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The Hormones of Hunger

January 29, 2013 in Hormone Regulation

I want to delve into the effects of diet and lifestyle on hunger and satiety signals in a series of upcoming posts.  I am mostly interested in the hormone dysregulation that occurs during metabolic syndrome, but also in how to optimize diet, exercise, sleep and stress management to achieve an ideal weight.

The feeling of hunger is regulated by a complex system of hormones that interact with neurotransmitters and neurotransmitter receptors within the hypothalamus region of the brain.  These hormones essentially activate or deactivate specific neurons in the hypothalamus that control hunger.  These neurons have receptors to Neuropeptide Y (NPY), the essential neurotransmitter in regulating hunger.  The hormones can increase or decrease hunger either through binding the receptors for NPY or increasing or decreasing NPY itself.  Essentially a hormone will increase hunger if its expression activates these NPY neurons whereas you will feel satiated if a hormone’s expression deactivates the NPY neurons.  The interplay between these hormones and your brain is complex and only partially understood.  However, what scientists do know about these hormones can help inform our decisions and compulsions regarding diet and other lifestyle factors. 

New hormones continue to be discovered and their roles in regulating appetite, satiety, metabolism and digestion continue to be studied.  As the full list of hunger hormones grows, understanding the complex interplay between these hormones, the types of food you eat, and the amount of muscle and fat on your body quickly becomes overwhelming.  I have tried to summarize the key players (at least as scientists currently understand them):

Hormones that tell your body you’re satiated:

Cholecystokinin (CCK) is secreted by the cells that line the duodenum (the first segment of the small intestine) when they detect the presence of fat.  This causes the release of digestive enzymes from the pancreas and bile from the gallbladder.  Increased levels of CCK signals to the stomach to slow down the speed of digestion so the small intestine can effectively digest the fats.  CKK is also a neuropeptide similar to NPY and has a direct action on neurons in the brain to signal satiety.  This is the most immediate hunger suppressing signal and is the reason why eating fat with your meals is so important.

Oxyntomodulin is released in response to protein and carbohydrates in the stomach and signals a change in energy status to the brain.  Oxyntomodulin enhances digestion by delaying gastric emptying and decreasing gastric acid secretion.

Peptide YY (PYY) is released by cells that line the jejunum, ileum (the next two segments of the small intestine) and colon in response to feeding and is especially sensitive to protein.  PYY signals to the gallbladder and pancreas to stop producing digestive enzymes.  PYY is important in increasing the efficiency of digestion and nutrient absorption after meal by slowing down gastric emptying, slowing down the speed of digestion, and increasing water and electrolyte absorption in the colon.  PYY interacts directly with NPY receptors in the hypothalamus in an inhibitory fashion, thereby turning off hunger signals.

Glucagon-Like Peptide-1 (GLP-1) is secreted in the ileum in response to carbohydrate, protein and fat.  It rapidly enters the circulation and is one of the fastest and shortest-lived satiety signals.  It inhibits acid secretion and gastric emptying in the stomach.  GLP-1 also increases insulin secretion and decreases glucagon secretion.  GLP-1 decreases hunger signals by reducing the amount of NPY.

Leptin plays a key role in regulating energy intake and energy expenditure, including appetite and metabolism.  Leptin is released both by adipocytes (fat cells) and by the cells that line the stomach, so it signals both that the body is fed and that there is sufficient energy storage.  This appetite inhibition is long-term, in contrast to the rapid inhibition of eating by CCK and the slower suppression of hunger between meals mediated by PYY.  Leptin both rapidly inhibits NPY production and deactivates NPY neurons in the brain to signal that the body has had enough to eat, producing a feeling of satiety. It is one of the most important adipose derived hormones (read more in this post).

Adiponectin is secreted from adipose tissue into the bloodstream where it signals decreased gluconeogenesis (when the body converts fats and proteins into  glucose for energy), increased glucose uptake, lipid catabolism (breaking down of fats), triglyceride clearance (storage of fats), increased insulin sensitivity, and control of energy metabolism.  Adiponectin acts directly on NPY neurons similarly to leptin but with additive effects.

