Circadian Rhythm Connections, Part 2: Weight Loss and Meal Timing

There are five key elements to weight loss from a circadian point of view: Timing of Meals; Light Exposure; Sleep; What to Eat, When; and Genetic Variants.  All of these can come together in our modern world to give you a propensity to gain weight – and all can be hacked to help you lose weight.


#1: Timing of Meals

Timing is everything when it comes to our bodies.

Midnight snacks, a bowl of cereal before bed, or even ‘saving’ desert until 9 or 10 pm. All of these are fairly normal behaviors these days. Just open up the fridge and pop something in the microwave to heat it up, anytime day or night. Modern convenience at its best; not something our ancestors would have been able to do.

This penchant for eating at any time, day or night, is one factor driving the obesity epidemic.

It is always interesting to look at animal models and agriculture to understand weight gain. Financially it makes the most sense to have animals gain weight quickly for food production, so a lot of research has gone into this topic. For example, farmers have known for decades that low doses of antibiotics increase weight in cattle. When it comes to the timing of eating, it has been known for a long time also that the amount of weight gained for the same quantity of food depends on the time of day that the food is given. For example, a study from 1982 found that catfish gain more weight when fed at a specific time of night.[ref]  A more recent example is a mouse study from 2009 that found that mice fed during the time that they normally would be resting gained more fat although they were eating the same number of calories as mice fed during their active period.[ref][ref]

Let’s take a look at the research on people: 
A study of a Mediterranean population of 420 looked at weight loss over a 20-week diet. Those who ate earlier in the day (defined here as eating lunch before 3 pm) lost more weight than those who ate later in the day.[ref]

Another study found that “Eating late is associated with decreased resting-energy expenditure, decreased fasting carbohydrate oxidation, decreased glucose tolerance, blunted daily profile in free cortisol concentrations and decreased thermal effect of food..”[ref]

One more example from a 2017 clinical trial that looked at the timing of meals in healthy 18-22-year-olds: “These results provide evidence that the consumption of food during the circadian evening and/or night, independent of more traditional risk factors such as amount or content of food intake and activity level, plays an important role in body composition.”[ref]

Finally, let’s sum this up with the first sentence from a study on circadian misalignment and glucose tolerance. “Glucose tolerance is lower in the evening and at night than in the morning.” Yes, the study goes on to quantify this as being 17% lower glucose tolerance at 8 pm vs 8 am.[ref]

Lifehacks:
The simple solution is to eat earlier in the day and to not snack at night. This is easier said than done, for some of us. So make a plan for your meals for a few days. Yes, actually sit down with a pencil and paper and come up with ideas for shifting your calories to the morning hours. If you are a habitual TV watcher at night (with a subsequent bowl of popcorn and a beer), plan out a couple of evening activities to get you out of the house for a few evenings while you break the snacking habit. Perhaps go for a walk, go see a movie and avoid the overpriced snacks, or dust off your bowling shoes for a quick game.

While this all may sound a bit cut-and-dried, we really are flexible creatures, able to withstand periodically eating at different times without drastic effects. The bigger picture is the chronic effects of eating at the wrong time, rather than just the one-off change up of our daily eating habits. So don’t beat yourself up if you nibble on something at an evening event. Just get back on track for the rest of the week.


#2: Light Exposure

Light is also important to weight gain.  While it seems strange to think about, again the research on this topic seems to point to an incontrovertible conclusion that light – both bright light exposure in the daytime and no light exposure at night – makes a significant difference to our weight.

Science-y Stuff about light and the Circadian Clock:
In Circadian Rhythm Connections, Part 1: Mood Disorders, I explained how light at a specific wavelength (~480nm, blue light) hits melanopsin containing photoreceptors in our eyes, signaling to our core circadian genes (CLOCK, BMAL1) in the brain that it is daytime.

Our body has both the strong central circadian clock in the suprachiasmatic nucleus in the brain as well as what are known as peripheral clocks in our organs. These peripheral clocks include the timing of functions in the liver, pancreas, etc.

The core clock genes are mainly entrained through the cycle of light and darkness, while the peripheral clock in the liver is more quickly reset, or entrained, by food intake. But the core clock genes do still affect the peripheral clocks.

The core circadian clock is located in a region of the hypothalamus called the suprachiasmatic nucleus (SCN).  The SCN signals to the adrenal system to increase adrenal glucocorticoids (e.g. cortisol is a glucocorticoid hormone) production just prior to waking. “This promotes arousal and alertness by enhancing liver gluconeogenesis (from amino acids and fatty acids), promoting the release of liver glucose to the blood, and increasing its uptake in the brain and muscles. Adrenal glucocorticoids have been implicated as a peripheral humoral cue for the entrainment of oscillators such as the liver.” [ref]  The SCN also controls the circadian rhythm of the hormones insulin, glucagon, and adrenalin.

That may sound like science mumbo-jumbo, but it has practical implications. For people waking up at 3:30 or 4:00 am every night, this could be caused by the circadian spike in cortisol levels. Personally, I used to see 4:00 am on the clock quite often. Blocking blue light in the evenings, going to be at a reasonable hour, and cutting out snacking after dinner has eliminated the 4 am wake-up for me.

Weight gain and light at night:
Again, animal studies for efficiently producing more meat show us a lot. Chickens have been studied under different lighting conditions for many decades to determine the quickest way to have plump chickens. One study found that chickens exposed to specific wavelengths of light (450-630nm) pack on the pounds better when exposed to the light from 8 am until midnight. The study also notes that poultry workers are adversely affected by blue or green wavelengths of light at night and thus suggests using light in the yellow wavelengths is almost as effective for chicken fattening.[ref]

What does light at night do to people? Shift work is a very well-studied risk factor for obesity. One study of rotating shift workers (Canadian men) found a 57% increase in the risk of obesity.[ref] Another study of shift workers (Korean women) found a 63% increased risk of obesity.[ref] Numerous other studies have similar results.

You may be thinking that all those shift workers are eating bags of Doritos all night long. Perhaps. But even a dim light at night has been linked to weight gain in animal studies that control for the number of calories eaten.[ref] Another mouse study looked at the effects of dim light at night (5 to 15 lux – similar to a night light) and found that mice fed the same number of calories gained weight when exposed to either dim or bright light at night.[ref]

Dim light at night was shown in a study to affect human weight as well. A large study looked at the amount of light in a bedroom at night and correlated higher light amounts to higher BMIs.[ref] Other studies have repeatedly shown the same results.[ref]

Lifehacks:
Solving this problem is as simple as shutting off that night light, getting some blackout curtains, and eliminating all the glowing LEDs from chargers in your bedroom.

Not enough light during the daytime:
Our modern world of cubicles and working indoors also affects our waistlines. Studies show that more light during the day — specifically outdoor light during the morning hours — is linked to weight loss.[ref]  One study that tracked people’s light exposure concluded “having a majority of the average daily light exposure above 500 lux (MLiT500) earlier in the day was associated with a lower BMI.”[ref] A study of people in the northern latitudes during the winter found that bright light therapy in the morning increased weight loss and suppressed appetite. [ref]

Lifehacks:
Make getting outside during the morning a priority. Drink your coffee on the porch, walk or bike to work, take a morning break outside, and eat lunch outside if possible.


#3: Sleep

Sleep is something that every health guru out there puts on their lists of “Top 5 ways to improve blah, blah, blah.” But does it really affect our weight and metabolism that much? Is the benefit worth the trade-off – e.g. is it worth going to bed before 11:00 each night rather than staying up late, having fun with friends or working long hours? Quick answer: Yep. Research shows that it really does make a significant difference.

Fun facts: The average amount of sleep per night has decreased by about 1.5 hours over the last century.[ref] And the recommended amount of sleep for children has decreased by over an hour from 1897 to today.[ref]

Not-so-fun fact: A meta-study of 75,000+ people found that sleeping 5 hours per night or less increased the risk of having metabolic syndrome (e.g. high blood pressure, high blood sugar, overweight) by over 50%. To not have an increased risk of metabolic syndrome, participants had to be sleeping over seven hours a night.[ref]

A 15-day in-patient study looked at the effect of 5 days of insufficient sleep, mimicking the effects of not sleeping enough during the work week.  The study found that insufficient sleep caused greater energy expenditure, but that extra energy expenditure was offset with greater food intake. After the two week trial, participants had gained almost 2 lbs. Women were more likely to be affected by weight gain than men.  (Impact of insufficient sleep on total daily energy expenditure, food intake, and weight gain)  Another larger study had similar findings, with additional results showing that African Americans gained slightly more weight than Caucasians with sleep insufficiency.[ref]

Another study looked at sleep insufficiency (5 hours/night of sleep) and found that insulin sensitivity decreased and inflammatory markers increased.[ref] 

Sleep timing also matters.  A study looked at the average sleeping time (over a week-long time period) and BMI.  The results showed that those who were late sleepers (defined as the midpoint of sleep being after 5:30 am) had an average higher BMI and a greater percentage of calories eaten after 8 pm.[ref]

So that was just three studies; there are hundreds of more studies on this topic showing similar results. The science is clear and unambiguous on this topic.

