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Neurobiology of Eating

The Physiology of Women’s Weight Loss Part II: Appetite and Weight Regulation

Posted by on May 13, 2012 in Blog, Neurobiology of Eating, Weight Loss | 4 comments

The Physiology of Women’s Weight Loss Part II: Appetite and Weight Regulation

In the first post I wrote on the physiology of women’s weight loss, I focused on the role estrogen plays in fat stores.  I noted at the end of the post that estrogen is involved with sending appetite-regulating signals to the brain.  This is an important factor in female weight loss.  Men have hormonal feedback that dictates their satiation, too, but their body is less attached to how much fat it has.  For a woman, having fat is crucial for pregnancy and childbirth.  For this reason, a woman’s body errs on the side of caution with respect to fat stores.  When in doubt, it screams “eat!”

What this means is that it is much easier for women to be barraged with physiological demands to eat.  These drives are not malicious things, and a woman can never be upset with her body for having them.  It’s natural, and it’s necessary for health.  Only by accepting our strong biological need for food as physiological fact can we women truly move forward with love, holistic healing, and positive, even pleasurable weight loss.

What follows below is an overview of the mechanisms by which women’s bodies “hang on” to fat stores.   This is not to say that the body wants to be overweight.  The body actually wants to be a proper, fit, attractive weight.  What happens is that normal weight-regulating factors get dysregulated by an inflammatory diet, and prolonged abuse drives a system further and further off-track.  The good news is that because a woman’s body wants to be an appropriate weight, once the woman starts treating her body with proper love and nourishment, the pounds naturally slide off.

Fat as a vital organ

Not too long ago, scientists thought that fat cells were simple units of energy storage.  Metabolism would grab the energy stored in the fat cells when it needed it, and then the fat cells would continue lying there inert.  Metabolism might deposit more energy into them at another time, and then later it would come grab the energy back.   Fat cells were considered storage units, and not anything more.

Since 1994 with the discovery of leptin, science has gradually unearthed the surprising notion that fat tissue is not just a storage space but is also an endocrine organ in and of itself.  Fat receives signals from hormones; it is actively involved in how much fat gets stored within its own reserves, and how; and it sends out potent signals of its own.  These signals are crucial.  They tell the brain how much energy is currently being stored in the form of fat.  Higher levels of leptin signal to the hypothalamus that an organism does not need to eat anymore.   Potent appetite stimulators such as neuropeptide Y and anandamide are inhibited by leptin in the hypothalamus, and the production of alpha-MSH, an appetite suppressant, is encouraged.  Though there are dozens of hormones and neurotransmitters involved in signalling appetite to and from the brain, what this demonstrates is that leptin more or less runs the show.   More leptin = less eating.

That is, unless the organism is leptin resistant.

Leptin resistance

Leptin resistance occurs when leptin has flooded a system.  In addition to originating in fat stores, leptin levels in the blood rise with food consumption.  Leptin 1) spikes after consumption of a large meal, particularly a carbohydrate-heavy meal, since leptin works in tandem with insulin, and 2) it sort of dribbles into the bloodstream if food is eaten in smaller quantities throughout the day.   So leptin levels rise whenever the body really thinks it has been well-fed.

Over-secretion of leptin is the primary means by which people dysregulate their leptin signalling, for example, if they eat too many meals without waiting for hunger to return in between them, or if they graze on food all day, or if they have a couple of snacks each day.   Basically, leptin resistance develops when normal weight-regulating drives are ignored.  This is easy to do in the presence of highly palatable food and drink.  Other factors that can throw someone’s leptin signals under a bus are stress, loss of sleep, problems with neurotransmitters, or nutrient deficiencies.   Under the influence of these factors, or perhaps several of them in conjunction, it becomes difficult for a woman to hear the leptin signalling in her hypothalamus.

Once people begin ignoring their leptin signals, they get easier and easier to ignore.   This is because constantly elevated leptin levels cause leptin receptors to become insensitive to the leptin floating around in the bloodstream.  Then, as the body realizes that it’s normal leptin signalling isn’t getting the job done, it incites more eating, more weight gain, and higher leptin levels in hopes that an increased leptin signal will get through.   For this reason, obesity is correlated with high leptin levels, even though many obese people complain of constant hunger.

Leptin resistance is a problem for everybody.  Both men and women.  Without fixing leptin sensitivity problems, it’s very difficult to lose weight, and it’s even more difficult to enact any kind of dietary restriction.   But women, who have higher levels of leptin than men (having higher body fat percentages) and who have HPA axes more attuned to energy conservation, are particularly sensitive to fluctuations in leptin levels.