Hormones that tell your body you’re hungry:

Ghrelin is considered the main hunger hormone.  It is secreted by the cells that line the stomach when the stomach is empty and also by the pancreas when it detects low blood sugar.  Also, the liver secretes ghrelin when its glycogen storage runs low (and glucagon is high).  When ghrelin is released into the circulation, it directly activates NPY neurons to stimulate appetite.  Increased levels of ghrelin are directly associated with the sensation of hunger. It is considered the counterpart of the hormone leptin.  Importantly, ghrelin is a potent stimulator of growth hormone (GH) secretion and regulates nutrient storage, thereby linking nutrient partitioning with growth and repair processes. Ghrelin activates several anti-inflammatory pathways in the body and promotes cell regeneration thereby promoting healing, especially within the gastrointestinal tract. Ghrelin regulates glucose homeostasis through a direct action on the pancreatic islet cells (the cells that secrete insulin).  It is also important for memory function and gastrointestinal motility.

Cortisol is well-known as a stress hormone, but it has key roles in regulating metabolism and hunger.  Cortisol levels determine whether the body uses glycogen stores or triglyceride stores for energy (stored carbohydrate or stored fat).  Cortisol can also stimulate gluconeogenesis, the process of converting amino acids (proteins) and lipids (fats) into glucose in the liver.  It is believed that cortisol directly influences food consumption by acting on NPY neurons in the brain as well as affecting the levels of NPY and leptin.  Cortisol seems to have a particular effect on the desire to eat foods high in fat and sugar.  This is why stress management (which really means controlling any factor that might mess with your natural cortisol levels) is so important.

Glucagon is a hormone secreted by the pancreas when it detects low blood glucose levels (typically between meals, but this can also happen as part of that “sugar crash” after eating something very high carbohydrate).  Glucagon signals the liver to convert stored glycogen into glucose, which is released into the bloodstream, a process known as glycogenolysis.  When glycogen stores are low, high glucagon levels drive gluconeogenesis, the process of creating glucose from amino acids and fatty acids.  Increased glucagon amplifies the hunger sensation.

Insulin is secreted by the pancreas in reaction to high blood glucose levels (for more on insulin, see this post).  Insulin causes cells in the liver, muscle, and fat tissue to take up glucose (and fatty acids in the case of adipocytes) from the blood, storing it as glycogen.  While insulin is released as a result of eating carbohydrates, it paradoxically increases hunger as opposed to decreasing it.  This is caused by direct action on the NPY neurons and is the reason why eating a carbohydrate-rich meal is not as satiating as eating a meal that includes fats and proteins.  It also explains how quickly we feel hungry again after a high-sugar snack.

These hormones have important roles both in regulating aspects of digestion and signaling to the brain whether or not you need to eat.  Many of these hormones are also critical in regulating your blood sugar both after a meal and between meals (fed and fasted states).  Some of these hormones also affect other systems in the body, for example, interacting with the immune system and controlling inflammation.  Understanding how your diet and lifestyle affect these hormones will help you make choices that regulate these hormones properly, allowing yourself to listen to your hunger cues and trust that your body knows what it’s doing.  And regulating hunger hormones is a key part of healing and being healthy.

hunger hormones

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The Hormones of Fat: Leptin and Insulin

October 23, 2012 in Hormone Regulation, Weight Loss/Gain

Hormones tell your body whether to burn fat and lose weight or to store fat and gain weight or to find balance and weight maintenance in between.  When it comes to your body “deciding” what state to be in, there are two key hormones that regulate food intake and energy balance:  the adipocyte hormone leptin and the pancreatic hormone insulin.  While there are many other hormone players with complex interactions between them, understanding these two hormones (which you could think of as the hormones of fat) will give you important insight into how the diet and lifestyle choices you make can help you achieve and maintain a healthy weight.

