Leptin Receptors: Genetics and Hunger

Do you wonder why other people don’t seem to struggle with wanting to eat more? Ever wished your body could just naturally know that it has had enough food and turn off the desire to eat?

It could be that you carry a genetic variant in the leptin receptor gene which is linked to not feeling as full or satisfied by your meal – and thus tend to eat just a little bit more. This may have been a survival advantage when times were lean and the only things to eat were unappetizing. Not the case in our modern era with highly palatable foods in easy abundance!

What is leptin?

Leptin is a hormone produced mainly by fat cells. It signals to the hypothalamus in the brain that you have enough stored energy already and don’t need to eat.

Leptin is the full signal, and it opposes ghrelin, the ‘hunger hormone’. Together, these two hormones regulate appetite and balance energy expenditure in the body.

When you go on a low-calorie diet, leptin increases, telling your brain that you are in starvation and need to conserve energy, lowering your metabolic rate. One way that this happens is through leptin signaling in the hypothalamus to decrease thyroid hormone levels.

Leptin in the brain:

Leptin is the signaling hormone, but that signal has to be received by the neuronal cells.  For people who are overweight or obese, there is usually plenty of leptin being produced in the fat cells, but often the leptin signal is not being received. Some researchers theorize that people can be leptin resistant — when your brain stops getting the signal that you are at the right level of stored energy.

Details on how the leptin receptor works in the hypothalamus: 
Neurons in the hypothalamus have leptin receptors and receive the signal from circulating leptin.

Specifically, the leptin receptors on the POMC and CART neurons cause the release of α-melanocyte–stimulating hormone (α-MSH) which in turn activates the melanocortin-4  receptor (MC4R gene). This induces the production of the appetite-suppressing peptides. Cocaine- and amphetamine-regulated transcript (CART) and POMC are both neuropeptide proteins that are involved in energy regulation in the hypothalamus.[ref]

CART causes suppression of appetite through leptin — and this is also probably why cocaine and meth both cause appetite suppression. (No, this is not a good weight loss solution!)[ref] MC4R is the receptor activated by alpha-MSH. Genetic variants in MC4R are also tied to obesity.

The other signals that the leptin receptor activates – neuropeptide Y and agouti-related protein – reduces the amount of hunger signal. It is like the break on the hunger signal. So leptin in the brain stops the hungry (neuropeptide Y) and increase the satiety (alpha-MSH).

What happens when the leptin receptor has a mutation?

There is a very small percentage of people who are overweight because they don’t produce enough of the leptin hormone, the signal for full.[ref]  So not producing enough of the signal (leptin) drives a craving for more and more food. Again – this is really rare.

The other side of that coin is having a rare mutation that practically eliminates the function of the leptin receptor. These mutations also cause people to be ‘hyperphagic’ — or insatiably hungry – because the signal isn’t being received in the brain.[ref]  Again – this is somewhat rare.

There are also fairly common changes, or variants, in the leptin receptor gene that are tied to an increased risk of being overweight or obese.

These more common variants are likely to increase your weight (somewhat) through increasing appetite and decreasing metabolism (a little).  But they aren’t the cause of drastic obesity.

Leptin Resistance

These leptin receptor variants that are tied to increased weight may also exacerbate leptin resistance.

Leptin resistance is when the hypothalamus doesn’t receive all of the leptin signal.  This may be due to a decreased amount of leptin that can cross the blood brain barrier and reach the hypothalamus.  Or leptin resistance could be due to signaling problems within the neurons — perhaps due to inflammation. Researchers honestly don’t have the final answers on what is causing leptin resistance. Here is a great new review paper on the topic if you want to dig into this more: Leptin resistance: underlying mechanisms and diagnosis.

What else does leptin do? 

Leptin is also a signal in the hypothalamus that is involved in your reproductive hormones.  This makes sense from an evolutionary point of view — you only want to reproduce when you have enough food on board.

Not enough leptin (such as when someone is very thin) can cause amenorrhea, or lack of menstrual cycle. This is thought to be the cause of amenorrhea in about 30% of women. [ref]

Too much leptin, on the other hand, causes girls to start menstruating earlier.  It also can cause infertility due to ovarian follicles not developing correctly. Leptin is a signaling molecule in the hypothalamic-pituitary-gonadal axis. [ref]

Additionally, high leptin levels are associated with pre-eclampsia during pregnancy. Leptin is actually secreted by the placenta, which is why leptin levels (and thus hunger) increase during pregnancy.[ref]

In people who have type 2 diabetes, high leptin levels correlate with depression and anxiety. People with higher leptin levels, indicative of leptin resistance, were at a 5-fold increased risk for depressive symptoms or moderate to severe anxiety.[ref]

Melatonin and leptin are inter-related. Melatonin is more than just a ‘sleep hormone’. Levels rise at night and act as a signaling molecule in quite a few circadian dependent processes.  Decreased melatonin levels have been shown to lead to leptin resistance. Animal studies show that adding melatonin ameliorates the leptin resistance. [ref]

What causes decreased melatonin? Exposure to light at night in the blue wavelengths. Try turning off overhead lights and shutting off the electronics (TV, phone, laptop) a couple of hours before bed.