Leptin and menstruation

Achieving a certain leptin level is the primary trigger for menarche (the first incidence of menstruation)   Stress, genetics, being exposed to smoking, and not being breast fed are other important factors.  So far as researchers can tell, throughout evolutionary history a woman’s period likely started around 15 or 16 years of age.  A few studies were conducted in the nineteenth century documenting menarche.    In 1850, girls began menstruating at an average age of 17;  by 1960 that age decreased to 13 years old.  Today in America,  approximately ten per cent of girls start to menstruate before 11 years of age, and ninety per cent of all US girls are menstruating by 13.75 years, with a median age of 12.43 years.   Both black and latino girls begin menstruating before white girls.

Many suspect that the higher body weights and higher leptin levels are responsible for the change in menarche.  A 2011 study found that each 1 kg/m2 increase in childhood BMI can be expected to result in a 6.5 per cent higher risk of menarche before  reaching 12 years of age.

Leptin and the reproductive set point

Knowing about puberty and menarche is so important for adult women because a woman’s reproductive functioning for the rest of her life is influenced by the conditions of her early reproductive years.  Having started menstruation with a certain leptin concentration in the blood, a woman’s body treats this as a “set point ” of sorts later on.   Having had a certain level of leptin, too, influences the young girl’s estrogen and progesterone levels,  such that these also become reproductive set points.  Therefore, if a woman drops too far below her set leptin or estrogen levels later in life by losing too much weight, her body will do its damndest to get those levels back up.  A similar phenomenon happens if she becomes overweight and leptin resistant.

Stimulating appetite in response to low leptin levels

The way a body tries to increase leptin and estrogen concentrations is to increase fat mass.  The way to increase fat mass is to increase appetite.  This is why leptin is such a potent signal in a woman’s brain.    With decreased leptin levels (or leptin insensitivity), appetite-stimulating neurons up-regulate powerfully.

Importantly, more women profess sugar addiction than men.  One of the neurons that detects decreasing leptin concentrations in the blood is called Neuropeptide Y.  Neuropeptide Y stimulates carbohydrate craving.   Women who are experiencing starvation– or at least women who’s hypothalama are detecting lower leptin levels than their bodies think are optimal — experience insidious carbohydrate cravings.

Are women stuck in leptin set points?

No.  Not necessarily.

The thing is, it’s complicated.  A woman’s body will never “want” to be overweight.   Women start menstruating at a certain leptin level and at a certain age, but even if this occurs at a very young age, the leptin is still around the same absolute level that another woman might experience, just many years earlier.   So her leptin levels, if higher earlier than optimal,  still are not shooting through the roof at menarche.

Moreover, if a young girl is overweight when she starts her period, at that time her body is probably fighting for and signalling a desire to lose weight.  It’s just not working because some of the signals have been disturbed by poor diet and lifestyle.   This woman’s body’s need for and desire to lose weight will persist for the rest of her life.   The hormone and appetite pathways are all still in place.  They are just begging to be restored to their normal function.   All the woman needs to do is listen, and to nourish her body properly.  In this way, it will be her partner in weight loss, rather than her adversary.

Other appetite stimulators

Appetite is stimulated via a few other important pathways.  They are not limited to women.  For example, an individual’s cravings for certain foods increases as a result of nutrient deficiencies.   Fluctuating insulin and blood sugar are important.  Stress is important.  Social conditioning, negative thought patterns, psychological responses to hardship, and body image issues also powerfully stimulate cravings.

Neurotransmitters as appetite stimulators

Perhaps most significant, however, is the relationship between neurotransmitters and food, specifically for women. When serotonin levels drop, cravings, again, particularly for carbohydrates, increase.  Serotonin levels can be disrupted by a vast number of problems.  These span from nutrient deficiencies to an omega 6 – omega 3 imbalance to poor sleep to obesity to exercise and to stress.    Serotonin levels also fluctuate with the menstrual cycle.  A drop in serotonin during the luteal phase (the last two weeks) of the menstrual cycle is thought to be by many the dominant cause of PMS.  This would explain why many women experience increased cravings for sweets throughout PMS.   These are natural, up to a point.  But PMS is an extreme fluctuation, and solving the underlying diet and lifestyle factors causing PMS should also decrease the wild swings in cravings that many women suffer throughout their menstrual cycles.

The role of neurotransmitters in appetite deserves several posts of its own.  They are forthcoming.  For now, it suffices to note that neural mood regulators are strong links between a woman’s reproductive system and her weight regulation mechanisms.  Sub-optimal serotonin levels in particular increase carbohydrate cravings.