The hormone insulin, which is released by the pancreas in response to increased blood sugar, facilitates the transport of glucose into the cells of your body and signals to the liver to convert glucose into glycogen for storage.  When glycogen stores are maxed out, increased insulin levels stimulate conversion of glucose into triglycerides (fat) for long-term storage in adipocytes (fat cells) 1.  But beyond this important action for the metabolism of fuels, insulin has an additional role as an adiposity signal to the brain, i.e., it tells the brain whether or not you should eat and informs the brain about the energy status of your body.

The major stimulant of insulin secretion is an increase of blood glucose levels, as detected by the pancreas (blood glucose levels go up when you eat carbohydrates).  Circulating insulin enters the brain (proportionally to the amount that is circulating in the blood) where it binds to receptors in the hypothalamus region of the brain.  Although the exact details are unknown, it is understood that through this interaction with the central nervous system, insulin stimulates a decrease in food intake 2,3.  This makes some sense.  You eat, your blood sugar level rises, your body releases insulin to store all that glucose, and that increase in insulin tells your brain that you’ve got enough energy, thank you very much.  Importantly, the degree of glucose-stimulated insulin secretion by the pancreas is a direct function of body fat 4,5.  The more body fat, the more insulin is secreted both at a basal level and in response to feeding.  There is also a maximum amount of insulin that can actually cross the blood-brain barrier to stimulate satiety.  As the blood concentration of insulin increases beyond this level, no further signaling to the brain can occur.  Insulin resistance occurs when more insulin is required to maintain a normal level of blood glucose, and potentially when there is a decrease in insulin receptors in the brain, meaning that those high levels of circulating insulin don’t decrease appetite the way they are supposed to.

Fat storage cells, called adipocytes, produce the hormone leptin, which acts as a negative feedback control for adiposity (fatness).  Leptin is secreted by adipocytes (fat cells) in direct proportion to the amount of stored body fat, in particular, the amount of subcutaneous fat.  Similar to insulin, circulating leptin enters the brain where it binds to receptors (there are receptors for leptin in the hypothalamus but also several other areas of the brain).  Again, the exact details are unknown, but it is understood that leptin’s interaction with the brain stimulates a reduction in food intake and increasing energy expenditure 6.  This also makes some sense.  You have a good amount of fat stores, leptin is released and tells your brain that you have enough energy so you don’t need to eat anymore and hey, let’s get moving!  And analogous to insulin resistance, the body can also become leptin resistant, although this can happen from both obesity and overconsumption of energy 7 and by fasting or consuming too few calories and losing weight 8!  Uh, yeah.  Leptin is tricky.

It was initially believed that leptin’s dominant role was to tell the brain to stop eating.  However, recent studies have shown that it mediates the adaptation to fasting 8.  Fasting or consuming too few calories on a regular basis can lower sensitivity to leptin, which leads to increased hunger, cravings and lack of energy.  This has a very important implication in weight maintenance after weight loss since reduced leptin sensitivity is likely responsible for lowered metabolism and increased hunger, a combination that tends to lead to weight gain (why it’s so hard to keep weight off after going on a diet).  There is also a link between leptin and cortisol release, potentially explaining the cortisol spike that many people experience in response to intermittent fasting.  The many roles of leptin in the human body are still being studied.  It has also been implicated in the regulation of the reproductive, thyroid, growth hormone, and adrenal axes, independent of its role in energy balance.

To date, only the hormones leptin and insulin are known to act as adiposity signals 9.  The amount of leptin and insulin in the blood correlates with adiposity.  There are receptors in the brain for both insulin and leptin in areas of the brain known to be important in the control of food intake and energy balance.  Studies which have injected insulin or leptin show that this causes a reduction in food intake, whereas injection of antibodies to block insulin and leptin causes an increase in food intake.  Importantly, recent studies have demonstrated that insulin and leptin have additive effects when administered simultaneously 10.

