Eat More, Burn More and Lose Fat Like on Crack with GLP-1!? Roux-en-y Bypass Study Sheds a Whole New Light on Satiety(Hormone)-Induced Weight Loss

Image 1: A gastric bypass should always be the last option; with all the possible complications it is nothing to treat lightly (img medcenterone.com)

Everyone who has read the Intermittent Thoughts on "Goal Setting and Programming Success" with the three somatypes, SuperSize Homer, Peter Griffin and Anorexic Stan, will be aware that I do acknowledge the oftentimes life-saving benefits of surgical anti-obesity interventions, when everything else fails. Until recently, I did however assume that"cutting off" a part of your stomach or using a sling or other devices to reduce its size would simply reduce a patients ability to overeat, thusly reduce hi caloric intake and help him to cut his weight back into a region that is no longer life-threatening. The recent publication of a study by scientists from the Harvard Medical School (Nestoridi. 2012) does yet suggest that the effects of roux-en-y gastric bypasses are in fact way more far reaching than, at least I, had previously thought.

Does a roux-en-y bypass "actively" burn fat!?

In their experiment Erini Nestoridi and her colleagues had observed that the overweight mice in the active arm of their study, i.e. those mice who were not just cut open (sham group), but had also received the roux-en-y gastric bypass (RYGB), did not only lose body fat like crazy, they did also consume significantly more calories, expended significantly more oxygen (a marker of fatty acid oxidation), had a significantly lower respiratory quotient (=burned more fat than glucose for fuel) and wasted almost twice as much energy in the form of body heat than their sham-operated peers, so that their overall energy balance looks like they were on DNP or any other "true" thermogenic fat burner (cf. figure 1)

Figure 1: Energy intake, respiratory quotient (higher levels = more glucose, less fatty acid oxidation), heat production, fat free mass and fat mass during and at the end of the 8-week intervention trial subsequent to either sham or roux-en-y gastric bypass operations on obese mice (data calculated based on Nestoridi. 2012)

In combination with the to-be-expected increase in fecal energy loss (44kcal/day vs. 13kcal/day), which occurred as a consequence of the decreased transit time and ability to absorb nutrients from the chow, these changes explain very well, why, at the end of the 8-week intervention period, the RYGB mice had lost all their unhealthy fat depots, while their sham operated had gained another 6g of body weight.

Gastric bypasses increase the GLP-1 response and thusly restore metabolic health

All that reminded me of some research with regard to the metabolic role of the so-called satiety hormones, CKK, PYY and above all GLP-1 I have been doing as of late. Glucagon-like-peptide 1 (GLP-1), in particular, exerts profound and far reaching metabolic effects, which have little to do with the satiety function its label "satiety hormone" does imply. Interestingly, the restoration of normal fasting blood glucose levels, the  normalization of the glucose response to an oral glucose tolerance test, the increased fatty acid oxidation and even the RYBG mice' profoundly reduced preference of the hypercaloric high fat chow (after the surgery the rodents had free access to normal and the highly palatable "high fat" chow, on which they had accumulated a 50% body fat percentage before the surgery) have all been associated with increases in GLP-1 levels in previous studies. In their 2005 review of the literature, Burcellini et al. even mention the involvement of cerebral GLP-1 in cognition and memory (Burcelin. 2005).

A 2012 case-report in which Myint et al. (Myint. 2012) describe a RYBG patient who suffered from recurrent episodes of hypo(=low)glycemia due to increased GLP-1 levels would support my hypothesis that GLP-1, or rather its increased expression subsequent to gastric bypass operations could be the root cause of all the beneficial metabolic effects in the rodent study at hand and the thousands of human beings whose lives have been saved by this surgical intervention, as of yet. That this is not just a transient or outlier effect, but something we see across the board in all RYGB patients and which remains, even at a10-year follow-up has been confirmed by Mohamad S. Dar and his colleagues from the East Carolina University, who examined the GLP-1 response to oral meal consumption in 5 RYGB patients 10 years after the operation and found that the "exaggerated GLP-1 response [is] maintained [...] despite statistically significant
weight loss".

The fat burning effect of eating to satiety

Image 2: Adelfo's progress during his contest prep are an excellent example for the highly desirable "side effects" of eating to satiety.