All that said…

Women come equipped with a system designed to maintain adequate fat mass.  If a woman is overweight, it’s because the normal weight regulators she has in place are not receiving the proper nourishment required for effective signalling.    Leptin insensitivity, in the case of an overweight woman, or low leptin levels, in the case of an underweight woman, compel her to eat and to eat and to eat.  Estrogen, as I noted in a previous post, is also a significant weight-regulator unique to women.  It, too, is disrupted with diet and lifestyle.  Therefore, with the restoration of the proper functioning of all of the underlying mechanisms at work in a woman’s body, specifically with leptin and with estrogen levels, a woman’s weight can slide off.  More on that in my upcoming post on the easiest, most natural way (paleo diet! decreased stress! self-love!) for women to lose weight.

 

 

 

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Neuropeptide Y: Appetite, Macronutrients, and Yo-Yo Dieting, or, Why Restriction Breeds Carb-Addicts and Disordered Eaters

Posted by on May 3, 2012 in Blog, Disordered Eating, Neurobiology of Eating | 4 comments

Neuropeptide Y: Appetite, Macronutrients, and Yo-Yo Dieting, or, Why Restriction Breeds Carb-Addicts and Disordered Eaters

Neuropeptide Y is one of several neuromodulators involved in regulating feeding.   These include classic neurotransmitters such as serotonin, GABA, or dopamine, molecules derived from fatty acids like endocannabinoids, and neuropeptides.   (All of which I will discuss at length eventually.)   Every neuromodulator can be classified as orexic or anorexic.  Orexic cells drive feeding.  Anorexic cells do the opposite.  Neuropeptide Y is one of the orexic cells, and it is in fact one of the strongest.

In the photo below (a snapshot I took of a page in an excellent textbook–Appetite and Body Weight by Tim C Kirkham) orexic and anorexic drivers are compared.  On the left are the orexics, on the right, anorexics.  Note how Neuropeptide Y and Leptin are situated at the top of the respective sides, demonstrating their antagonistic behaviors against each other.

 

So NPY is strongly orexic.  When injected into the brains of several species of animals, NPY induces several-fold increases in food intake at any time in the dark-light cycle.  Additionally, it is highly involved in the motivation and search for food.  NPY-injected animals are ravenous and incessant: they will eat even when they have to work really hard for it, even if they have to tolerate electric shocks, and even when the food is altered from the natural product and may in fact contain substances they have aversions to, such as quinine.   In animals lacking NPY, eating is delayed and the animal’s efforts at attaining food are sluggish.

NPY delays satiety throughout a meal.  Thus it augments meal size, time spent eating, and meal duration, irrespective of what food is provided.   Animals certainly have preferences for what to eat, but they will take anything and eat it at length if they cannot get their paws on sweet foods.  This action of NPY, along with other orexins, explains why many disordered eaters need to eat and eat and eat, regardless of how much they like the food.

The most fascinating aspect of NPY, however, in my opinion, is the way in which it interplays with macronutrient cravings.    NPY increases carbohydrate cravings first and foremost: NPY-injected animals show an enormous preference for sweet foods.   But NPY also has a fed-fasted-state feedback mechanism: after weeks of being fed either a high-carbohydrate or a high fat diet–so long as it is high calorie–NPY levels fall (though the animals certainly prefer the high-carbohydrate diet), and the animals stop craving carbohydrates that much.

This all occurs in light of the fact that when one is starving at all, NPY levels rise.  They rise in response to fasting, in response to chronic food restriction, and in response to any sort of starvation signal whatsoever, for example, a drop in leptin levels.   NPY levels also continue to increase as the time spent in the fasting state gets longer and longer.   This means that the NPY-driven craving for sweets increases as the fasted state endures.

Once regular feeding is restored, however, NPY levels fall back to baseline.  In this way,  NPY is meant to moderate energy consumption, with a clear preference for carbohydrates.  Why?  Because glucose is the fastest way to get a “fed” signal firing in the brain, at least on an immediate time-scale.   Glucose spikes insulin levels and therefore leptin, which in turn  signals to the NPY right away that the organism is fed.  However, the “fed” state must endure through longer time scales than one simple meal in which leptin levels spike.   Therefore, a long-term undertaking of feeding with any type of macronutrient ratios should be sufficient to mitigate NPY-related problems, so long as energy intake is sufficient to account for energy expenditure.    In the short-term, however, as mentioned, sometimes glucose is the only way to get the NPY neurons (as well as the hypocretin neurons responsible for wakefulness while hungry) to shut up.