What are the implications of this information for those who want to lose weight?  I think there are two major take home points here:

  1. Controlling insulin by avoiding high blood sugar is important for regulating hunger.
  2. Slow and steady wins the race in terms of weight loss and leptin sensitivity. 

I will be continuing to discuss many different hormones and the roles they play in health and weight loss over the next few months.  Leptin and insulin will feature prominently in these posts.

1. Click here for more information on insulin and its role in metabolism.

2. Begg DP and Woods SC. “The central insulin system and energy balance.” Handb Exp Pharmacol. 2012;(209):111-29.

3. Woods SC et al “Signals that regulate food intake and energy homeostasis”. Science. 1998 May 29;280(5368):1378-83.

4. Polonsky K S et al “Twenty-four-hour profiles and pulsatile patterns of insulin secretion in normal and obese subjects.” J Clin Invest. 1988 February; 81(2): 442–448.

5. Polonsky KS et al “Quantitative study of insulin secretion and clearance in normal and obese subjects.” J Clin Invest. 1988 Feb;81(2):435-41.

6. Ahima RS et al. “Leptin regulation of neuroendocrine systems.” Front Neuroendocrinol. 2000 Jul;21(3):263-307.

7. Enriori PJ et al “Leptin Resistance and Obesity” Obesity (2006) 14, 254S–258S; doi: 10.1038/oby.2006.319

8. Ahima RS.  “Revisiting leptin’s role in obesity and weight loss.” J Clin Invest. 2008 Jul;118(7):2380-3.

9. Benoit, SC. “Insulin and Leptin as Adiposity Signals” Recent Progress in Hormone Research 59:267-285 (2004) (link to the paper here)

10. Air EL et al “Insulin and leptin combine additively to reduce food intake and body weight in rats.” Endocrinology. 2002 Jun;143(6):2449-52. (link to the paper here)

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Why is Exercise so Important?

September 18, 2012 in Exercise, Hormone Regulation

Let’s get one thing straight:  exercise is not about “burning calories”.  The amount of calories you actually burn exercising compared to sitting and doing nothing is not really that much.  It certainly adds up very slowly when you consider that 3500 calories is equivalent to one pound of stored energy.  If you want to lose weight, focus on your diet (see my post Tips and Tricks For Losing Weight).  But, while diet changes will make the largest contribution to weight loss, it’s important not to ignore exercise!  However, think of exercise as your hormone management, not your calorie burning.

 Hormones are chemical messengers in contact with virtually every cell in your body, sensitive to the demands of your cells, sensing changes in your body’s chemistry, and responding rapidly to ensure that the cells in your body get everything they need to stay healthy.  Exercise has a profound effect on every hormone system in your body.  Whether that exercise is aerobic or anaerobic, cardio intensive or strength training, low-intensity or high-intensity, and short duration or long duration, changes how that exercise affects each hormone system.  It also matters what time of day you exercise, whether or not you exercise in a fasted state, and what other stressors are present (mental stress, lack of sleep, poor quality diet, etc.).  However, what is uniformly true is that exercise is beneficial to hormone regulation. 

 Some of the benefits of exercise are obvious.  Increasing muscle mass causes an increase in metabolism, making it easier to maintain a healthy weight.  Most people like the way they look better when they have bigger and more defined muscles (I do!).   And it’s just plain handy to be stronger, faster, more flexible and more agile.  But there are some additional benefits that you might not immediately think of as you contemplate adding more or different types of activity to your life.  The field of exercise endocrinology (how exercise affects hormones) is enormous and I will be tackling many key areas in upcoming posts.  In particular, I will touch on each of the following benefits to exercise:

 Appetite and Weight Control:  Exercise is known to regulate key hunger hormones such as leptin and ghrelin (I have a whole post on hunger hormones coming soon!) and may even promote healthier digestion through hormone regulation.  It is not necessarily true that exercise makes you hungrier, although it may feel that way.  In fact, for many people (and depending on the type of exercise), exercise makes it easier to naturally consume fewer calories in an entire day (even if you eat a bigger meal right after working out).  Not only does exercise regulate your appetite, but many people find that they naturally crave more nutrient-dense foods.  I myself crave fish and vegetables after an intense workout and while I feel famished, I actually fill up much more quickly than on days that I don’t exercise as much or as intensely.  Exercise is also believed to help lower your bodyweight “set-point” (a controversial idea that basically says that there is a weight which your body “wants” to be, which is determined by your hormones, which are in turn influenced by diet and lifestyle).