Genetic variants of the LEPR gene:

Genetically obese mouse due to leptin deficiency

Leptin receptors (LEPR) are a transmembrane-domain receptor that carries the signal from the leptin hormone into the cell to be acted upon. Deficiencies in leptin receptors are associated with being overweight or obesity.  In fact, to create obese mice for use in studies on obesity, diabetes, and dyslipidemia, scientists created a mouse strain called db/db, which are bred to have a mutation in the leptin receptor.

Most of the genetic variants below are very common; in fact, up to half of some populations carry the variant. So while leptin receptors may play a role in obesity, if genetics were completely to blame, half the population would be overweight. (Wait, that is actually true…  In the US, 68% of the population is now considered overweight or obese.[ref]  But no, it can’t all be blamed on this variant.)

Note that there are other leptin receptor variants associated with obesity that aren’t covered by 23andme, AncestryDNA, or other common genetic data sources.

Check your genetic data for rs1137101 (23andMev 4, v5 ; AncestryDNA):

  • A/A: normal
  • A/G: increased risk of being overweight or obese, diabetes
  • G/G: increased risk of being overweight or obese, diabetes

The studies on rs1137101 show that the G allele is associated with:

  • Associated with higher risk of obesity in many (but not all) populations and with an increased risk of type-2 diabetes.[ref]
  • Increased risk of polycystic ovarian syndrome (PCOS) [ref]
  • Increased weight gain (avg. 28lbs!) in women with G/G on antipsychotic medications [study]
  • 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 A/A genotype, respectively.” [ref]
  • Increased risk of thyroid cancer  for those with A/G or G/G (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]
  • also known as 668 A>G and Q223R  and Gln223Arg in studies

Check your genetic data for rs1137100 (23andMe v4, v5; AncestryDNA):

  • A/A: normal
  • A/G: increased risk of obesity, diabetes
  • G/G: increased risk of obesity, diabetes

The studies on rs1137100 show:

  • Note that this is a really common variant
  • Associated with the risk of obesity in many (but not all) 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]
  • Also known as K109R, Lys109Arg and 326 A>G

Check your genetic data for rs3790433  (23andMe v4; AncestryDNA):

  • C/C: normal
  • C/T: decreased risk of insulin resistance, metabolic syndrome
  • T/T: decreased risk of insulin resistance, metabolic syndrome[study]

Lifehacks:

Ashwagandha

Ashwagandha is an adaptogenic Ayurvedic herb that has been found to be a leptin sensitizer. A 2016 mouse study found that one of the constituents of ashwagandha, withaferin A, reduced diet-induced obesity by 25%.[study]  Human trials have found ashwagandha (300 mg) somewhat effective in weight loss (~5lbs in two months) for people under chronic stress.[study] Ashwagandha can be purchased as a powdered herb or in capsules. Everyone has different tastes, but in my opinion, ashwagandha has a fairly strong herbal taste and I go with capsules.

Reduce Omega 6 Fats:

A human study found that those with LEPR variants who had higher insulin concentrations and higher insulin resistance, the increased risk was modified by the ratio of omega 6: omega 3 fats in their diet. Only those who had a low omega 3 and high omega 6 levels had an increased risk of metabolic syndrome.[study]
A low-fat, high complex carbohydrate diet for 12 weeks enhanced insulin sensitivity and reduced insulin resistance only in those with the variant and who also supplemented with 1.24g/day of omega-3 fats.  Those on the low-fat, high complex carb diet alone or when supplementing with monounsaturated fats had no increase in insulin sensitivity.[study]

Don’t do severe calorie restriction:

Calorie or food restriction doesn’t work well for weight loss in db/db mice (bred to have LEPR mutation). In fact, after six weeks of food restriction, db/db mice also had higher plasma glucose levels.[ref]

Timing of Food:

A recent mouse study found that eating during their inactive period (daytime for the mice, nighttime for us humans) caused leptin resistance and increased obesity and metabolic syndrome. Leptin levels fluctuate over the course of a day (circadian rhythm) and eating at the wrong time seems to cause big problems.  [ref]  For people, this may mean that not eating at night will help reduce leptin resistance. So eat dinner a little earlier and stop with the midnight snacks.