This phenomenon explains in part the failure of so many diets.  Neuropeptide Y is one of the strongest stimulators of appetite, and is it triggered first and foremost by low leptin levels and caloric restriction.  Any detection of a fasted state will lead  to the organism craving carbohydrates moreso than usual, and the cravings won’t really subside unless the organism can convince the NPY neurons that it’s not starving.   Herein lies the rub: people restrict, and drives toward feeding rise.  In particular because of NPY-type drives, that drive is focused on carbohydrates.  The more successful a person is at restriction and at willpower, the harder and harder it gets to maintain that level of restriction.   Eventually the stamina fails, and the organism caves, often to a sweet food.  Recall that NPY delays satiation and prolongs feeding quantity and duration.  What this means is that this one bite of sweet food the person allows himself is all-of-the-sudden one thousand bites of sweet foods.  This willpowering individual feels awful about what he’s done, so he gets back into his routine of chronic restriction.   This is a hell of a cycle to be caught in.  My Pepper readers know this all too well.

Re: what NPY-type activity means for fasting and for ketogenic diets:

Glucose availability in the brain is important for NPY regulation.    Glucoprivation- that is, deliberately blocking glucose activity–has been shown to induce feeding and activate hypothalamic NPY neurons in rats.  What this means is that a brain that runs on limited glucose stores may have increased NPY activity.   Ketogenic organisms run on limited glucose stores.

Since many people who fast and/or undertake ketosis experience decreased appetite, there are clearly other, stronger mechanisms at play in the modulation of their appetite than NPY drives; for example, perhaps the simple strength of leptin sensitivity in signalling to the NPY is powerful enough in these individuals to squelch the drive to carbohydrates.   Or perhaps in some individuals moreso than others gluconeogenesis from the liver is functioning well-enough to get adequate glucose supplies to the brain.  I suspect that both of those ideas are in part true.  Nonetheless, NPY explains in part why some people binge so hard on sugar once they take a step off of the fasting or very-low-carb ladders, even if they are not in explicit restriction like the yo-yo dieters I mentioned above.

Many people talk about the addictive power of carbohydrates.  I agree–it’s horrible.  I’ve talked about it many times, and at great length.  Yet what might be worse in some cases is the physiological basis NPY demonstrates for carbohydrate longing.  And the role that restriction plays in the demonic need for sweet foods.   Being in a energy-restricted state might play one of the more powerful roles in why carbohydrate is so insidious in the contemporary American food psyche.

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Night Eating Syndrome: An Effect of HPA axis and Appetite Dysregulation (among other things)

Posted by on May 2, 2012 in Blog, Neurobiology of Eating, Sleep | 2 comments

Night Eating Syndrome: An Effect of HPA axis and Appetite Dysregulation (among other things)

Night Eating Syndrome isn’t something that gets talked about very often. But disordered eating researchers are hyper aware of it.  It’s also an enlightening topic for a variety of reasons, least of which being the relationship between the endocrine system, circadian rhythms, and feeding schedules.

The diagnosis and experience of night eaters is now well-parameterized, though the causal factors are not.  Night eaters usually eat very little in the mornings, eat more snacks during the day time than others, and wake up often several times each evening in order to eat.  They usually sleep at normal times, but their sleep is disturbed by their need to eat.   Night eaters experience lower levels of leptin both at night and during the day, lower levels of growth hormone, and higher levels of TSH.  In general, insulin and glucose are elevated, and rates of depression are also higher.   But still the crux of the night eating problem is timing:  Leptin and insulin are delayed between 1 and 3 hours.   Melatonin is delayed by a couple of hours.   Ghrelin, the primary hormone that stimulates food intake, is phased forward by as much as five hours.   Glucose rhythms are almost entirely reversed.   Night eaters also experience several “amplitude” attenuations.  What this means is that both the spikes and the troughs of different cycles are minimized, such that hormone levels flatten out and disrupt the endocrine system’s ability to hit the triggers for normal functioning.

Researchers are not sure what causes night eating syndrome.  Metabolic dysregulation for sure, but “obesity” still doesn’t provide the answers.    What is clear is that the central timing of circadian rhythms (via the suprachiasmatic nucleus in the brain) undergoes some kind of disconnect with other clocks located throughout the body, particularly those found in the stomach and the liver.  Many researchers recommend using lighting and other environmental triggers to get NES sufferer’s clocks back on schedule, but that only addresses one portion of what controls timing.  The SCN is the ruler of the circadian system, but it cannot force peripheral organs into line.  I believe liver and stomach signalling need to be addressed independently.  For an excellent discussion of what mechanisms may be at play in peripheral clock signalling, check out this review.

The mechanism by which these clocks become de-coupled is not quite known.  First, it is generally assumed that a switch in feeding times tells the body to expect different signals, such that moving meals around really can phase shift organs.  Yet it goes deeper; most everyone with night eating syndrome still eats at regular mealtimes.  Something must account for what’s making them so hungry at nighttime.  In investigating the link, some researchers injected the glucose-receptor agonist dexamethasone into mice at different times during the day.  Dexamethasone is a synthetic glucocorticoid, stronger than cortisol.   With the dexamethasone in their systems, the mice’s livers became phase-shifted within a day or so.  With less, it took longer.  What this demonstrates is that the presence of cortisol in a system accelerates whatever phase changes might be occurring.   The SCN is capable of arousing CRH (a precursor to cortisol) production.  Many researchers speculate that this is a mechanism by which the SCN generally attempts to modulate peripheral organ activity.  Yet if cortisol runs amok, the effects can occur absent the usually cause.