 Metabolism and Insulin Sensitivity:  Exercise helps to improve insulin sensitivity through a direct action on the glucose transport molecules in the individual cells of your muscles.  It also affects the full range of hormones related to accessing stored energy and regulating how that energy is used.  This “boost” in metabolism is one reason why exercising can make you feel more energetic throughout the day.

 Body Composition and Bone Health:  When you exercise, your muscles get stronger (and sometimes bigger, depending on the exercise).  This is one contributor to increased metabolism.  And very importantly for long-term health, exercise (especially weight-bearing exercise) stimulates your body to make stronger and denser bones.  Exercise or lack thereof is, in fact, a bigger determinant of osteoporosis risk than diet.

 Stress Management:  Exercise is very effective at modulating cortisol levels.  This is a bit of a double-edged sword because exercising too intensely for your body can increase your cortisol level too high and lead to adrenal fatigue.  However, if you keep exercise to a more appropriate duration and intensity for your fitness level (and appropriate for how well you eat, sleep and manage stress in other areas of your life), exercise becomes very potent at reducing and normalizing cortisol levels (which can also help reduce inflammation and promote healing).  This makes it easier to burn stored energy (especially fat), improves your sleep, and makes you feel more relaxed and able to cope with life’s surprises.

 Sleep Quality:  Beyond its effect on cortisol, exercise regulates several key hormones related to circadian rhythms.  This means that when you exercise during the day, you fall asleep easier, sleep more soundly, and experience more restorative sleep so you wake up feeling more refreshed (providing you allot adequate time for sleeping).  Sleeping better positively affects just about everything in your body, from your cortisol levels to your body’s ability to heal and resolve inflammation.  This is another double-edged sword because exercising too intensely too late in the day can make it more difficult to fall asleep.

 Mood:  Beyond its effect on the stress hormone cortisol, exercise releases endorphins which has a direct reflect on several key neurotransmitters that are related to mood.  This means that making time to exercise can help fight depression and anxiety and improve your general outlook on life.  Exercising also increases blood flow to the brain which can help reduce inflammation in the brain (which also has the net effect of boosting your mood), which is an important strategy for those with gut-brain axis problems.

 What exercise is best?  There are different benefits of exercise, depending on type, duration and intensity, but with the exception of over-training (exercising more too intensely or for too long of a duration for your body and current fitness level), all exercise is extremely beneficial.  What exercise is best for you depends on your goals and your current health status.  As I delve into the specific effects of different types of exercise on different hormone systems in upcoming posts, hopefully you will find enough information to guide your decision making when it comes to prioritizing one activity over another.  But, what matters most is that you do something—even just a gentle stroll.  And even better, do something you enjoy (for me, that’s yoga!).  If you enjoy your activity, you are far more likely to keep doing it.

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Is Breakfast Really the Most Important Meal of The Day?

June 28, 2012 in FAQ, Food Issues, Hormone Regulation, Weight Loss/Gain

The paleo community is accustomed to pushing back against dietary recommendations from the USDA and medical establishment.  We like to argue that whole grains and legumes are universally detrimental to human health, that the high omega-6 fatty acid content of modern vegetable oils and grain-fed meat is responsible for the rise in cardiovascular disease seen in the last three decades, and that eating refined sugars causes decreased insulin and leptin sensitivity and is responsible for the current diabetes epidemic.  These arguments are all extremely well backed-up with solid science, which is one of the reasons why the paleo diet is so successful.  The paleo diet is the first diet to be based on comprehensive, current, high-quality scientific evidence of the effect of specific foods on our overall health (and structured with an ancestral health perspective).  And while aspects of this diet will almost certainly change as more research is performed, the foundation is rock solid.