Why sleep is important to our metabolism:
There are several players involve here, with melatonin being an important one.  Melatonin, a hormone that rises and peaks at night while we sleep, is important to our basal metabolism for a couple of reasons that I will go into below. Light at ~480nm (blue wavelength of light) hitting the retina of our eye stops melatonin production. It is surprisingly quick, with 15 seconds of light stopping melatonin production for over 30 minutes and two minutes of blue light suppressing melatonin for more than 45 minutes.[ref] Thus, turning on the bathroom light in the middle of the night means it will take a long time to fall back to sleep.

Thyroid and basal metabolic rate:
What is melatonin doing at night while we sleep? Among other things (like acting as an antioxidant), melatonin modulates the secretion of leptin, the hunger hormone.  There are also melatonin receptors that regulate the synthesis and secretion of thyroid hormones. “During long photoperiods, higher levels of TSHβ and DIO2 favors the conversion of thyroxin (T4) to triiodothyronine (T3), increasing energy expenditure and basal metabolic rate. Lower, short-photoperiod levels of TSHβ promote dominant DIO3 activity, which convert T4 to both inactive reverse T3 and diiodothyronine T2, increasing food intake and adipose deposits” [ref]

Glucose metabolism and insulin resistance:
First, let’s take a look at a 2003 study that just kind of makes logical sense.  The study looked at medical students who were ‘nocturnal’ – e.g. staying up until 1:30 am and sleeping in until 8:30 am – vs. those who were ‘diurnal’, which would be going to bed well before midnight and getting up when it is light.  The nocturnal med students skipped breakfast and ate more of their calories later at night. This caused glucose impairment as well as decreased melatonin and leptin secretion.

It has been known for decades that people are more insulin sensitive in the morning (again why we shouldn’t eat a big meal at night).[ref] Another study states: “Multiple studies have shown that in healthy humans, both insulin sensitivity and beta-cell responsivity to glucose are lower at dinner than at breakfast”. It goes on to explain that mouse models show that deleting one of the core clock genes (BMAL1) in the pancreas causes insulin resistance.[Multiple studies have shown that in healthy humans, both insulin sensitivity and beta-cell responsivity to glucose are lower at dinner than at breakfast] Circadian disruption is intimately coupled with poor glucose metabolism and insulin resistance.

Lifehacks:
Blue light at night effectively shuts down melatonin production, so you need to block all blue wavelengths for a couple of hours before bed.  You may be thinking… “ha! I don’t need to wear silly looking blue-blocking glasses because I have night shift enabled on my phone/tablet.”  Well, it turns out that researchers studied the night shift mode at a couple of different settings, and it did very little to prevent melatonin production from being suppressed.  So either (shock face!) put away electronic devices a couple hours before bed or get a pair of blue-blocking glasses.

It takes a couple of weeks to get your body’s melatonin production up to optimal after you start blocking blue light at night.  In the meantime, you could increase your consumption of foods that contain melatonin. Foods high in melatonin include tart cherries, grapes, and almonds. Interestingly, melatonin levels fluctuate in plants as well, so the time of harvest, season, and other environmental conditions may affect the levels found in plants.

Why not take a melatonin pill instead of blocking blue light at night? Well, your body’s production of melatonin (without unnatural light) is a bell-shaped curve. Taking a pill gives you a big dose immediately that then gets metabolized and eliminated. Most people are better off with increasing their natural production of melatonin.


#4: What to eat, when

The liver coordinates our metabolism through the synthesis of lipids from carbohydrates and storage of both fats and carbs as glycogen.  The liver’s peripheral circadian clock is powered by both the SCN (core clock) and by feeding timing. CLOCK and BMAL1 genes are thus involved in the rhythm of glucose metabolism and release.

What does this mean? Our body is primed to break things down (metabolize) better at different times of the day. This applies to everything coming into the liver – from foods that we eat to toxins we are exposed to. Here are a couple of studies on food as examples:

A study of 93 overweight women looked at the effects of either a higher calorie breakfast or a higher calorie dinner over a 12-week diet plan.  The results showed that those eating the higher calories at breakfast lost 2.5 times the amount of weight as the high dinner group.  The higher calorie breakfast group also had a decrease in triglycerides by 33% compared with the high-calorie dinner group which had an increase in triglycerides.

A mouse study found that mice given glucose during their rest period gained more weight than mice given the same amount of glucose during their active period. [ref]

Generally, we can sum it up as glucose metabolism is best in the morning.[ref] It makes sense, then, if you are eating a mixed diet of carbs, proteins, and fats to shift your carb intake towards the morning hours and eat fewer carbs at your evening meal. This is even more evident in studies of people who already have impaired glucose tolerance. One study looked at the differences between high fat in the morning and high carb in the evening or the reverse (high carb morning/high fat dinner). It found that the high fat morning/high carb dinner “shows an unfavourable effect on glycaemic control” especially in those with already impaired glucose tolerance. “Consequently, large, carbohydrate-rich dinners should be avoided, primarily by subjects with impaired glucose metabolism.”[ref]

What about time-restricted eating?
Time restricted eating (TRE) is a concept whereby people eat all of their daily calories within a specific window of time.  There have been several good animal studies showing that eating the same number of calories during a restricted feeding window (8 hrs to 10 hrs) causes mice to weigh less than the control groups that are eating the same number of calories spread throughout the 24 hour day.  It can also reverse the progression of metabolic diseases such as type-2 diabetes.[ref][ref]

What time of the day should you do TRE?
A time-restricted feeding study for an 8 week period had participants eating their normal amount of calories during a 4-hour window in the evening (5 – 9 pm). Participants did lose a little weight, but they also had increased fasting blood glucose levels and impaired glucose tolerance.[ref] This seems to indicate that a time restricted feeding plan at any time does work to reduce weight, but the feeding window needs to be earlier in the day so as to not impair glucose tolerance.

TRE doesn’t have to be nearly as strict as a four-hour eating window to be effective.  A study of overweight individuals who normally had a 14-hour eating window found that reducing their eating window to 10-11 hours caused them to lose about 7lbs over 16 weeks. This was maintained over the next 12 months.[ref]

A cross-over study had participants eat their first meal of the day either a half hour after waking or 5.5 hours after waking. One of the findings was that PER2 expression was delayed by about an hour when the people shifted their mealtime later in the day. Another finding was that glucose levels remained high in those eating late.[ref]

Lifehacks:
The research really is good on the effectiveness of a time-restricted eating program. If you are the type of person likes experimenting and who needs to set some rules for yourself, try a TRE program. Example: eat a good breakfast at 7:30 before heading out the door to work; lunch around noon; and then finish up with a light meal around 6:30 pm. This gives you an 11-hour eating window. Simple. And shown to be effective.


#5: Genetics

Of course, I have to talk about genetics here. We are all different, and our genes play a role in our natural circadian rhythm. I’ve written other articles on this topic as well, so I won’t go too in depth here.

The most obvious example of genes affecting our circadian rhythm and our propensity to gain weight is the aptly named CLOCK (Circadian Locomotor Output Cycles Kaput) gene. This is one of our core circadian genes, setting the daily rhythms for the rest of our body.

One well-studied variant of the CLOCK gene is known as 3111T/C or rs1801260. Those who carry the TT (AA for 23andMe orientation) genotype have the normal type, while those who carry a C (G for 23andMe orientation) allele (CC or CT) are thought to have higher expression of the CLOCK gene and of PER2. Those with CC or CT are more likely to be obese, and in a clinical trial, they lost 23% less weight than those with TT on the same type of diet. [ref]

A small trial with 40 middle-aged women (half were TT, half were CT or CC) found that those who carried the C allele lost less weight (about 7lbs less) and also woke up ~30 minutes later in the morning.  They also ate breakfast about an hour later than those with TT.   Additionally, the study looked at heart rate variability and several markers of autonomic nervous system function.  It found that “As compared with TT carriers, risk allele C carriers had a reduction of 34–57% in the daily rhythm amplitude of parasympathetic activity…” The C allele carriers had reduced parasympathetic tone during the night and increased parasympathetic tone during the day.  Think of it as an overall flattened sine wave.  The study also found that those with a higher amplitude (think taller sine wave graph) of parasympathetic tone had greater weight loss during the 30-week study.[ref]

Overall, the CLOCK gene variant leads to an ‘evening’ chronotype. Bipolar patients carrying the C allele are, on average, likely to stay up 79 minutes later at night and sleep less on average as well.[ref]  Bariatric surgery patients who carry the variant are more likely to be evening types and also to lose less weight than those without the variant. [ref]

Another study of this variant showed that morning gastric motility may be slower in C allele carriers. Variant carriers also had somewhat lower morning diastolic blood pressure.[ref] This may play a role in timing for breakfast, with C allele carriers perhaps wanting to eat breakfast an hour or two later.