The same goes for people.  One study tested CRH levels in night eaters.  They found that in night eaters compared with controls, the CRH-induced cortisol response was significantly decreased. In conclusion, disturbances in the hypothalamic-pituitary-adrenal axis with an attenuated ACTH and cortisol response to CRH were found in subjects with night-eating syndrome.

Lesions on the SCN abolish glucocorticoid and feeding rhythms.   In “clock mutant” mice, the feeding schedule is distorted in a way that almost doubles calorie intake.  Mice typically eat 75 percent of their calories in the nighttime, yet when they become Mutant Clocks they end up consuming the same volume of food also in the day time.   These mice also experience diurnal variation in glucose and triglyceride levels.  Their gluconeogenesis is almost entirely suppressed.  Why this happens is not known, though it is clear that the signalling from the SCN clock must be received and interpreted in the liver in order for gluconeogenesis to function properly.  This is especially interesting because we see that feeding-stimulating (orexic) and feeding-inhibiting (anorexigenic) genes in these mice are both decreased as a result of the clock mutation.  We would think, then, that these two decreases would balance each other out.  And maybe they do.  What seems to be the real problem with night eating syndrome is the dysregulation in the communication between the SCN and the digestive organs.

Throwing off glucose metabolism in this way begets leptin problems as well.  And how does leptin dysregulation contribute to the development of night eating syndrome?    It’s a slow but insidious process.  Sleep curtailment inhibits the leptin response. Decreased leptin levels leads to an increased need to eat–particularly of carbohydrates.  This is likely due to a whole host of types of neurons that respond to starvation signalling (ie, low leptin levels or poor leptin sensitivity) with drives toward carbohydrate refueling, particularly Neuropeptide Y and hypocretin neurons.  When sleep-curtailed individuals wake up in the morning, they have impaired glucose tolerance and crave carbohydrates right away.  Throughout the day, blood sugar swings and inhibited leptin signalling and responsiveness lead to incessant snacking.   Additionally, an altered cortisol profile from the disturbed sleep disrupts the liver and stomach clocks.  These several phenomena result in an increased need for food and for calories late in the day.  Leptin levels have dipped, glucose and insulin functioning has been impaired, cortisol has been on the rise, and the brain has been told it’s starving.  Thenso late in the day, the individual eats because he is hungry.   His leptin levels will rise, particularly in response to a high carbohydrate, high insulin meal.  This can help him sleep, via calming hypocretin neurons, as well as sooth his cravings.   But it’s not over.  With other timers off in the stomach and the liver, the brain will get appetite and waking signals (again, partly facilitated by hypocretins) strong enough to rouse the individual from sleep.   If hypocretin neurons are significantly stimulated, the organism will always rise.  Continually then throughout the night hypocretin neurons respond to all of the hormones coming out of the liver and the stomach and get the organism up to feed.

This all results in a vicious cycle.   What needs to be done about it is not exactly known.  Patients can supplement with 5 HTP and tyrosine in order to raise brain neurotransmitter levels, which can curb appetite.  Patients can do light therapy in order to strengthen the power of the suprachiasmatic signalling.  And patients can perhaps take melatonin or valerian, or any other sleep aid, in order to try and get a full night’s rest and a full night’s recovery of leptin signalling capabilities.   Mealtimes can be gradually shifted and snacking reduced such that the individual can still fall asleep and sleep well at the appropriate times.  Finally, reducing stress is also–as always–one of the most helpful factors.

 

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Hypocretin Neurons: The Link Between Fasting, Stress, and Arousal, or, Why Fasting Breeds Insomniacs

Posted by on Apr 30, 2012 in Blog, Fasting, HPA axis, Neurobiology of Eating, Sleep | 16 comments

Hypocretin Neurons: The Link Between Fasting, Stress, and Arousal, or, Why Fasting Breeds Insomniacs

There is a hell of a dichotomy occurring in the Paleo blogosphere this month.   99 percent of the time I am pleased as Pooh stuck up a honey tree, nestled in my esoteric corner of paleo-feminist rage, but every once in a while I wish more people could hear what I have to say.  Today is one of those days.

The split I am talking about is not all that nefarious.  In most cases, it’s benign and can be ignored.   But in general I would like to draw attention to it, because I think there’s a lot going on beneath the surface (and here, the depths are not just Nemo and Dory but are instead people’s lives), and that depth requires speaking to.  Immediately.

