Ok, although this is one of those topics that truly could have endless posts made about it, most of what I wanted to cover regarding bodyweight regulation and such was covered in the posts on leptin.
However, as I mentioned in that series, leptin turns out to be far from the only hormone involved in this.
I already talked a little about insulin in that series but there are still more hormones of some importance. With more likely to be discovered as time goes on. Oxyntomodulin, GLP-1, PP and others are being discussed in recent reviews and further research will go towards determining what in the hell is actually going on.
Tangentially, this is one of the big problems in trying to find a true ‘solution’ to the issue of weight loss and obesity: the human body has a number of overlapping, integrated and redundant pathways that all send signals to the brain. Fix one and something else eventually steps in to fill the role and cause problems.
From a pharmacological standpoint, this likely means that multiple drug therapy will be required; I also suspect that research and testing will help to identify whether any given individual has a specific pathway that is more of a contribution, perhaps allowing drug or nutritional therapy to be more individually tailored. However, this is likely to be years off from practical application.
Anyhow, I want to finish up by talking about a few of these other hormones focusing on three main ones: Cholecystokinin, ghrelin and Peptide YY as these three currently have the most research on them.
Cholecystokinin, or CCK, was one of the first fullness hormones found, originally discovered back in the late 1960’s. Released from the intestines in response to nutrient intake, it goes to the brain, binds to its specific receptor and helps to signal fullness on a meal to meal basis. CCK doesn’t appear to play much of a role in the long-term regulation of bodyweight, its simply a fullness signal in response to meals.
Nutritionally, protein, fat and fiber play a primary role in stimulating CCK with carbohydrate having a much smaller effect; this may explain part of the appetite blunting effect of many low-carbohydrate diets (which are generally high in protein, fat and fiber).
As I mentioned in a previous post, CCK doesn’t work very well when leptin is low explaining why lean dieters can do everything ‘right’ nutritionally and still be a hungry an hour later.
Released primarily from the stomach, ghrelin goes to the brain where, predictable, there is a specific receptor. Among other functions, ghrelin raises levels of growth hormone. But that’s far from all.
Ghrelin also stimulates hunger (the only hormone so far found to do so) and appears to be a key hormone in initiating the hunger that goes along with meals; ghrelin drops prior to hunger and injection of ghrelin stimulates hunger specifically.
Even more interestingly, there is research suggesting that ghrelin levels become entrained to normal meal times.
So if you normally eat at 3pm (or whatever), you’ll likely find yourself becoming hungry at 3pm; this appears to occur from changes in ghrelin. I suspect this explains why people often have problems changing meal frequency, at least until ghrelin re-entrains itself to the new frequency.
That is, moving from a higher to lower frequency of meals is often accompanied by hunger at the previously ‘normal’ meal times. Moving from lower to higher is often accompanied by a lack of hunger until the body adjusts to the new frequency. I haven’t seen any work examining how long this takes but empirically it seems like it’s a couple of weeks or so.
Increased ghrelin also negatively impacts on pretty much all aspects of metabolism, slowing metabolism and increasing fat storage, at least it does this in rats with daily infusion.
In this vein, I’ve heard rumors that ghrelin is being promoted as a bulking aid for athletes and bodybuilders, both for the appetite increasing effects and the GH release. Given the negative aspects of ghrelin on metabolism, this is truly an awful idea unless the goal is to just get really fat.
As it turns out, ghrelin changes in the opposite direction of leptin; while leptin falls on a diet, ghrelin goes up. It almost goes without saying that leptin levels have a hand in controlling ghrelin; leptin appears to restrain both grhelin release from the gut and its stimulation of hunger.
So dieting, as usual is a double whammy in this regards: leptin goes down as ghrelin is going up with the reduction in leptin being partly responsible for the increase in ghrelin.
Ghrelin appears to play a role in both short- and long-term hunger and long-term bodyweight regulation. As mentioned above, ghrelin goes up prior to a meal; it also comes back down after eating.
However, ghrelin levels also increase overall with a loss of weight/bodyfat, decreasing when weight is gained. Individuals with a high BMI have lower ghrelin (and the idea of ghrelin resistance has been thrown around) and anorexics have higher ghrelin (which decreases with refeeding).