When it comes to whether or not breakfast is important, the paleo community is firmly divided.  Many supporters of intermittent fasting prefer to skip breakfast at least a couple of times per week (Chris Kresser has stated that he skips breakfast 2-3 times per week), while other paleo gurus almost never eat breakfast at all (Mark Sisson has stated that he almost never eats breakfast, Mat Lalonde doesn’t eat until lunch and sometimes only eats one meal per day).  The rationale behind skipping breakfast comes from two places:  listening to our bodies and not eating until we’re hungry and the benefits of intermittent fasting.  Many in the paleo community will tell you that breakfast is “just another meal” and there is nothing special about it.  Many will tell you that if you aren’t hungry in the morning, you shouldn’t eat.  I believe this to be true for people who are already extremely healthy, but if you have a history of metabolic derangement (i.e., if you were ever very overweight) or a history of adrenal fatigue, then skipping breakfast might not be such a good idea.

Cortisol management is a key goal of a paleolithic lifestyle and is essential for regulating inflammation, boosting the immune system, and regulating energy and mood.  Cortisol is an essential hormone, involved not only in the body’s normal stress response, but also in regulating blood sugar and circadian rhythms.  Cortisol is naturally at its highest in the morning.  If you are getting adequate sleep and managing your stress, your cortisol level gradually decreases throughout the day and the first three quarters of your night’s sleep.  There are two ways your cortisol can be disregulated.  The first is chronically elevated cortisol, where your cortisol still decreases throughout the day but remains higher than normal at all times.  The second is where your cortisol starts off low in the morning and increases through the day, which is the source of that second wind in the evening for many who are chronically sleep-deprived (this is called the “tired and wired”: pattern).  If you have a history of adrenal fatigue, inadequate sleep or poor sleep quality, metabolic syndrome or obesity, or poor stress management, then you may not have normal cortisol levels (you might have chronically elevated cortisol or tired and wired cortisol expression).  And even if you have made progress toward addressing these issues, your cortisol management may be tenuous.  This is what happened to me.

The issue with skipping breakfast is that your body increases cortisol in order to stimulate glycolysis or gluconeogenesis to raise your blood sugar so that your body has energy for whatever you are doing.  If you have a morning coffee, your cortisol will increase even more.  In a very healthy individual with perfectly normal cortisol levels and well-regulated expression of hunger hormones, good insulin-sensitivity and good leptin-sensitivity, this rise is temporary and the body adapts beautifully.  But if you don’t have normal cortisol levels or optimal insulin sensitivity or optimal leptin sensitivity or well-regulated ghrelin, this rise in cortisol in the morning can lead to increased cortisol throughout the day or abnormal swings in cortisol levels.  Importantly, there is evidence that women are more susceptible to an exaggerated cortisol response to fasting.  Women, therefore, are less likely to see a benefit to routinely skipping breakfast.  When I started skipping breakfast on a regular basis, I noticed that my weight started creeping up and that my sleep quality deteriorated, classic signs of high cortisol (of course it took me two months to figure this out!).  When I started eating breakfast again, I found that my hunger was less throughout the day, I lost the weight that I had gained quite quickly, and I started sleeping much better.

If your goal is weight loss, then skipping breakfast routinely is probably not the best choice (it’s probably fine and maybe even beneficial if you are already quite lean and very healthy).  In fact, eating breakfast every day is one of the three habits known to correlate very strongly with not only weight loss success but also in maintaining that weight loss once your goal weight is reached.  Of course, this doesn’t mean that you can’t experiment with Intermittent Fasting.  And it doesn’t mean that skipping breakfast on a regular basis won’t work well for you in the future.  Just be mindful of how it’s affecting you so that you can gauge whether or not breakfast really is the most important meal of the day for you.

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