Mark’s Daily Apple has recently done a beautiful series on the benefits of fasting.   I loved it.  I learned plenty, as I always do on MDA.  The series was well-written and -organized, and in fact I ended up directing people who are unfamiliar with fasting to the site in hopes of swaying their opinions.   (So let it be clear: I am not against fasting per se.) Yet Chris Kresser has also done an April “Best your Stress” challenge.   Serendipitously enough, it concludes today.  And it is exactly what it sounds like: an endeavor to spend 30 days taking practical steps to counteract stress.  Chris’s idea was that people often spend 30 days trying to get their diets in line.  But what about their stress, and their lives?  I couldn’t agree more.   This man is a gale of fresh, important ideas.

The reason I say these two Big Themes are at odds is because they are.  Fasting is a stressor.  Period.  Mark Sisson would agree.  All people who advocate fasting would agree.  But all they ever do is put an asterisk at the end of their posts: *people who are stressed should probably not fast, they say.   But why?  Who is affected, and how?   What can fasting and other forms of restriction do to our brains, and to our lives?

What I want to draw attention to today are little loci that sit on the border of the hypothalamus called Hypocretin Neurons.    Hypocretin neurons (also called Orexins–and note that the word “orexin” means “appetite increasing”) were discovered just 14 years ago in 1998, but they have radically altered the landscape of eating neurobiology since then.   No, they are not the sole molecules responsible for sleep and waking.  Mice that have had these neurons removed still sleep and wake in roughly normal patterns.  But they never feel alert, and they never suffer insomnia.  And when the neurons are activated, the mice leap into action.  Hypocretin neurons wake animals up.  This much is certain.

The lack of Hypocretin Neuron signalling is the cause of narcolepsy, while elevated Hypocretin levels induce arousal, elevate food intake, and elevate adiposity.  Hypocretin Neurons  upregulate the production of molecules down several other pathways, too: these include noradrenergic, histaminergic, cholinergic, dopamine, and serotonergic.

The anatomy of Hypocretin Neurons is also coming into greater light.   When are the neurons active?  What signals do they receive, and what signals do they produce?     Research is beginning to show that Hypocretin Neurons are excited by excitatory synaptic currents and asymmetric synapses with minimum inhibitory input.   The fact of asymmetry is important.  It means that Hypocretin Neurons are instead always acted upon by mostly uniform – excitatory - signals they receive.    Hypocretin Neurons only ever up-regulate and relax.  They do not down-regulate.   Excitatory signals outnumber inhibitory signals 10:1.

One notable source of excitation is corticotrophin releasing hormone, which suggests that stress activates the activity of Hypocretin Neurons.    GABA neurons also create a bridge between Neuropeptite Y, which is the molecule that arguably has the strongest appetite-stimulating effect on the brain, and Hypocretin Neurons (more on Neuropeptide Y later this week).  From there, Hypocretin Neurons project to all regions of the brain, including the hypothalamus, cerebral cortex, brain stem, and spinal cord.   It seems as though Hypocretin Neurons may act as a nexus of signal input for the appropriate synchronization of various autonomic, endocrine, and metabolic processes.

Food restriction further augments recruitment of excitatory inputs onto Hypocretin cells.   This explains the relationship between insomnia and adiposity: because of the easy excitability of Hypocretin Neurons, any signal that triggers their activity, regardless of homeostatic needs, will elevate the need to feed in brain circuits such as the locus coeruleus and the melanocortin system while also promoting wakefulness through activation of noradrenaline-stimulating neurons.  Anything that promotes the release of corticotrophin releasing hormone (CRH) such as reduced sleep will further trigger Hyocretin Neuron firing and Appetite.   This is a vicious cycle.  Hypocretin Neurons play the role both of trigger and of accelerator, taking states of wakefulness, insomnia, stress, and obesity into continual positive feedback loops.

So how does leptin factor in?  Hypocretin Neurons express leptin receptors.   Moreover, some recent complicated neurobiological work done on mice has shown that injecting them with leptin decreases the activity of their Hypocretin Neurons.   What this means is that Hypocretin Neuron activity is stimulated in part by decreasing levels of leptin in the blood, and that increased leptin levels reduce the level of excitation running through Hypocretin Neurons.   This is coupled by ghrelin activity, which is also detected by Hypocretin Neurons.   Ghrelin, which originates in the gut and is known to stimulate appetite, also excites Hypocretin Neurons.   What does feeding do, then, for Hypocretin Neuron excitation?   Experiments on mice show that re-feeding restores normal Hypocretin activity, to an extent.  Repeated abuse takes longer to recover from, but the simple presence of leptin in the blood normalizes the brains of mice.