Lifehacks:
Around 30 – 40 percent of the population carries this CLOCK gene variant. For these people, it may be even more important to watch your blue-light exposure at night so that you aren’t fighting a lack of melatonin alongside your natural propensity for staying up a little later. Get into a good routine for getting to bed at a reasonable hour, and, if possible, shift your morning work schedule a little later to allow you to get enough sleep. Yes, I know that is easier said than done. While you may not be the person who wants to get up at 6:30 am, this variant is more of an hour or two shift rather than an ‘I should sleep in until noon’ excuse.

 

More to read:

 

 

 

Growing up ‘big boned’: MC4R gene and obesity

There are several key players in our body’s regulation of hunger, satiety, and energy expenditure. Leptin and ghrelin are two pivotal hormones involved in our desire to eat. Within that leptin pathway, another key regulator of our body weight is MC4R.

This explanation is going to get a bit complicated, so for all of you impatient people:  Jump ahead to check your genes for MC4R variants.

Within our brains is a region of the hypothalamus called the arcuate nucleus. This cluster of nerve cells has several important functions including controlling appetite.

Leptin is a hormone that is released when you have eaten; it is the satiety hormone.

After a while, when leptin levels fall, ghrelin is released to signal that you need to eat; it is the hunger hormone.

Along that leptin signaling pathway is the MC4R receptor, which is part of transmitting the signal into the neuronal cells.

So the normal way things work is that you eat, you’re full for a while, and then your body signals that you should eat again.

Why, then, would anyone eat more than their body needs? Along the way, that natural cascade of reactions can go awry in several ways: leptin receptor gene variants cause the signal from leptin not to be heard; ghrelin, the hunger hormone, can be increased; or within the hypothalamus, the melanocortin-4 receptors (MC4R) can be genetically impaired. (Yes, there are many other players here as well. One interesting example is a mother’s diet can play an epigenetic role in obesity in their offspring: Agouti mouse study.)

There are hundreds of research studies on the genetic variants of MC4R, and most of the variants studied show a decrease in MC4R, resulting in increased BMI.  If there aren’t enough of the receptors generated by the cell, then the ‘stop eating’ signal can be impaired. Thyroid hormone levels also play a role in how much MC4R is produced. [ref]

Digging a little deeper, the melanocortin-4 receptor (MC4R gene) is a receptor that binds to a hormone called α-MSH, which is a melanocyte-stimulating hormone. α-MSH binding to the MC4R receptor gets the ‘full signal’ through. Another molecule called the agouti-signaling peptide also can bind to the MC4R receptor, blocking it from binding with α-MSH. The agouti-signaling peptide can be thought of as an ‘off switch’, with α-MSH being the ‘on switch’.

MC4R deficiency is not only tied to increased appetite and higher BMI throughout life, but it is also tied to greater muscle mass as well. In my mind, the term ‘big boned’ leaps to mind, which is backed up by studies showing the relation to bone mass, fat mass, and the MC4R variants.[ref][ref]

Note that I said above that some MC4R variants are tied to higher BMI throughout life. A study looked at infants carrying the MC4R variant and found no differences in birthweight based on the variant, but by 2 weeks of age, they could detect a difference in BMI and appetite.[ref]

An interesting aside: α-MSH does more than just bind to the MC4R receptor and moderate feeding, it also stimulates the production of pigment (melanin) in hair and skin. The agouti-related peptide also plays a role in pigmentation and is named for the agouti coloring of animal coats. α-MSH is derived from the POMC hormone, which is a pituitary gland hormone that is the precursor to ACTH and other MSH’s.  There are other melanocortin-receptors as well: MC1R is the receptor controlling hair color, which genetic variants of MC1R producing red hair.


MC4R genetic variations:

Below are some of the better studied MC4R variants along with a few of the studies about them.  There are quite a few additional studies, so please do more research if you are interested in this topic.

Keep in mind that, as with most genetic variants, the variants listed below do not necessarily mean that a person will become obese. Everyone has lots of different genetic variants that interact differently with diet and environment. Epigenetics, the turning off and on of genes, also plays a role here.

Check your 23andme results for rs17782313  (v.4 and v. 5):

  • CC: risk of increased BMI in both children and adults[ref][ref][ref]
  • CT: risk of increased BMI in both children and adults
  • TT: normal

23andMe results for rs17700633  (v.4 and v. 5):

  • AA: risk of increased BMI, obesity[ref][ref][ref]
  • AG: risk of increased BMI, obesity
  • GG: normal

Check your 23andMe results for rs12970134 (v.4 and v. 5):

  • AA: risk of increased BMI, increased waist circumference[ref][ref][ref]
  • AG: risk of increased BMI, increased waist circumference
  • GG: normal

Check your 23andMe results for rs571312 (v.4 and v. 5):

  • TT: risk of increased BMI [ref][ref] [ref]
  • GT: risk of increased BMI
  • GG: normal

Just as genetic variants can cause a deficiency in MC4R, other variants can cause a more active version of the gene that protects against obesity.

Check your 23andMe results for rs2229616  (v.4 and v. 5):

  • TT: protective against obesity[ref][ref]
  • CT: protective against obesity
  • CC: normal

Lifehacks:

What do you do if you are overweight and carry the MC4R variants? That seems to be the million dollar question – quite literally, for the pharmaceutical company that figures out the answer.  There is, of course, great interest in finding a way to increase the activation of the receptor. Here is one company that is currently in clinical trials for a prescription medication option.

Activity: In studies of MC4R genetic variants in childhood obesity, it was found that activity offset the propensity towards higher BMI. In other words, more active children with the variant were less likely to be obese than sedentary children with the variant.[ref] While I can see some of you mentally saying ‘duh’, the point is that while some kids can be sedentary and thin, not everyone is made that way. So this is one more reason for encouraging (not nagging or bullying) kids to be more active.

Mold: α-MSH binds to and activates the MC4R receptor. It makes sense that you would want plentiful α-MSH to bind to the MC4R receptors. Reduced α-MSH production is found in mold illness, and mold illness is often linked to weight gain.  The Surviving Mold website has an explanation of the proposed mechanism.  Make sure your home is not water damaged with mold growth.

BPA: The other side of the equation is Agouti signaling protein, the “off” switch for MC4R, which isn’t good when it comes to obesity. Studies in mice show that BPA exposure increases agouti-signaling protein, changing coat color and increasing weight.[ref]  If you haven’t read about Agouti mice studies before, the article Obesity, Epigenetics, and Gene Regulation is a great introduction and explains how epigenetics altered mice offspring causing a change in hair color and obesity. The article points to BPA in plastic bottles as being a trigger to produce obese yellow mice.

Protein: One study found that those with an MC4R deficient variant had better weight loss results on a low protein instead of a high protein diet (with no difference found for carbs and fat variation). This contradicts most weight loss studies that show higher protein levels leading to satiety, but I included it here in case it works for you.

Blame your mom: Several studies point to the influence of maternal diet in the regulation of MC4R and obesity. Maternal BPA consumption and fat consumption both downregulate MC4R. [ref]  (Blaming your mom does no good…  so if my kids are reading this, stop blaming me :-)

So you may have noticed that my “Lifehacks” are pretty slim for this gene.  I’m hoping that some of this background information will help you to look into this more and come up with your own action steps, because, frankly, other than not feeding babies from  BPA-containing plastic baby bottles and not living in a moldy house, I don’t really have a nutrition plan to work around the MC4R variants.