Sleep and Light at Night:

Leptin, like most of our hormones, has a daily rhythm that is impacted by sleep and light. Melatonin plays a key role in leptin levels.[study][study]  Read through Color TV is Making Us Fat: Melatonin, Genetics, and Light at Night for more information. Seriously consider blocking blue light at night with blue-blocking glasses.

A recent study found that the amount of sleep is also tied to leptin levels. The study included more than 1,000 people and found that those who slept 5 hours or less at night had a 15% decrease in leptin levels and a 14% increase in ghrelin. They were (quite logically) more likely to be overweight. [ref]

Ginseng:

A recent mouse study found that a bioactive component of ginseng, ginsenoside Rb1, improved leptin sensitivity and signaling in fat mice.[study] There are quite a few studies showing weight loss in mice/rats with ginseng, but not nearly as many in humans.[review] One study in middle-aged females found an average weight loss of a few pounds after two months.[study] Panex Ginseng can be purchased in powder or capsules.

Berberine:

An alkaloid found in goldenseal, barberry, and Oregon grape, berberine has been used traditionally in many herbal supplements for its anti-diabetic effects. One study (human) found improved leptin ratios as well as decreased BMI after three months of berberine (300mg/3x per day).  Berberine is available as a supplement. [study]

Rapamyacin?

This Lifehack is something to look into (not necessarily something I wholeheartedly recommend).  Animal studies show that rapamycin normalizes leptin levels and reduce obesity due to aging.  “Our data suggest that the dosing schedule of rapamycin acts on peripheral targets to inhibit mTORC1 signaling, preferentially reducing adiposity and sparing lean mass in an aged model of obesity resulting in favorable outcomes on blood triglycerides, increasing lean/fat ratio, and normalizing elevated serum leptin with age.” [ref]

 

 



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6 Comments on “Leptin Receptors: Genetics and Hunger

  1. Hi. Do you know anything about POMC in relation to overappetite ?. Deficiency of POMC is usually described as incredibly rare, but I am not convinced it is an ‘all or nothing’ situation. See: ‘Setmelanotide’.
    Can raw data from 23andme be used to look for genetic issues around POMC ?
    Thanks

    • Hi Martin,
      I’ve come across quite a few studies in regards to weight and POMC, but I haven’t put together anything into a blog post yet about it. (I’ll add it to the ‘to do’ list). Just pulling a few things from my notes regarding POMC variants:
      rs1042571 (which is only in version 4 of 23andMe) A is the risk allele and associated with increased BMI in some population
      rs121918111 (which is only in version 5 of 23andMe) T is the risk allele, rare, and pathogenic for POMC deficiency
      rs121918112 (also only in version 5) A is the risk allele, again rare and considered pathogenic for POMC deficiency

      To answer your ‘all or nothing’ question – quite a few of the incredibly rare genetic disorders are being discovered to be not quite as rare as previously thought and also to be more of a spectrum where heterozygous (carriers) people have partial symptoms.

      I do have an article on MC4R on my blog, but a quick look at it shows me that I need to put it on the list to update it. I’ve learned a lot over the past few years, and research is changing quickly as well :-)

      Hope this helps gets you started on looking into the topic,
      Debbie

      • Thanks Debbie. I know a little about POMC / MCR issues but what I am not sure of is whether the raw data from 23andme is adequate to be used to by a geneticist to look at this for an individual. I find myself wondering if e.g. partial deficiency could easily ‘hide in plain sight’ in some populations, more than others, such as Scottish / Irish Diaspora. Another question- are you aware of people taking their raw data to professionals to be interpreted ?

        • Hi Martin,
          Yes, there are practitioners who work with people’s raw data file. Often naturopathic doctors are able/willing to do this. Most genetic counselors, though, are probably going to want to run their own, more thorough tests.

          As far as POMC partial deficiency hiding in plain sight, I would actually be a little surprised if that were the case. There have been tons of large population studies, particularly on Caucasian populations, looking into genetic influences on weight. The MC4R variants were found that way, and they would be associated with POMC through alpha-MSH. FTO variants were also discovered through genome-wide studies. I updated my article on MC4R with more recent studies this week, if you want to take a look.

          What might be a better path to look into as far as POMC are epigenetic effects – perhaps there is something environmental that is turning down the production of that gene on a wider scale. Epigenetics is a way that our body can decrease or increase the products of genes.
          Debbie

  2. Hi Debbie
    What is the source of everything you said? Can you share it? I’m making a project over here :)

    • The links to all of the research papers are right in the article. Just click on the [ref].

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