Appetite regulation part 2: Gut hormones to treat obesity

Updated: Jan 3, 2021

Onto the million-dollar question, how can we reduce appetite? Well, different pharmaceutical therapies that inhibit appetite are certainly worth more than a million dollars, and this is becoming an extremely hot area of research. In part 2, we're going to delve a little deeper into these novel and exciting interventions.

Why is reducing appetite important?

You may be asking yourself why this is relevant, or why is this one of the most important factors of obesity to focus on? Well, it's actually pretty simple. Reducing appetite reduces food intake, which in turn reduces the amount of energy we consume. Reducing energy intake (providing we're expending more energy than we consume) will result in weight loss.

This is important because we're in the midst of an obesity epidemic, and if we can find an effective drug that targets the appetite suppressing pathways (See post 1!) or an easy applicable lifestyle intervention, then this is a crucial factor to help the overweight and obese lose weight and improve their overall health and longevity.

Stop the stigma

I think an important point to note before we discuss this topic further is for many people losing weight, or fighting the desire and urge to eat is no easy task. There's an ignorant aura in how the wider public perceives obese and overweight individuals, with descriptive terms loosely thrown around such as 'lazy' or 'greedy' when in reality, there are underlying biological pre-determining factors that make it incredibly difficult for many to sustain a healthy weight.

I can't think of any other condition that receives as much stigma as obesity. It's so easy to assume people are overweight simply because they consume more than they expend. This is the outcome and ignores the disrupted process that results in feeding. Recent evidence shows there are predisposing factors that influence one's appetite, for example, across numerous studies baseline and post-prandial circulating anorexigenic hormone levels of PYY & GLP-1 are lower in obese individuals compared to lean individuals (1,2).

  • PYY levels in obese subjects (•) and normal-weight subjects (○) at 90 min after different calorie content meals

What this shows is lean individual's appetite-suppressing response is higher compared to an obese individual following a calorie-controlled meal. With baseline (before any food ingestion), circulating appetite-suppressing hormones also significantly lower for obese individuals compared to lean individuals, the differences in appetite signalling is clear.

In addition to this, a nice study showed that obese individuals do not exert a calorie-dependent suppression in postprandial circulating ghrelin, but lean individual do (3). Ghrelin, the 'hunger hormone', did not decrease as calorie intake increased for the obese, but it did so for the lean. The most interesting observation in this study was that it seemed the increased energy requirements for the obese did not influence ghrelin response, as a 1000-kcal meal suppressed lean subjects ghrelin levels more than a 3000-kcal meal did for obese subjects.

Like with many conditions, there will be some who are more susceptible than overs, and there will also be environmental changes that increase one's susceptibility (epigenetics). There has also been some interesting research exploring the eating traits (ET) genetic susceptibility to obesity, amongst many other genes which are correlated with obesity that could well influence one's risk. The point is, not all, but some will find it much more difficult to maintain a healthy weight. The good news, these disrupted signals can be managed or maybe even fixed, and we're learning more and more about how we can suppress hunger and stay feeling full throughout the day.

The latest interventions to suppress appetite

This is where it gets interesting. There have been numerous advances over recent years in the development of pharmaceutical interventions that have been shown to reduce appetite and energy intake, resulting in weight loss.

If you are yet to read the mechanisms that control appetite, you can do so here, as it's important to have an understanding of the mechanisms that govern appetite to better understand the premise for peptide analogues as a therapy. As discussed in part 1, the discovery of leptin caused widespread excitement as leptin therapy-induced weight loss and appetite suppression in obese mice. However, these results were not replicated in human subjects due to disruptions in leptin signalling.

Once other anorexigenic peptides were discovered like Glucagon Like Peptide-1 (GLP-1), Peptide YY (PYY), Oxyntomodulin and Cholecystokinin (CCK), it was then a question of whether these anorexigenic peptides would do what Leptin couldn't... work for overweight humans!

The effect of PYY infusion on appetite 

First up, PYY. An anorexigenic hormone secreted throughout the gastrointestinal tract (GI tract) that signals to the hypothalamus to reduce food intake. In a randomised, double-blinded cross-over trial, 12 obese and 12 lean participants were randomly allocated either on 2 separate study visits:

  • Intervention arm (PYY anologue)

  • Control arm (placebo - saline)

All participants were blinded to the treatment, meaning they had no idea whether they would be receiving PYY or a placebo and were also fasted prior to the study visit. Participants were infused with either a PYY analogue or placebo (saline) and then were given a buffet meal to eat until full. Participants caloric intake, subjective feelings of hunger and 24-hour post-treatment food intake were measured (4).

What did they find?