More to read:

Hacking BDNF for weight loss (Patreon only)

Brain-derived neurotrophic factor (BDNF) is a fascinating growth hormone that does a lot in our brains.
So what does BDNF do? Quite a bit! It is involved in supporting neurons and neuronal growth in the brain; it also plays a role in long-term memory and in obesity.
Why focus on obesity when everyone knows that fat people are lazy and eat too much? It turns out that our genes may play a larger role in obesity that a lot of people want to concede.
Sidetrack to talk about genetics and weight:
A study of over 10000 twins in the UK found that BMI and waist circumference are highly heritable (77%), with a smaller environmental effect (e.g. sedentary, food choices, sleep) in children.[
study] Other, even larger twin studies, have also shown a large genetic component to weight.[study]
So while genetics is undoubtedly involved in obesity, personal choice comes in to play also. Obviously, cutting down on junk food and French fries is important. Additionally, taking the responsibility for understanding and working with your own genetics is another personal choice. Instead of blaming genetics, take an active role in learning and understanding the influence and role that it plays in your own personal biochemistry.
Back to BDNF and obesity: Mouse studies have shown that not enough BDNF in the hippocampus causes ‘hyperphagic behavior’, which is a fancy way of saying that they were driven to overeat.[study] (Like when you aren’t really hungry but start munching on some Doritos and then the bag is suddenly half empty – hyperphagic behavior.) Mouse studies also show that increased or overexpression of BDNF in the hypothalamus increases the conversion of white fat to brown fat. Brown fat increases energy metabolism, and mice with more BDNF stay lean.[study]

Genetic variants:

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Leptin Receptors: Genetics and Hunger

Ever wished your body could just naturally know that it has had enough food and turn off the cravings for donuts or Doritos? Your body is actually supposed to work that way.

Leptin, a hormone produced mainly by fat cells, signals to the hypothalamus in the brain that you have enough stored energy. 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, thus lowering your metabolic rate. One way that this happens is through leptin signaling in the hypothalamus to decrease thyroid hormone levels.

Leptin resistance is when your brain stops getting the signal that you are at the right level of stored energy. For people who are overweight or obese, there is usually plenty of leptin being produced in the fat cells, but the leptin signal is not being received. Obese people usually produce more leptin than lean people. There is a small percentage of people who are overweight because they don’t produce enough leptin, but that is a fairly rare phenomenon.[ref]

Leptin resistance is still considered a theory, and there have been several recent studies that contradict that model. Last year, a study from the University of Cincinnati found: “…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]


Genetic variants of LEPR gene:

Leptin receptors (LEPR) are a transmembrane-domain receptor, and deficiencies in leptin receptors are associated with 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; 50% 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. (But wait, that is actually true…  In the US, 68% of the population is now considered overweight or obese.[ref]  But genetics is just one piece of a huge obesity puzzle.)

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

  • AA: normal
  • AG: increased risk of obesity, diabetes
  • GG: increased risk of obesity, 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 (13 kg) in women with GG on antipsychotics [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]

 

 

Metabolism, obesity, inflammation… hacking your endocannabinoid system for weight loss (Patrons only)

Cannabis and marijuana may be the first thing that comes to mind when learning about the body’s cannabinoid receptors.  And yes, cannabis acts upon the receptors, activating them and causing the pleasant effects on mood as well as the increase in appetite. But there is a lot more to this system’s role in our body than the effects of marijuana.

This article looks at the role of cannabinoid receptors in the body, focusing on the role that endocannabinoids and their receptors play in metabolism, inflammation, and obesity. We will look at genetic variants that increase the risk of obesity, and then investigate a few options for mitigating the risk.

The rest of this article is available to patrons-only through Patreon.  I appreciate your support!

Weight Loss: Optimizing your diet based on your genes

Diet gurus, talking heads on TV, government food pyramids, and your friend who lost 20 pounds…

What do they all have in common?  They all know the perfect diet that will whip you into shape and make you feel good.

If that diet doesn’t work for you?  Well, you must have been cheating. You didn’t eat clean enough.  You didn’t stick it out through the ‘keto flu’ long enough….

It must be all your fault that you are failing on their perfect diet.
Or is it?  We all accept and embrace our differences when it comes to skin color, hair color, etc — different phenotypes based on our gene expression.  It is time for everyone to realize that we are all different when it comes to diet and weight loss as well.

Table of Contents:
The Very Basics
Circadian Foundation
Matching your genes to current diet trends
Genes Related to Weight Gain
The Gut Microbiome Influences Weight
Final Thoughts


The Very Basics

I’m assuming that most people reading this already have the basics in place:  eating healthy food, organic when possible, and not smoking or drinking alcohol in excess.  If you are eating a PopTart for breakfast and washing it down with Mountain Dew, well…    back up and start off by getting rid of the processed junk food.

Why get rid of junk food?  I think most of us have a sense that the preservatives, additives, colorings, and unrecognizable words on the ingredients list are probably not all that healthy. One thing that you may not have considered, though, is the impact of emulsifiers and surfactants in foods. Recent studies have looked at the effects of some substances, such as cellulose and polysorbate 80, which are used as emulsifiers to change the texture of foods. They found that these food additives, which are considered safe by the FDA, change the mucosal barrier in the intestines, allowing bacteria closer contact with the surface of our intestinal cells, leading to irritation/ inflammation. This leads to weight gain without increased food intake, and for some, an increased risk of IBD.  Read through the following article to check to see if your genes put you at a higher risk for having problems with emulsifiers in foods:  Microbiome Microbiome + Genetics + Emulsifiers = Obesity

Building the platform for good health
Most people want to lose weight to ‘get healthy’. We are inundated with stories on the horrible health consequences of being overweight, accompanied by photos of protruding bellies and people eating giant burgers. Being overweight causes cancer, diabetes, heart attacks… and well, it is just generally loathed because fat people are smelly slobs with no common sense or self-control. Right? Well, maybe not. For example, read up on the ‘obesity paradox’, where large studies (~250,000 people) have shown that mortality rates are lower for those who are overweight. It is a U shaped curve for mortality after heart attacks, where those who are overweight are least likely to die and those who are underweight or morbidly obese being at the highest risk for death.[study]

Perhaps we are all looking at weight loss backward. Instead of losing weight to get healthy, we should get healthy and then naturally lose weight. We can look at being overweight or obese as a symptom of the wrong diet and lifestyle for our genes, with finding our own genetically correct diet and lifestyle as the way to get to get healthy first.


Circadian Foundation

Fundamental to health for everyone is good sleep and a healthy circadian rhythm.

Don’t stop reading here! Even if you are thinking, “I sleep ok”, please read on.

Circadian rhythms — biological activities tied to the 24-hour cycle of light and dark — are something that we all recognize in animals and plants. We all know that there are nocturnal animals and insects, and we’ve all seen the cool time-lapse videos of flowers opening in the day and closing at night. But somehow it seems to escape us that circadian rhythms, fundamental to all life forms, apply to humans. They are foundational to our biology and our health.

Thomas Edison invented the lightbulb in the late 1800’s, and cities began lighting up at night just over 100 years ago. Prior to that, humans only had light from fire (candle, oil lamps) in the evenings, which emit a yellow/red shifted light. More recently, color TV’s came into everyone’s living room by the ’80s, computers in the ’90s, and then we all got laptops, smartphones, and tablets in the 2000’s. Edison’s incandescent bulb, with its warm yellow light, went by the wayside with the introduction of the CFL bulb and subsequent leap to LED bulbs.

Light at night disrupts our circadian rhythm, which makes sense when you think about it. But the bigger problem came with the TV, computer, cell phones, and CFL/LED bulbs. They all produce a lot of light in the shorter, blue wavelengths (~480 nm), which is the wavelength that signals through receptors in our retina to set our circadian clocks. For the thousands of years before electricity, our bodies’ exposure to blue wavelengths came each day when the sun came up in the morning. Now blue wavelengths are inundating us late into the night, making our body think that it is still mornings.

Before anything else for our health, we need strong circadian rhythms with melatonin onset in the evening when the sun goes down and sunlight hitting our eye in the morning as the sun comes back up.

There is a ton of research coming out about the health effects of messing with our circadian rhythm, and the Nobel Prize was just given for the discovery of the circadian clock genes.

Why am I going on and on about this for a weight loss article? Studies show that low levels of light at night (like from a night light or street lights shining through the window) cause mice to gain fat compared to mice eating the exact same amount of calories but with dark at night. Weight gain due to light at night is backed up by many studies of people working late shifts. Other circadian rhythm disruption consequences include increased risks of cancers, heart disease, and diabetes (yep, same health risk list as above for obesity).

Genetically, some of us are more sensitive to disruptions of circadian rhythms and melatonin production than others. Some people are a double the risk of diabetes from a melatonin receptor variant, and that risk can be mitigated through the timing of meals and, perhaps, blocking blue light at night. Read through my Melatonin and Circadian Rhythms articles to check your genes for higher susceptibility to circadian disruption: Color TV has made us fat: Melatonin, Genetics, and Light at Night and Circadian Rhythms: Genes at the Core of Our Internal Clocks

Even if you aren’t at a higher risk genetically, blocking blue light in the evening with blue-blocking glasses will benefit everyone from a health standpoint. From all the research studies that I’ve read, the biggest thing that we can do for our health (other than not smoking or excess alcohol) is to get our circadian rhythms on track by blocking blue light for two or three hours before bed, sleeping in the dark, and getting outside in the morning to see the sun.