Hooray!  This is good for fasting, right?  So long as one re-feeds appropriately, everything should be fine?  Well, yes.  In a healthfully functioning individual.  But not in a) someone who is both stressed and leptin resistant, since increased leptin levels from the re-feed might not be powerful enough to offset other excitatory pathways b) someone who is currently emerging from yo-yo dieting or caloric restriction c) someone who is dealing with an over-stimulated appetite, d) someone experiencing stress, e) someone who has had a history of insomnia, f) someone who is underweight, since they have low leptin levels, g) anyone who has ever had an eating disorder, particularly bulimia or binge eating disorder or h) anyone with HPA axis or endocrine dysregulation, particularly women, including overt stress, hypogonadism, hypothalamic amenorrhea, hypercortisolism, or hypocortisolism (adrenal fatigue.)  I am sure the list is incomplete.

In animals, Hypocretin Neurons serve an important evolutionary function.  Arousal is a vital behavior in all species.    And normally, Hypocretin Neurons respond quickly to changes in input.  But in situations of chronic metabolic or endocrine stress, or of recovering from a stressor, they can lead to hyper-activity and hyper-feeding.

Researchers have long known about the link between leptin, sleep, and obesity.  The less someone sleeps, the lower her leptin levels, so the more she eats, and the heavier she gets.  Hypocretin Neurons may serve as one of the answers to the question of exactly how that phenomenon comes about.  Or at least it plays a role.  Because 1) Hypocretins simultaneously stimulate appetite and wakefulness, particularly through orexigenic output of the melanocortin system, and subsequent release of CRH, which activates the stress response, and 2) while Hypocretin Neurons wake us up, they also need to be quiet enough for people to go to sleep.

Finally, I raise the questions: how many disordered eaters have trouble sleeping?  How many anorexics, binge eaters, calorie restrictors, exercise-addicts, stressed-out individuals, and very low-carb dieters have trouble sleeping?   How many people try intermittent fasting and find that it disrupts their sleep or circadian rhythms?  How many people wake up in the middle of the night or early in the morning, even though they still need sleep, but for the life of them feel so awake?  Part of that answer lies in blood sugar metabolism, for sure.  And in other places.  Sleep is a hell of a complex phenomenon.  But here– Hypocretin Neurons can become overburdened by excitatory signals.  They get hyped up in the face of both decreasing leptin levels and leptin insensitivity.   They are upset by restriction, and they are upset by fasting.  Hypocretin Neurons demonstrate why so many people have difficulty with their appetite and their sleep.  If you find that fasting disturbs your sleep, or that you are suffering disordered circadian rhythms along with stress or appetite problems, do you best to relax your system.  Don’t fast.  Relax.  Exercise less.  Reduce stress.  Eat more.  Put on weight.  Eat more carbohydrates.  Don’t graze.  Increase your leptin sensitivity.  And listen to your body.

Coming up next: nighttime eating syndrome, and how it’s all related.

 

 

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Leptin, Sleep, and Obesity: Is Reduced Sleep Making America Fat?

Posted by on Apr 30, 2012 in Blog, HPA axis, Neurobiology of Eating, Sleep | 0 comments

Leptin, Sleep, and Obesity: Is Reduced Sleep Making America Fat?

The literature on sleep and obesity is becoming dense.  Lots of things happen to people when they sleep.   One of them has to do with appetite regulation, so many researchers are coming to believe that sleep plays a dominant role in today’s vast American Overfeed.

This hunch is supported by striking correlations.

In 1960, a survey of over 1 million people found a modal sleep duration of 8-9 hours. In 2002, polls conducted by the National Sleep Foundation indicated that the average duration of sleep for Americans had fallen to 6.9-7 hours.  Recent data indicate that a higher percentage of adult Americans report sleeping 6 hours or less. In 2005, in the US, more than 30% of adult men and women between the ages of 30 and 64 years reported sleeping on average less than 6 hours each night.   This decrease in sleep duration has occurred over the same time as the increase in the prevalence of obesity and diabetes.

Leptin has a distinct diurnal and circadian rhythm.  It has minimum values during daytime and a nocturnal rise with maximum values during early to mid sleep.  The amplitude of the circadian variation averages approximately thirty per cent.    Leptin levels rise during the night to suppress appetite while sleeping.   Moreover, the reduction of leptin at night spells bad news for the rest of the day: it sets the individual up not just with lower leptin levels in general but also decreased glucose tolerance and an increased craving for carbohydrates.

In order to test the effects of sleep deprivation on leptin production, a number of studies have been conducted.  They’re all fascinating, so I have provided a quick review of some of the more revealing studies.