Now, it would not only be plain out stupid to get a gastric bypass done, when that is not medicinally necessary, it would also compromise the value of "my" hypothesis that GLP-1 could in fact be the main working mechanism behing RYGB induced weight loss, if it was not (a) increased / higher in the billions of people who do not get obese in the first place and if there were not (b) other most prominently dietary means to increase GLP-1 which trigger similar beneficial metabolic effects. As you may imagine, I would not have proposed this hypothesis, if I had not already come across pertinent research, such as a 2006 study by Nicola Pannacciulli et al. in which the NIH researchers found a statistically significant association between GLP-1 levels and resting energy expenditure in 46 glucose tolerant male and female subjects with BMIs ranging from 18.6-50m²/kg (Pannacciulli. 2006).

A preliminary GLP-1 cheat sheet for the obese and non-obese dieter

The following list of dietary GLP-1 "agonists" is yet still "work in progress" and more of a preview on a future, comprehensive blogposts of the role of the metabolic function of the incretin hormones, I am currently working on (whenever I have 1s of time to spare ;-):

• short chain fatty acids (Tulhurst. 2012) 
• fermentable fiber (Greenway. 2007)
• fermentable resistant starches (Zhou. 2008)
• bile acid (Katsuma. 2005; Parker. 2012)
• egg and meat hydrosolates (Cordier-Bussat. 1998)
• milk proteins (Hall. 2003; Juvonen. 2011)
• fish oil (only if administered interperitoneal; Motoshita. 2008)
• fats, when added to starchy carbs (e.g. Frost. 2003)

Unfortunately, things can become quite confusing, because despite all those "starches" and "fibers" in the list, there are studies, which report the exact opposite effects for some of the classic dietary fibers, like psyllium, for example (Karhunen. 2010). Conflicting results by Wang et al. who report 2x increased GLP-1 levels in response to psyllium or sugarcane fiber enriched high fat diets (Wang. 2007), do thusly raise the question if the GLP-1 response is either (a) species-specific (the Wang study was done on mice), (b) depends on the accompanying nutrients (both studies used rather high fat foods / chow, though), or whether (c) the difference is a simple consequence of the study design, i.e. acute (Karhunen) vs. chronic (Wang) ingestion of fiber-(en)rich(ed) food / chow.

Could it not be about insulin, but about GLP-1?

And although we certainly cannot rule out (a) completely and must acknowledge that (b), i.e. man vs. mouse, will always make a difference, I personally believe that overall (c), i.e. the differences between the acute, the longer term and the chronic effects are, are most likely responsible for the differences in GLP-1 response and the ensuing metabolic effects. After all, fermentable fiber, fermentable resistant starches and psyllium all increase the production of short chain fatty acids in the colon. The beneficial effects the latter have on the amount of GLP-1 that is released will however arise at a very late stage of the digestion process. the decrease in GLP-1 Karhunen et al. report in their study, on the other hand, was measured right after the ingestion of the meal.

Don't forget: In non-insulin resistant individuals, glucose, or rather its transportation via the GLUT-2 receptors is a stimulator of GLP-1 release, as well. It is thusly not really surprising that Lee et al. have recently been able to show that its release is impaired in diabetic rats (Lee. 2012). With an intact GIP response (cf. WMHDP article for more on how GIP is making you fat) diabetics and most likely also "just insulin resistant" individuals are thusly getting all the negative without any of the beneficial effects of carbohydrate ingestion, so that GLP-1 is yet another piece in the "why low-to-no-carb works / may even be necessary for obese diabetics, but is unnecessary for healthy individuals" puzzle, I've been putting together with a whole host of posts over the past couple of weeks.

Given GLP-1's role as a mediator of glucose disposal and fatty acid metabolism, it is thus likely that the long-term health benefits I have hinted at in the context of the gastric bypass study, arise only when we have a steady "elevation" or rather steadily high-normal levels of GLP-1, instead of some punctuated spikes, as Karhunen observed them for "non-fibrous" foodstuff or Juvonen for low viscosity foods (Juvonen. 2009).

If we also take into account that Cheong et al. report that large fluctuations in blood glucose levels exert greater ER stress on rat insolinoma cells than chronic hyperglycemia and that the former, i.e.the large blood sugar fluctuations, yet not chronic hyperglycemia downregulate the GLP-1 receptor expression (which would induce a metablic state we would have to label "GLP-1 resistance") on these cells (Cheong. 2011). We could go as far as to speculate that the ups and downs of the glucagon-like-polypeptide 1 and the subsequent down-regulation of its receptors at the cellular level and not our contemporary scapegoat, insulin, could be at the heart of the diabesity epidemic... but I will get deeper into that in the upcoming incretin hormone special, so stay tuned!