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

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 would be a survival advantage when times were lean and the only things to eat were unappetizing, but in this modern era with highly palatable foods in easy abundance, it can lead to gaining weight.

Leptin, a hormone produced mainly by fat cells, 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 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. Leptin resistance is when your brain stops getting the signal that you are at the right level of stored energy. Overweight people are usually producing more leptin than lean people.

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 “proopiomelanocortin (POMC)/cocaine- and amphetamine-regulated transcript neurons results in production of α-melanocyte–stimulating hormone that activates the melanocortin-4 receptor (MC4R) and thereby induces satiety signals. LEPR activation on neuropeptide-Y/agouti-related protein (AgRP) neurons leads to reduced production of orexigenic peptides”.  Digging into that explanation –  cocaine- and amphetamine-regulated transcript (CART) and POMC are both neuropeptide proteins that are involved in energy regulation in the hypothalamus. CART causes suppression of appetite through leptin — and this is also probably why cocaine and meth both cause appetite suppression.[ref] MC4R is the receptor activated by alpha-MSH. Genetic variants in MC4R are also tied to obesity.

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] The other side of that coin is having a rare mutation that practically eliminates the function of the leptin receptor. These mutations cause people to be ‘hyperphagic’ — or insatiably hungry.[ref]

Rare mutations aside, there are fairly common changes, or variants, in the leptin receptor gene that are tied to an increased risk of obesity. The variants that are included in 23 and Me data are listed below.

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.)

Check your 23andMe results for rs1137101 (v4, v5):

  • AA: normal
  • AG: increased risk of being overweight or obese, diabetes
  • GG: increased risk of being overweight or obese, diabetes

Some of the studies on this variant:

  • Associated with higher risk of obesity in many (but not all) populations and with an increased risk of type-2 diabetes.[ref]
  • Increased weight gain (28lbs!) in women with GG 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 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]
  • also known as 668 A>G and Q223R  and Gln223Arg in studies

Check your 23andMe results for rs1137100 (v4, v5)

  • AA: normal
  • AG: increased risk of obesity, diabetes
  • GG: increased risk of obesity, diabetes

Some of the studies on this variant:

  • 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 23andMe results for rs3790433 (v4):

  • CC: normal
  • CT: decreased risk of insulin resistance, metabolic syndrome
  • TT: decreased risk of insulin resistance, metabolic syndrome[study]

Lifehacks:

Ashwagandha, an adaptogenic Ayurvedic herb, 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]

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]

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.

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.

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]

 

 


6 Comments

Martin · April 12, 2018 at 7:48 pm

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

    Debbie Moon · April 12, 2018 at 8:37 pm

    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

      Martin · April 14, 2018 at 9:47 am

      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 ?

        Debbie Moon · April 15, 2018 at 3:37 pm

        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

Astrid · January 31, 2019 at 3:46 am

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

    Debbie Moon · February 1, 2019 at 12:05 pm

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

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