1)   Many studies are conducted on people with sleep apnea.   Epidemiological studies show that they are heavier than the rest of the population.  They have greater rates of diabetes and metabolic syndrome.  Yet when their sleep apnea is corrected, these people lose weight naturally, and their metabolisms normalize.  This probably has to do both with decreased appetite as well as improved metabolic functioning.

2) In one study at the University of Chicago, doctors measured levels of leptin and ghrelin in 12 healthy men. They also noted their hunger and appetite levels. Soon after, the men were subjected to two days of sleep deprivation followed by two days of extended sleep. During this time doctors continued to monitor hormone levels, appetite, and activity.  The end result: When sleep was restricted, leptin levels went down and ghrelin levels went up. Not surprisingly, the men’s appetite also increased proportionally. Their desire for high carbohydrate, calorie-dense foods increased by a whopping 45%.

3) In another study at the University of Chicago, a similar protocol was conducted but men were asked to return a year later for a comparison. For six days they got four hours of sleep — their week of sleep deprivation.  The men’s food and activity levels were strictly regulated and hormone levels were taken during the day and while they slept.   One year later, the men returned for a six-day study with an 8-hour sleep period, so they served as their own comparison group.  The results: After their six-day sleep deprivation period, volunteers had a leptin decrease ranging from 19-26 percent.

4) In another study — a joint project between Stanford and the University of Wisconsin — about 1,000 volunteers reported the number of hours they slept each night. Doctors then measured their levels of ghrelin and leptin, as well as adiponectin, insulin, glucose, a lipid profile, and they also charted their weight.  The result: Those who slept less than eight hours a night not only had lower levels of leptin and higher levels of ghrelin, but they also had a higher level of body fat. What’s more, that level of body fat seemed to correlate with their sleep patterns. Specifically, those who slept the fewest hours per night weighed the most.

5)   In the final study, young, healthy subjects who were studied after 6 days of sleep restriction where they were allowed four hours in bed. After full sleep recovery, their levels of blood glucose after breakfast were higher in the state of sleep debt despite normal or even slightly elevated insulin responses. The difference in peak glucose levels in response to breakfast averaged was large enough to suggest a clinically significant impairment of glucose tolerance. These findings were confirmed by the results of intravenous glucose tolerance testing. Indeed, the rate of disappearance of glucose post injection was nearly 40 per cent slower in the sleep-debt condition than after recovery, and the acute insulin response to glucose was reduced by 30 per cent.

How fast do leptin levels recover from sleep deprivation?

Leptin levels recover almost as soon as regular sleep is resumed, at least in controlled studies.  In the first night.  However, these studies occur over a week or two at most.  If the sleep deprivation is chronic, it seems to have the same effect as fasting does on leptin.  Levels remain low–at least for some time–despite resumption of “normal” sleep or eating.  It takes time for the system to re-equilibrate after chronic stressors.

How does stress act on this system?

Stress activates cortisol secretion, but it also stimulates sympathetic nervous system activity.  This gets adrenaline running in the system, increases heart rate, and increases blood pressure.  These two things increase during both partial and acute sleep deprivation.  It is well kown that andrenergic (adrenal-related) receptor activation is suppressive of leptin production, and that leptin is reduced in response to adrenaline infusions.  For this reason, whatever dampening that stress puts on sleep negatively affects appetite activity.

There are other downstream effects of sleep deprivation.   I’ll cover some of them briefly here, then hopefully return to them each on their own.

1)  More cortisol dysregulation.  One effect of sleep deprivation is a decrease early evening cortisol levels.   Normally at that time of day, cortisol concentrations are rapidly decreasing in order to attain minimal levels shortly before habitual bedtime.  Yet in one study the rate of decrease of cortisol concentrations in the early evening was approximately 6-fold slower in subjects who had undergone 6 days of sleep restriction than in subjects who were fully rested. This means, basically, that it takes longer for people who have lost sleep to ramp down from that stress and be able to go to sleep again.

2)  Thyroid reduction.  In one study, after 6 days of 4-hour sleep time, people experienced a striking decrease in the normal nocturnal TSH rise, and the overall mean TSH levels were reduced by more than 30%. A normal pattern of TSH release reappeared when the subjects had fully recovered. T4 was higher in the sleep-restricted condition than the normal condition, indicating that decreased sleep decreases the body’s rate of conversion from T4 to T3.

3)  Growth hormone reduction.  The temporal organization of Growth Hormone secretion is also altered by chronic partial sleep loss. The normal single GH pulse occurring shortly after people fall asleep splits into 2 smaller pulses, 1 before sleep and 1 after sleep.  With decreased sleep, peripheral tissues are exposed to high GH levels for an extended period of time.  GH has anti-insulin-like effects, so an increased overnight exposure to GH negatively impacts insulin sensitivity and glucose tolerance.

 

 

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