Matching Your Genes to Current Diet Trends:

If you are looking at current diet trends to give you some ‘rules’ to follow, you may be reading up on Paleo, ketogenic, intermittent fasting, Mediterranean, vegan, juice fasts, and detox cleanses.

How do your genes play a role in which diet to choose? Well, they actually may play more of a role in which diet to eliminate…

Saturated fat consumption is tied to increased risk of heart disease for people with certain genetic variants. So a diet high in saturated fat, such as Paleo or keto, might not be a great long-term solution for some people depending on their genes. Read Saturated Fat and Your Genes and check your genetic data to see if you are at risk.

Fasting or a ketogenic diet is counter-indicated for people carrying genetic mutations that decrease their ability to burn fatty acids for energy. Check out Short Chain Acyl-CoA Dehydrogenase Deficiency and Medium Chain Acyl-CoA Dehydrogenase Deficiency to see if you carry one of those mutations.

Some people are genetically better at breaking down carbs than others. Amylase is the enzyme your body produces to break down starches, and we vary genetically in the amount of amylase that we produce. Read through Digesting Carbohydrates: Amylase Variants to determine if you are a high or low amylase producer. This plays more of a role in whether you are likely to regain weight rather than in initial weight loss.

Carbohydrates play a role in blood glucose levels as well, and this is modified by your genetic variants. A Paleo diet which is low in carbohydrates may work well for someone who has a higher insulin reaction to carbs. Check out your likely reaction to carbs in Carbohydrate metabolism: Your genes play a role in insulin and blood glucose levels

When you eat may be more important than what you eat. If you are considering Intermittent Fasting (or really, any diet), you should check on your melatonin receptor genetic variants. Melatonin interacts with insulin release and overnight blood glucose levels, and some people are at a higher risk of diabetes if they eat later in the evening. Read Color TV has made us fat: melatonin, genetics, and light at night.

Clean eating may be a key for those who have problems with detoxifying endocrine disruptors, which can lead to weight gain. Check out BPA: Genetics and Detoxification and Detoxifying Phthalates: Genes and Diet.


Genes related to weight gain

There isn’t one smoking gun ‘fat gene’ that makes people gain weight, with a few rare exceptions. But there are a lot of minor players in the field of genetics and obesity. Quite a few different genes have been found to correlate to an increase in BMI of say a half to one or two points. Knowing how you are genetically predisposed to weighing a little more may help you find a diet that works for you.

FTO genetic variants have been linked in many studies to an increased risk of obesity. Check your FTO variants and read about the possible lifestyle and diet solutions.

MC4R is a gene involved in regulation of appetite and metabolism. Variants in the gene have been linked to a higher risk of obesity and metabolic dysfunction.  Read more and check your genetic variants in the article Obesity Genes: MC4R.

Our cannabinoid receptors are involved in more than just getting high on cannabis.  Some people have more active cannabis receptors which have been linked to increased appetite and weight gain.  I think of it as a minor case of the munchies.  Check your cannabinoid receptors: Cannabinoid receptors, metabolism, inflammation, and obesity.


The Gut Microbiome Influence Weight

There have been several studies showing the influence of the gut microbiome on weight. The most intriguing studies have shown that transplanting the fecal microbiome from an obese mouse to a normal weight mouse will make the normal mouse become obese.

How can you know if your gut microbiome is to blame? You could do a test through a service like uBiome. They can tell you how your microbiome compares to other people’s samples, but they can’t give you a miracle probiotic pill to change anything.

Your genes also play a role in your gut microbiome, influencing which bacteria are likely to thrive there. Bifidobacteria strains have been associated with a reduced risk for obesity.
Read more: How our genes shape our gut microbiome and our weight


Final Thoughts

For almost all of us, gaining too much weight isn’t something that has just one cause. Thus, losing weight may need multiple solutions applied together.  Focusing first on health may bring about the weight changes naturally.

Getting the foundation down through blocking blue light in the evening, thus increasing melatonin synthesis and regulating circadian rhythm, will help with many aspects of health including weight loss.

Prioritize the rest — whether to remove toxins, go on a ketogenic diet, or try intermittent fasting — based on your genetics.

Finally, ensure that your gut microbiome is healthy and not adding to your weight problems.

Circadian Rhythms: Genes at the Core of Our Internal Clocks

Circadian rhythms are the natural biological rhythms that shape our biology.  Most people know about the master clock in our brain that keeps us on a wake-sleep cycle over 24 hours.  This is driven by our master “clock’ genes.

It turns out that we also have circadian cycles (peripheral clocks) in most organs such as the liver, pancreas, and fat cells. These peripheral rhythms drive cyclical production of proteins in our organs. One example of why this is important is the research being done on the timing of chemotherapy drugs based on the circadian rhythm of enzymes produced in the liver. [study]

Not to be left out, our gut microbiome also has a circadian rhythm, and disruption of our circadian rhythm can disrupt the microbial rhythm. [study]

Getting a little Geeky…
There is some pretty cool terminology involved in chronobiology (a nifty term for the study of biological rhythms) that you will want to be familiar with before digging into the research papers on the topic.  The part of the hypothalamus that controls the central clock is called the “suprachiasmatic nucleus” (SCN), which sounds a little sci-fi to me.  And the external environmental inputs, like the time the sun rises or lights at night, are known as zeitgebers.  Some things are named more predictably, like one gene controlling circadian rhythms which is called the CLOCK gene ( an acronym for Circadian Locomotor Output Cycles Kaput).

It is probably not a big surprise that our core circadian rhythm is set by sunlight since night/day rhythms can be seen in all animals.  In a nutshell, light from the sun in the short, blue wavelengths hits receptors in the eye (intrinsic photosensitive retinal ganglion cells) which signals to the suprachiasmatic nucleus synchronizing the circadian 24-hour cycle.

There are two factors that can mess up our circadian rhythms:  light at night (specifically, blue wavelengths ~450-480nm) and lack of sunlight in the morning.  Add to that the individual genetic variants that affect our clock gene functions and you can begin see the importance of this topic.

So what happens when our circadian rhythms go askew?  The effects can be far ranging and include increased risk for the following: diabetes, cardiovascular disease, certain cancers, mood disorders, and obesity.  The amount of scientific research coming out on the topic in the past few years is astounding.  While not talked about much in the mainstream press, the evidence is strong enough that in 2007 the IARC (cancer research arm of the World Health Organization) listed chronic exposure to light at night as a possible carcinogen.

Quick Recap:
Circadian rhythm is at the base of good health.
Blue wavelengths set circadian rhythm.
Sunlight in the morning is good; blue light in evening alters the circadian system.

Genetic Variants in Clock Genes:

The CLOCK and BMAL1 (ARNTL) genes are the core clock genes that target and turn on other genes. They are regulated and turned off by rising levels of the cryptochromes, CRY1 and CRY2,  and the period genes, PER1, PER2, and PER3.[ref]  This forms the daily feedback loop of rising CLOCK and BMAL1 that are then inhibited by rising levels of CRY and PER giving a 24-hour rhythm.

CLOCK gene variants:

One well-studied variant of CLOCK is rs1801260 (G is the minor allele for 23andMe orientation, also known as 3111T/C ) with quite a variety of effects:

  • Carriers of the G allele have higher activity in the evening, delayed sleep onset, and less overall sleep time on average.  [ref][ref]
  • A 2016 study looked at body temperature changes, activity and position in a group of women based on carriers of the G allele. They found that those with the minor allele had higher evening activity, and different body temperature variations over a day leading to a conclusion of ‘less robust circadian rhythm’.  [ref]
  • Carriers of the G allele had higher BMI and less weight loss on a calorie restricted diet in a study of obese patients[ref]. They also lose less weight after bariatric surgery.[ref]
  • Those with the G allele had slower gastric motility.[ref]
  • G allele carriers had higher resistance to weight loss, lower intake of total carbohydrates and monounsaturated fat, and high intake of saturated fat.  Ghrelin (hunger hormone) concentrations were also higher. [ref] [ref] [ref]
  • Blood pressure circadian rhythms are lower in those carrying the G allele [ref]
  • In those with bipolar disorder, the G allele is associated with increase manic episodes [ref]

Check your 23andMe results for rs1801260 (v.4 and v.5):

  • GG: higher activity in the evening, possible delayed sleep onset, risk for obesity
  • AG: somewhere in between
  • AA: normal

Another CLOCK gene variant, rs11932595 (G is the minor allele), has also been found to affect circadian function:

Check your 23andMe results for rs11932595 (v.4 and v.5):

  • GG: somewhat increased risk of miscarriage, risk of male infertility, shorter sleep
  • AG: somewhat increased risk of miscarriage, risk of male infertility, shorter sleep
  • AA: normal, longer sleep duration

Studies show:

  • Sleep duration for those with the AA genotype is likely to be longer [ref]
  • Those with the minor allele were less likely to have non-alcoholic fatty liver disease. [ref] and sleep disturbance in depression [study]
  • An increased risk of miscarriage was found for those with AG, GG[ref]
  • An increased risk (1.9x) for male infertility for those with the G allele.[ref]

 

Check your 23andMe results forrs4864548(v.4 and v.5):

  • GG:  increased risk of obesity[ref][ref]
  • AG:  increased risk of obesity
  • AA: normal

 

BMAL1 (ARNTL gene):
BMAL1 binds with CLOCK to increase the production of the PER and CRY circadian genes.  One of the BMAL1 variants, rs3816358 (A is the minor allele), has been studied in reference to breast cancer risk, cardiovascular disease risk, and diabetes risk.

