333 (C is the minor allele in 23andme orientation)
- CC homozygous associated with insulin resistance. This was even more evident in those with low plasma omega-3 or high plasma omega-6. [ref]
Leptin receptors and the vagus nerve
The vagus nerve controls so much of a body’s parasympathetic system including breathing, swallowing, talking, heart rate, and gastrointestinal stimulation. An interesting study in 2014 looked at the influence of leptin receptor deficiency specifically only in relation to the vagus nerve. The scientists used mice that were deficient only in the vagus nerve-related receptors but with still functioning hypothalamic leptin receptors. The study found that deletion of the leptin receptors in the vagus nerve pathway did lead to obesity, specifically a 40% increase in fat. The leptin receptor deleted mice were found to eat more than normal mice, but the increased eating was only during the first three-hour window of darkness (mice are nocturnal). Another interesting part of the study involved feeding part of the mice a high-fat diet for 12 weeks. The wild-type mice all became even more obese than the leptin receptor-deficient mice on that same high fat diet. So while the leptin receptor-deficient vagus nerve mice gained weight on a normal diet, a high-fat diet didn’t add any more weight gain. Read the whole study for more information on gut hormone signaling, CCK, JAK2 and leptin. [ref]
A 2012 review looked at cholinergic activation of the vagus nerve to suppress obesity-associated inflammation. It found that “Targeting cholinergic mechanisms in the inflammatory reflex using α7nAChR agonists or a centrally-acting acetylcholinesterase inhibitor could alleviate inflammation and metabolic complications in obesity.” Nicotine is an α7nAChR agonist and it was found in mice to suppress inflammatory markers in fat tissue. [ref]
Possible weight loss options for leptin receptor variants:
I decided to look at what works in mice (db/db mice) that are bred to have leptin receptor deficiency and found the following:
- A 2002 study looked at the effects of advanced glycation end products (AGEs) in db/db mice. Those on a low AGE content diet have increased response to glucose and insulin after 20 weeks compared to mice on a high AGE diet. Overall body weight declined (after 8 weeks) and serum leptin levels were lower in the mice on the low AGEs diet. [ref] Advanced glycation end products are formed when heating food at a high temperature — think Maillard reaction, which causes meat to brown in a pan or on a grill. Grilling, broiling, frying, and roasting all cause increase AGE production. Marinating meat in an acidic marinade (vinegar, lemon juice) inhibits some of the production of AGEs. [ref] Anti-oxidants such as Vitamin C and phenols such as resveratrol can help prevent the formation of AGEs.
- Calorie or food restriction doesn’t work well for weight loss in db/db mice. In fact, after six weeks of food restriction, db/db mice had higher plasma glucose levels. [ref]
- Forced treadmill exercise had detrimental effects on db/db mice. [ref] You should probably still do some type of exercise, maybe a nice walk outside instead of forced treadmill exercise…
- Panax ginseng berry extract caused obese, db/db mice to reduce their fasting blood glucose level, while normal mice did not decrease their fasting blood glucose level with the extract. The obese mice also decreased their body weight by 10% in the same 12 day period. [ref] One big thing to note is that the Panax ginseng berry extract was injected at a dose of 150mg/kg. If I’m doing the math right (see this article for the conversion), that comes to 12 mg/kg or a little over 1000 mg/day for a 200 lb person. I’m not sure how the injection vs. pill form vs. ginseng tea would compare. Note on ginseng — it is possibly estrogenic in large doses. [ref]
- SGLT inhibitors seem to work well for db/db mice. [ref] This is a class of pharmaceutical drugs for diabetes. So if you have diabetes and your doctor prescribes this type of drug, you may end up losing a little weight.
- db/db mice get sicker due to lipopolysaccharides (also known as endotoxins). [ref] Reducing LPS by reducing gut permeability may possibly help those with LEPR variants to reduce inflammation. Here is another study on the gut microbiome in relation to weight loss including information on bacterial strains most commonly found in db/db mice.
- Nicotine and other α7nAChR agonist administered to db/db mice reduce weight gain, food intake, HbA1c, triglycerides, and blood glucose levels. [ref]
- Berberine “increases energy expenditure, limits weight gain, improves cold tolerance and enhances brown adipose tissue (BAT) activity in obese db/db mice.”[ref]
- Thunder God Vine extract was found not to work for db/db mice [ref], and SIRT1 activators are not the way to go, either: “Despite the dramatic reduction in hyperglycemia, db/db mice displayed worsening insulin resistance, diminished physical activity and further weight gain. These findings along with reduced food intake and reduction in body temperature resembled torpor and hibernation.”[ref]
- GSK3 inhibitors lower glucose levels in db/db mice [ref]
Human studies for LEPR and diet:
A human study found that those with LEPR variants had higher insulin concentrations and higher insulin resistance — only in those who had a low omega 3 and high omega 6 level. [ref] A low-fat, high complex carbohydrate diet for 12 weeks enhanced insulin sensitivity and reduced insulin resistance in those with the variant who also supplemented with 1.24g/day of omega-3 fats. Those on the low-fat, high complex carb diet who supplemented with high-oleic acid (mono-unsaturated fat such as olive oil) did not have improvements and neither did the group that was just low-fat, high complex carb. You can read the whole study in the Journal of Nutrition.
My takeaway is that those with a LEPR variant should cut out omega-6 fats and make sure that they are getting some omega-3 fats. Of course, there is are a lot of studies showing the inflammatory aspects of omega-6 fats, and I really don’t think anyone should eat very much omega-6 fat.
Omega-3 fats can be found in fish and in flax seed. You can find out which one is better for you by looking at your FADS1 variants.