In obese participants, PYY decreased caloric intake by 30% during the buffet meal and decreased 24-hour food intake by16%, demonstrating a significant reduction in appetite during and after the meal. What's interesting to note is that food intake decreased for all obese subjects (in addition to lean), highlighting little variability between participants. While the sample size was relatively low (12 obese and 12 lean participants), the cross-over design helps account for the variation, increasing the validity of the results.

The effect of GLP-1 on appetite

PYY exerting a significant effect on appetite confirms its role in appetite regulation, with the mechanisms thought to be through the NPY and POMC pathway, as discussed in part 1. Similar to PYY, GLP-1 is another anorexigenic hormone which physiologically inhibits appetite. A meta-analysis pooled results across 9 randomised cross-over design trials exploring the effect of GLP-1 analogue on appetite and demonstrated on average across all trials an 11% reduction in energy intake. However, 3 of these trials demonstrated no significant differences in energy intake likely down to the lower GLP-1 infusion rate. Nonetheless, a clear suppression of appetite observed (5).

Combining GLP-1 & PYY on appetite and energy intake

With both GLP-1 and PYY infusion individually producing a significant reduction in appetite and energy intake, it was therefore hypothesised that combining the two anorexigenic peptides would produce an additional reduction compared to an isolated infusion of either. A study at Imperial College London put this to the test. In a randomised, double-blinded cross-over trial, 16 healthy subjects were infused with either:

  • Fasted saline (placebo)

  • Fed saline (breakfast consumed before buffet lunch(

  • PYY

  • GLP-1

  • PYY & GLP-1

Afterwards, participants were asked to consume a buffet meal of choice. Energy intake in addition to subjective hunger scored was recorded.

  • Energy intake across all treatments.

Results demonstrated a significant reduction in energy intake under both PYY (12.3%) and GLP-1 (15.7%). Interestingly, combining both PYY & GLP-1 produced an even greater reduction in appetite with a total summed effect of GLP-1 & PYY (27%) (6).

These results were important for 2 reasons

  1. Energy intake significantly reduced identifying a potentially effective therapy to treat obesity

  2. It demonstrated that combining different peptides has an additive effect on appetite suppression

The mechanisms as to why appetite was further reduced when combining both hormones is not fully understood, although one potential explanation is they could stimulate different anorectic pathways, with GLP-1 binding to GLP-1 receptors in the hypothalamus and PYY binding to NPY2 receptor, each involved in the different anorectic activity (7, 8).

OXM is another anorectic peptide that binds to both GLP-1 and NPY2 receptors in the hypothalamus, although it's affinity is much less compared to PYY and GLP-1, however, could the addition of OXM to both GLP-1 & PYY produce an even greater effect on appetite? (9)

The perfect cocktail? GLP-1, Oxyntomodulin and PYY (GOP)

Following the promising results of GLP-1 and PYY, it was then hypothesised that a GOP combination would induce even greater effects on appetite.

  • (a) Food intake on GOP vs saline, for lunch, dinner & lunch and dinner, (b) individual food intake on GOP vs saline.

The GOP combination reduced energy intake in obese participants by 32%, producing an even greater suppression of appetite. It's also worth noting this was effective for each individual participant in the study, who was blinded to each treatment (10).

Considerations & limitations 

It's worth remembering the studies presented measured acute and 24-hour appetite response. There needs to be studies exploring the long-term effect of peptide therapy to test the relevance in obesity, and whether the short-term appetite suppression response observed above would produce similar results when administrated over a longer duration.

GLP-1, PYY and OXM are all significantly elevated after Roux-en-Y gastric bypass (RYGB), which results in significant weight loss. Replicating the hormonal response through peptide therapy may provide an effective alternative to RYGB, and longer duration studies will be able to confirm or dispute this hypothesis. The method of infusing subcutaneous peptides is certainly not a realistic nor applicable administration method for the wider population and new forms of delivery need to be explored to make this an effective therapy.

There are drugs on the market that you take orally which activate the anorectic receptors in the hypothalamus, such as liraglutide and semaglutide which are GLP-1 receptor agonists. However, these have a high proportion of non-responders in addition to some rather unpleasant side effects (11 ). What makes the results above interesting is the consistency observed across all participants, alongside very few adverse effects.

It's also worth remembering this is a pharmaceutical approach to weight-loss, which is entirely effective for just that, weight loss. However, for many, this would just paper over the cracks. No doubt will long-term weight loss improve overall health and longevity, but if individuals are still eating unhealthy foods, then there will be other health concerns that need to be addressed with a more holistic approach through diet and lifestyle changes. This is exactly what we're going to explore next, in the final part of this appetite regulation series!

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