Check your 23andMe results for rs3816358 (v.4 only):

  • AA: less of a risk of breast cancer than other shift workers [ref]
  • AC: less of a risk of breast cancer than other shift workes
  • CC: regular risk of breast cancer compared with other shift workers


rs7950226
(A is the minor allele)

  • increased risk of diabetes and gestational diabetes [ref] [ref]

PER1 gene:
PER1 codes for the ‘period circadian protein homolog 1’ protein which, along with CRY (below), is the other half of the core genes involved in our circadian rhythm.

A study in 2012 found that a variant, rs7221412, altered the natural timing of activity. Those with the AA genotype may naturally wake up about an hour earlier than those with GG, while AG falls in the middle.

Check your 23andMe results for rs7221412 (v.4 only):

  • AA: one hour earlier peak in circadian rhythm, more like to wake earlier [ref] [Article]
  • AG: peak was midway between AA and GG
  • GG: one hour later peak in circadian rhythm, more likely to wake later

PER2 gene:
A recent study looked at the expression of clock genes after weight loss and found that PER2 expression was increased after weight loss. [ref]

Check your 23andMe results for rs2304672 (v.4 only):

  • CC: associated with abdominal obesity, snacking, stress with dieting [ref] higher lipids [ref]
  • CG: associated with abdominal obesity, snacking, stress with dieting, higher lipid levels
  • GG: normal type (23andme orientation)

CRY2 gene:
A study of obese and lean women tracked their clock gene expressions in fat tissue over a 24-hour period.  The study found that CRY2 and REV-ERB  ALPHA are up-regulated in obesity over a 24-hour period.  [ref]

For rs7123390, postmenopausal women with AA had half the risk of estrogen and progesterone receptor-negative breast cancer.  [ref]

NR1D1 (REV-ERB Alpha)

rs2314339 (T is the minor allele)

  • REV-ERB alpha is associated both with a circadian mechanism and the biological action of lithium carbonate.  For bipolar disorder, those with at least one copy of the T allele were 3.5x less likely to improve on lithium carbonate therapy.  [ref]
  • Minor allele (T) carriers are less likely to be abdominally obese. [ref]

rs2071427 (T is the minor allele)

  • The minor allele, T, is associated with higher risk of obesity and higher BMI. [ref]

Other genes:

FTO is a gene with variants that are associated with increased risk of obesity (nicknamed the fatso gene).  A 2015 study found that FTO deficient mice had robust circadian locomotor activity rhythms, while “Overexpression of FTO represses the transcriptional activation by CLOCK and BMAL1.”[ref]  Other studies have shown that over-expression of FTO leads to increased body fat.[ref]


Lifehacks:

Blocking Blue Light:
Blue light at night has a big effect on your circadian rhythms. (Read my melatonin article).  Blocking blue light in the evening for a few hours before bed with blue-blocking glasses is one solution that will have multiple positive benefits on sleep and circadian rhythm. Get some inexpensive orange safety goggles and wear them every evening. Or upgrade to some nicer looking blue-blocking glasses. This seriously makes a difference in sleep quality and circadian function.

Sleep in the dark:
Even dim light at night can affect the body.  A study found that after two weeks with dim light during their dark cycle, “mice gained significantly more mass, reduced whole-body energy expenditure, increased carbohydrate over fat oxidation, and altered temperature circadian rhythms.” [ref]  So get some light blocking curtains, put electrical tape on any LED charger lights, and sleep in true darkness.

Time your meals right:
When you eat may matter more than what you eat:  “we recently showed that the timing of the main meal was predictive of weight loss during a 20-week dietary intervention and that this effect was independent from total 24-h caloric intake. The importance of caloric distribution across the day on weight loss therapy was supported by a recent 12-week experimental study showing that subjects assigned to high caloric intake during breakfast lost significantly more weight than those assigned to high caloric intake during the dinner.”[ref]  Another study showed that for bariatric surgery patients, those who ate their main meal later in the day were much more likely to be poor responders and lose less weight. [ref]

For those with melatonin receptor variants, eating dinner earlier can significantly decrease the risk of type 2 diabetes!

Intermittent fasting or restricted feeding time would also be something to explore.  Mouse studies on restricting feeding time to a four-hour window resulted in less weight gain, even though equal calories were eaten.  Possibly more importantly, it reset some of the circadian rhythm markers in those mice.  [ref]

Ketogenic Diet alters circadian system:
A mouse study looked at the effects of a ketogenic diet on clock genes.  It found that: “Clock genes showed delayed rhythms under KD. In the brain of KD-fed mice, amplitudes of clock genes were down-regulated, whereas 6-fold up-regulation was found in the liver. The metabolic state under KD indicates reduced satiety in the brain and reduced anabolism alongside increased gluconeogenesis in the liver.”  The study also found that the ketogenic diet “led to 1.5-fold increased levels of blood glucose and insulin.”  [ref]  There are other studies as well on the circadian rhythm changes induced by a ketogenic diet [ref]

NAC:
N-acetyl-cysteine (NAC) reversed the effects of BMAL1 deficiency in mice in regards to aging and oxidative stress.  Additionally, “Bmal1-deficient mice that received NAC weigh less than the corresponding control animals drinking regular water”, but they also drank less water.[ref]  This may be something to look into more as far as the timing of when it is best to take NAC.

Colors shift on iOS:
You can turn on an accessibility feature on iPhones to set up the phone to do a complete shift to red light. This is a handy feature if you need to look at your phone for some reason during the night.  Turning on a color shift to red on iOS phones. 

Final thoughts:
There is an incredible amount of research coming out about the impacts of disruptions to our circadian rhythms, which has convinced me that this is one of the most important bases for good health.  Significant increases in the risk for breast and prostate cancer have been tied to being exposed to light at night, as well as increased risk of metabolic syndrome and diabetes.

Personal update: While I’m not ready to go back to using candles for illumination in the evening, I am rocking the orange glasses every evening and sleeping like a rock each night.  Plus I’ve moved my evening meal earlier (5:30  or 6 pm) and cut out snacking at night to give my body the signal that the day is done.  All of this has resulted in weight loss without cutting out calories or changing my regular way of eating.

More to read:

Circadian Rhythm and Mood Disorders

Circadian Rhythm and Weight Loss

 

 Updated and revised Dec 2017, Aug. 2018

Digesting Carbohydrates: Amylase variants

Carbohydrate digestion begins in the mouth with an enzyme called amylase.  Saliva mixes with your food as you chew it, and the amylase in saliva begins breaking down carbohydrates into simple sugars.  Amylase is also produced by the pancreas and used for further breaking down carbs in the small intestines.

Amylase isn’t the only enzyme involved in breaking down carbohydrates; it is just the first step.  Amylase helps convert starches eventually into maltose or maltotriose, which are then converted by the enzymes maltase into glucose in the small intestines. Glucose then is utilized by the body for energy production.   (Vampire bats are the only mammals not to produce maltase)

Continue reading “Digesting Carbohydrates: Amylase variants”

Detoxifying Phthalates:  Genes and Diet

PhthalateGeneticsThere have been several recent studies about phthalates that have piqued my interest. I decided it was time to look into the science behind the stories and see if there really is anything to the scare-tactic type headlines about phthalates. Below are my notes with links to studies. I encourage you to check out the research and come to your own conclusions about whether phthalates are something to worry about for your body — and whether there is really anything you can do…

What are phthalates?
Phthalates are a type of chemical used as plasticizers to make plastics more pliable. They are not bonded to the plastic, thus allowing them to come out of plastic products when exposed to heat or solvents. “Because they are not covalently bound into plastic when used as plasticizers, phthalates have been found to leach or migrate from PVC-containing items into air, dust, water, soils, and sediment ” [study]

Phthalates are commonly found in adhesives, caulk, vinyl products, flooring, coatings on pharmaceuticals, flexible coatings on extension cords and appliance cords, nail polish, food and other packaging, fragrances, personal care products, paints, carpet backing, faux leather, printing inks, and apparently in mac and cheese.  Several types of phthalates are banned in the US and the EU now for use in toys and other objects, such as teething rings, that can fit in a child’s mouth.