Nutritionally, carbohydrates appear to play a primary role in regulating ghrelin levels with dietary fat having less of an impact, the effect of protein is currently unclear. In one study, a high carbohydrate/low-fat diet generated weight loss without the normal increase in ghrelin levels.
And although only tested in anorexics, at least one study showed that the consumption of non-caloric fiber reduced ghrelin levels. Consuming small amounts of guar gum or psyllium fiber between meals might help to keep ghrelin down during a diet.
Perhaps ironically, it appears that low-sodium intakes increase ghrelin levels (although there is a racial effect). As I discussed in this article, I wonder if the low-sodium intakes taht contest bodybuilders and figure competitors often obsess about isn’t making things worse rather than better.
In one study increases in ghrelin with weight loss were related primarily to fat free mass loss but not body fat loss per se. As good reason as any to ensure that the diet is set up to prevent lean body mass loss.
Of some interest, one of the ways that bariatric surgery appears to be so successful is that, despite the massive weight loss generated, there is often no increase in ghrelin levels as would be seen with diet induced weight loss.
This may explain why weight is so rapidly lost, seemingly without hunger, with that surgery. I’d note that research also suggests that other hormone (such as Peptide YY, discussed next, and Glucagon like peptide 1, are more relevant to the hunger suppressing effect of the surgery).
Finally is peptide YY (PYY), another important hormone released primarily from the small intestine. Like CCK, PYY decreases hunger and appetite although it may do so for longer periods. Infusion of PYY blunts hunger in humans for up to 24 hours.
More physiologically, PYY increases with 15 minutes of eating and may stay elevated for up to 5 hours. Of some relevance to the issue of overweight, obese individuals have been found to have lower basal PYY levels and less of an increase with meals.
Of course, since this is all interconnected, administration of PYY has been shown to reduce fasting PYY levels as well as preventing the normal increase in ghrelin before meals.
Nutritionally, PYY appears to be related primarily to the energy content of the meal although work suggests that dietary fat has the biggest impact on PYY. The appetite supressing effect of protein appears to be related to increased PYY levels as well. Fiber increases PYY as well.
Of some interest, one study comparing a lowcarb/highfat to highcarb/low fat diet found that the lowcarb/high fat diet had a greater sustained effect on PYY levels in obese individuals.
Where does this all leave us?
As I mentioned above, there’s a lot of interacting and overalapping things going on when it comes to appetite/hunger and bodyweight/bodyfat regulation. Even looking at the above hormones it’s clearly complicated without worrying about leptin, insulin, blood glucose and everything else.
For example, one study finds that high carbs and low fat is better for supressing ghrelin while another finds that lowcarb and high fat has a bigger impact on peptide YY (which may be low in the obese to begin with).
Which diet is better?
Looking at individual macronutrients carbs have the largest impact in supressing ghrelin while protein, fat and fiber appear to have the biggest impact on CCK and peptide YY.
Is one hormone relatively more important than the other or is a moderate approach to dieting, where each meal contains all four macronutrients (plenty of lean protein, moderate fat, dietary fiber and moderate amounts of carbohydrates) going to be superior by targetting all of the gut hormones (in addition to providing the greatest dietary flexibility and variety)?
Is keeping ghrelin from going up relatively more important than increasing CCK and PYY or does it simply depend on the individual? If raising PYY with plenty of protein, fat and fiber not only helps with short-term fullness but also blunts ghrelin increases (as infusion studies suggest) does that avoid the whole issue since you accomplish both (increased PYY and lowered ghrelin) with the same intervention?
Does all of this lend more credence to the use of low-carbohydrate diets for the treatment of obesity? There’s an additional interaction of diet with insulin sensitivity as well; something I haven’t talked about in this series but discuss in Insulin Sensitivity and Fat Loss.
As I noted above, my gut (ha ha, get it?) says that different individuals are going to be relatively more or less responsive to the different hormones.
If ghrelin is a bigger issue than the other hormones (and insulin sensitivity is good), then a high carb/low-fat diet may very well be the superior choice for a given individual. If PYY is dominant (and insulin sensitivity is poor), a low-carb/higher fat diet may be the best choice.
I’m not saying that I have the answers, I’m not sure anybody does at this point. As noted, I suspect that we will get to the point that basic testing of gut hormone levels, insulin sensitivity, etc. will get us to the point that diet optimization can occur. I’m not sure when that’s going to happen, though.