In addition to food containing phthalates due to processing or packaging, prescription and over the counter medicines (2012) can contain phthalates as excipients. [study]  In 2010 the FDA created a list of products that they had tested for phthalates – fragrances were a huge source of phthalates of the products they tested.

Are phthalates really a problem?
I guess to answer that question, you would have to define ‘problem’.  Phthalate exposure is probably not going to kill you outright. They are not a new substance, and there have been quite a few toxicity tests dating back to the 1970’s using rats as a model.  US government toxicology studies in 1995 on rats showed that it didn’t kill adult rats in 13 weeks, but the doses used did kill baby rats.

There is some question, though, as to whether rodent studies are good models for human metabolism of phthalates, and newer studies now indicated that rats do not metabolize phthalates the same way that humans do.  [study] Exposure limits based on mouse studies are set fairly high, at around 100 mg/kg/day, as far as tumorigenesis. But California does include 6 types of phthalates on their list of possible carcinogens in their Prop 65 regulations.

Even though they probably aren’t going to kill you and probably won’t give you cancer, some of the harms of phthalates have been clearly shown, especially with infant and child exposures. Some types of phthalates have been removed over the past 15 years or so from teething rings and bottle nipples (EU and FDA regulations) and in 2009 US banned certain phthalates from use in children’s toys.

Some of the evidence showing that phthalates do have an effect on people and animals in low, chronic doses includes:

  1. Phthalates act as an endocrine disruptor
  2. As an endocrine disruptor, phthalates may increase the risk of fibroids, obesity, asthma, ADHD, IVF problems, and reproductive problems in men.
  3. It may be leading to a global decrease in amphibians – phthalates at very, very low, chronic levels are affecting frogs’ sperm.

So if low, chronic doses of phthalates are a problem, where are they coming from?
It turns out that phthalates are ubiquitous – literally everywhere – in our food supply.  For example, 2014 Norwegian study found phthalates in all foods and beverages commonly consumed (and BPA in 54%).  Exposure was highest in meat and grains, but levels were on average less than European max exposure levels.  Phthalates are even a problem for those trying to eat clean, organic food which is stored in glass. A study found that levels in junk food were the same as for those eating a controlled organic diet with food stored in glass containers instead of plastic.

How do phthalates get into our body?
One study sums up the routes of exposure well: “According to a review by Cao, phthalates can migrate into food from plasticized PVC materials such as tubing typically used in the milking process, lid gaskets, food-packaging films, gloves used in the preparation of foods, and conveyor belts [19,20]. These compounds are also found in printing inks and adhesives on food wrappers as well as coatings on cookware that have been contaminated by packaging [20-22]. Foods high in fat are contaminated by higher weight phthalates that are more lipophilic such as DEHP [19].”

Another study notes: “In the United States, phthalates have been approved by the Food and Drug Administration (FDA) as plasticizers in food packaging materials and food contact substances used during processing and storage while the European Commission and Chinese authorities have limited phthalates in food contact materials made of plastic since 2008–2009”

Finally, if you aren’t eating or breathing phthalates, they may be in medications that you take.  Some pharmaceuticals also use phthalates as plasticizers their drug capsules or coatings; even if not deliberately added to drugs, a recent study in China found phthalates at varying levels in all medications that they tested.

phthalate-linkedWhat are the effects of phthalates on the body?
Below are just some of the studies that show different effects of phthalates.  This is not a comprehensive list, so I hope you will do some researching on your own if you are interested in other effects of phthalates.  As with most environmental factors, it is likely that phthalates affect different people in different ways based on their genetic susceptibility.

  • ADHD “Consistent with previous studies [18], we found a significant correlation between the urine phthalate metabolite concentrations and the poor attentional performance” [study]
  • Lower odds of in vitro fertilization working for those with higher phthalate levels.  This study found that those in the top quartile for phthalate metabolites had about half the chance of IVF working.
  • Low dose, long-term study (mice) found decreased reproduction in males and decreased testosterone levels
  • The main problem with phthalates stems from their role as endocrine disruptors, which could cause problems with obesity, thyroid function, and uterine issues.
  • Obesity and weight gain:
    • Contaminated dust containing phthalates (which was found in all of the household dust sampled) was found to cause human cells to create triglycerides and also to cause mice to get fat.
    • Previous studies in cells have similar findings for phthalates promoting fat accumulation.
    • Sometimes the best way to figure out the impact of a substance on a population as a whole is to put a price on it. This is especially true in countries with government provided healthcare, and a recent European study calculated the cost of obesity caused by phthalates.   “The panel also identified a 40% to 69% probability of phthalate exposure causing 53 900 cases of obesity in older women and €15.6 billion in associated costs. Phthalate exposure was also found to have a 40% to 69% probability of causing 20 500 new-onset cases of diabetes in older women with €607 million in associated costs.”
    • A March 2017 study says “Most data support the effects of bisphenol A and some phthalates … on the development obesity and type 2 diabetes mellitus.”
  • Thyroid function is also affected by phthalates:
    • Several studies link urinary phthalate levels to depressed thyroid levels.
    • A Korean study found phthalate metabolite levels to correlate to lower FT4, FT3 and just slightly higher TSH levels.
    • Rat study showing that phthalates decrease T4, T3 and TRH but not TSH
    • Most doctors prescribe thyroid medications based on TSH, so if phthalates are messing with Free T3 and Free T4 but not TSH, there could be a lot of people with lower thyroid function that are being missed by doctors.  Check out Stop the Thyroid Madness for more information on FT4, FT3, and all the other thyroid hormones.
    • Another study explains how this links to obesity: “Another possible mechanism by which phthalates might promote obesity is through the disruption of thyroid function, which plays a key role in the regulation of energy balance and metabolism. … In rodent studies, exposure to DEHP lowered plasma thyroxine and decreased iodide uptake of thyroid follicular cells26,27). Recent human studies have also demonstrated possible effects of phthalate exposure on thyroid function in children and adults”
  • Uterine fibroids:
    • There are quite a few studies linking phthalates and other endocrine disruptors to fibroids and other uterine problems. Although most of the studies seem to be small or else reliant on self-reported cases of fibroids, the studies all seem to point to the same thing – a link between endocrine disrupting phthalate metabolites and fibroids.
    • Again, putting a price on the issue may give a bigger picture to what is going on.   A 2016 study estimated the cost of endocrine disruptor caused fibroids at 1.3 billion euros in the EU.
    • The truth may lie in the fact that not everyone is affected the same way by phthalates. A study showed that women with certain CYP17A1 and ESR1 variants had both higher phthalate levels and greater risk of uterine fibroids.
  • Histamine / Mast Cell / Allergy connection:

What happens to phthalates in your body?
According to this study, phthalates are metabolized rapidly and excreted in urine and feces.  Phase I metabolism involves hydrolysis by lipases, which are enzymes produced in the pancreas and stomach.  Depending on whether the phthalates are high or low molecular weight, they can also be further metabolized the oxidation.  The oxidative metabolites can then go through glucuronidation in phase II metabolism.

So which genes are involved in breaking down and getting rid of phthalates?

  • A GSTP1 variant, rs1695 AA, is associated with increased risk of asthma with phthalate exposure
  • “Humans are mainly exposed to DEHP via ingestion of food. Once absorbed into the body, DEHP is rapidly hydrolyzed to mono(2-ethylhexyl)phthalate (MEHP) and 2-ethylhexanol (2-EH) by the catalytic action of lipase [2, 3]. A part of MEHP is further oxidized by various cytochrome P450s (CYPs), followed by alcohol dehydrogenase (ADH) or aldehyde dehydrogenase (ALDH), to produce dicarboxylic acid or ketones. The remaining MEHP is excreted in the urine directly or in the conjugation form by the catalytic action of UDP-glucuronocyltransferase (UGT). 2-EH is metabolized mainly to carboxylic acid [mainly 2-ethylhexanoic acid, 2-EHA] via 2-ethylhexanal by the catalytic action of ADH and ALDH [2]. The 2-EHA formed is further oxidized to a dicarboxylic acid in a way similar to MEHP oxidation.” https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3944035/
  • Phase 1 detoxification is thought to be mainly through hydrolysis by lipases. Lipases are a type of enzyme produced in the pancreas, saliva, and bile.  They are what break down the fats that you eat.
    I found one EPA report that implies that the PNLIP and LIPF genes code for the pancreatic and gastric lipases that break down phthalates, but I couldn’t find any other studies to confirm this.
  • Some phthalate metabolites also induce CYP450 genes including CYP2B6.
  • While I didn’t find any specific studies on CYP2B6 variants and phthalates, there are a couple of variants that cause impaired metabolism by CYP2B6.
  • UGT enzymes involved in the glucuronidation (phase II metabolism) of phthalates include UGT1A9, UGT1A3, UGT1A7, UGT1A10, UGT2B7  — check out my article on UGT genes
  • GSTM1 (Glutathione S-Transferase Mu 1) has been shown in several studies to interact with phthalates.  The main variant of GSTM1 is known as GSTM1 null, meaning it is absent.
    • A small study, but one that has been replicated and cited by quite a few other studies, found that for those with GSTM1 null genotypes and phthalate exposure, the risk of fibroids was about 5 times greater.
    • Check your genetic data for rs366631. (v.4) It is a proxy for GSTM1 null with the AA genotype corresponding to null.  About 50% of the population is null.

So what can you do about phthalates, especially if you genetically may not be detoxifying them well?

  • First, while avoiding plastics and not heating your food up wrapped in plastic wrap may help a bit overall, I think that studies have shown that almost all food these days contains low levels of phthalates. A lot of fragrances have phthalates in them, so removing air fresheners (or switching to essential oils) may help as well.
  • Vegans eating only organic do have slightly lower levels of phthalates.   I’m not sure that switching to an organic, vegan diet is worth it just for the slight decrease in phthalate levels.
  • High frequency of dusting does decrease phthalates in the air at home. But make sure you aren’t using a furniture polish or spray that contains phthalates.
  • While I have read mixed results before about sweating out toxins, studies do show that phthalates can be excreted in sweat, thus saunas and exercise may be a good way to get rid of phthalates.
  • If you have a GSTM1 null gene type (see above), high fruit and vegetable consumption should help out.
  • Supplementing with the antioxidants vitamin E and C may help with GSTM1 null. Especially vitamin C.
  • If you have UGT polymorphisms (and even if you don’t), one way to boost the power of these phase II enzymes is to inhibit beta-glucuronidase, an enzyme produced by gut bacteria that basically reverses the glucuronidation of toxins by UGT enzymes. Calcium D-glucarate supplements are one way to inhibit beta-glucuronidase.  Bifidobacteria longum, l. plantarum, and l. acidophilus also inhibit the bacteria that produce beta-glucuronidase.

Personal Plan of Action:
A lot of the above problems and genetic variants apply to me personally.  My personal plan of action includes:

More to read:

 

How our genes shape our gut microbiome and our weight

Several studies have come out recently showing that those who are overweight have a different gut microbiome composition than those who are lean.  There have also been interesting mouse studies showing that transplanting feces from obese mice into lean mice causes the lean mice to become obese.  A 2010 study that found that supplementation with the probiotic Lactobacillus gasseri SBT2055 decreased abdominal fat and body weight.  The case for our microbes helping to shape our weight is fairly strong.

But why do some people have higher gut microbe populations of certain beneficial species than others?  Genetics!  Along with diet and environment, of course!

I find it fascinating that genetics plays a big role in the types of microbes that can live in our bodies.  Specific genetic variants can promote or discourage microbes in our guts.  For example, a FUT2 polymorphism causes some people to be immune to the Norovirus and the rotavirus (sometimes called the stomach flu).

Here are a few of the genes that play a role in determining which microbes inhabit the gut microbiome:

APOA5
This gene affects plasma lipoprotein levels including triglyceride levels as well as levels of certain gut bacteria.  Several SNPs in this gene have been associated with triglyceride levels and obesity risk.

An April 2016 twin study looked at metabolic syndrome (including weight) and found that rs651821 was associated with metabolic syndrome (MetS).  The study results found that metabolic syndrome was more common in those with the C allele and, for each C allele, there was an average increase in triglycerides of 24.65 mg/dL.  In looking at the gut microbiome, the study found that those with the minor allele (C) had fewer Bifidobacterium regardless of their MetS status.   Bifidobacterium species have been linked (in this study and in others) to lower BMI and better overall health.[ref]

Check your 23andMe results for rs651821:

  • TT: common (wildtype)
  • CT: reduced Bifidobacterium levels, higher triglycerides, and MetS risk
  • CC: reduced Bifidobacterium levels, higher triglycerides, and MetS risk


MYD88

  • A mouse study using mice bred to be deficient in (MyD88 knockout) found that the mice had significantly reduced levels of Lactobacillaceae (Firmicutes), Rikenellaceae (Bacteroidetes),  and Porphoromadaceae (Bacteroidetes) bacteria compared to mice with normal MyD88.  The study was looking at the influence of the microbiome and genetics in type 1 diabetes and is worthwhile to read through if you have T1D.
  • Another study found that MyD88 is important in clearing Listeria monocytogenes infection.  Listeria infections usually come by eating contaminated foods, giving some people a nasty case of food poisoning.  Normally the intestinal mucosa can protect against systemic infection, but MyD88 deficiency increases susceptibility to systemic infection by the pathogen.
  • A recent mouse study found that MyD88 knockout mice had an increased number of bacteria in contact with the epithelial wall of the intestine.  Normally, the intestinal mucosal layers protect the cell wall of the intestines from direct contact with bacteria.
  • Other mouse studies have found that MyD88 knockout mice are more susceptible to tuberculosis.  This has been confirmed in humans with MyD88 polymorphisms as well.

Several MYD88 variants have been found to reduce levels of MYD88 (most are not covered by 23andMe data).  These are just reduced levels, though, not a complete ‘knockout’, so the results of the mouse studies may not be completely applicable.

Check your 23andMe results for rs4988453:

  • CC: common (wildtype)
  • AC: reduced MYD88 (5x risk of tuberculosis)
  • AA: reduced MYD88 (5x risk of tuberculosis) [ref]

 

Check your 23andMe results for i5000725 (rs137853065):

  • TT: common (wildtype)
  • CC: Rare mutation, listed as pathogenic for MYD88 deficiency

 

Check your 23andMe results for i5000726 (rs137853064  ):

  • CC: common (wildtype)
  • TT: Rare mutation, listed as pathogenic for MYD88 deficiency


NOD1

Nucleotide-binding oligomerization domain containing 1 (or NOD1)

Mice deficient in Nod1 have increased susceptibility to H. pylori.  Other studies have shown that NOD1 variants lead to increased risk of inflammatory bowel diseases in some population.  One study concluded, “Taken together, these data may suggest that NOD1 plays a variable role in different populations that could depend upon environmental and dietary factors.” [ref]

Check your 23andMe results for rs2075822 :

  • AA: common (wildtype)
  • AG: increased risk of IBD
  • GG: increased risk of IBD [ref]


TLR4

Toll-like receptor 4 (TLR4) plays an important role in our innate immunity and is especially active against gram-negative bacterial infections. TLR4 variants have been investigated in conjunction with cancer risk, vaccine response, and transplant rejection among other things.

Check your 23andMe results for rs4986790:

  • AA: common (wildtype)
  • GG: increased risk of gram-negative bacterial infection, septic shock[ref] [ref], and metabolic syndrome [ref]

 

Check your 23andMe results for rs10759932:

  • TT: common (wildtype)
  • CC: decreased risk of H. pylori [ref]


SLC39A8

From Genetics Home Reference: “This gene encodes a member of the SLC39 family of solute-carrier genes, which show structural characteristics of zinc transporters. The encoded protein is glycosylated and found in the plasma membrane and mitochondria, and functions in the cellular import of zinc at the onset of inflammation. It is also thought to be the primary transporter of the toxic cation cadmium, which is found in cigarette smoke.”

Check your 23andMe results for rs13107325:

  • CC: common (wildtype)
  • CT: changes in gut microbiome, obesity, and Crohn’s disease risk
  • TT: changes in gut microbiome, obesity, and Crohn’s disease risk [ref]

Lifehacks

Eating prebiotic fiber, such as inulin / FOS may increase your bifidobacteria.[study]

There are probiotics available containing multiple strains of bifidobacteria.

More to read:

A recent study did extensive analysis on the microbes associated with visceral fat, BMI, and other obesity markers.  The study also found several genes correlated with specific bacteria that are associated with obesity.  The SNPs (none of which are included in 23andMe results) were in the FHIT, TDRGI, and ELAVL4 genes.  The full study is open to read and worth checking out.