On some level, calories in calories out has to be true. But these variables are not independent. Bodies respond to exercise by getting hungry and to calorie deficit by getting tired. Even absent that, bodies know how much food they want, and if you don’t give it to them they will tell you at increasing volume until you give in (not all bodies, of course, but quiet stomachs aren’t the target market for GLP-1s). A new breed of drugs, GLP-1 agonists, offer a way out of the latter trap by telling your body you’ve eaten, even when you haven’t, but leave many people fatigued. The newest GLP-1, retatrutide, may escape that trap too, with a mechanism so beautiful I almost don’t believe it. 

How Jelly Beans Become Fat

Unfortunately in order to understand the beauty of retatrutide, you’re going to have to learn the basics of energy metabolism in the body. I’m sorry.

You have probably heard of mitochondria, the power house of the cell. What that means is mitochondria takes in sugar, protein, or (components of) fat and turns them into ATP, which is then used to power chemical reactions in your cells. This is the equivalent of a power plant that uses nuclear, coal, and hydro to power small batteries and mail them to your house. 

Sugar is a desirable fuel because it can produce ATP very quickly, and if push comes to shove, can do so without oxygen. Your body works to maintain a particular concentration of sugar in your bloodstream, so your cells can take in more when they need it. This is especially important for your brain, which runs mostly on sugar.

Fat is your body’s long-term energy storage. If you eat fat and don’t immediately burn it, it will be directly added to adipose (fat) cells. Dietary sugar you don’t use will be converted into fat and stored in the same cells. This is beneficial because fat is very space-efficient, but the process of converting sugar to fat is calorie-inefficient: you lose 10-25% of the energy in sugar in the conversion to fat (this means that how many calories you get from a jelly bean will depend on whether you burn the sugar immediately or store it as fat and burn it later)

Under the right circumstances (weasel worded because I’ve yet to find a satisfactory explanation of when this happens), fat will break down into fatty acids, which circulate like sugar until a cell draws them in to create ATP.  Breakdown of fatty acids can also produce ketone bodies, which are what powers your brain during fasts. Breaking down fat to produce ATP takes minutes.

So sugar works fast, but takes up a lot of storage space, is prone to undesirable reactions with nearby proteins, and is osmotically unstable*. Fat is space efficient and non-reactive but breaks down slowly, and frequent conversion is costly. Glycogen is somewhere in the middle- it’s a store of energy that breaks down into sugar faster than fat can produce fatty acids, but is more stable than raw sugar. If you’ve ever eaten a carb heavy meal and seen the scale go up way more than could be accounted for by calorie count, that’s the glycogen. Each gram of sugar is stored with 3-4 grams of water, so it can cause major swings in weight without touching fat cells. 

There are glycogen stores in your muscles for their personal use during intense activity. There’s also a large chunk in your liver, which is used to regulate blood sugar across your entire body. If your blood sugar is low, your liver will break down glycogen into glucose and release it into the blood, where whatever organ that needs it can grab it. If you’re familiar with “the wall” in endurance exercise: that’s your body running out of glycogen. Your second wind is fat being released in sufficient quantities. In general your body would rather use glycogen than fat, because glycogen loses almost no energy in the conversion from and to sugar and fat loses a lot. 

The Power Plant Managers

Managing these stores of energy is a complicated web of hormones. 

When your blood sugar is high, the hormone insulin is released to trigger certain cells, including muscle and fat cells, to take said sugar from the blood and use it. Type 1 diabetics don’t produce enough insulin. Type 2 diabetics produce insulin but their cells respond to it more weakly (known as insulin resistance). 

When your blood sugar is low, the hormone glucagon triggers your liver to break down glycogen to release sugar, raising your blood sugar, suppressing insulin, and giving you more energy. It more weakly triggers the breakdown of fat. release. Glucagon also triggers the release of the hormone cortisol.

Cortisol gets a bad name as the stress hormone, but the only thing worse than stress with high cortisol is stress with low cortisol. If you stumble along a tiger in the jungle, you want cortisol. It also increases blood sugar and energy levels (to provide energy to escape the tiger). Energy for running sounds good for weight loss but empirically cortisol promotes fat storage and muscle breakdown, and increases insulin resistance. This may be why raising glucagon alone does not cause weight loss. 

Glucagon-like peptide 1, or GLP-1 is one of the hormones that tells your brain “I’m eating food”. It is triggered by the presence of calories in the gut, bile in the stomach, or even the knowledge that you’re about to eat. It suppresses appetite and glucagon (preventing the breakdown of glycogen), increases insulin (and thus sugar uptake into cells), and slows down the movement of food through your intestines. 

The hormone glucose-dependent insulinotropic polypeptide (abbreviated GIP for historical reasons) is also triggered by calories in the gut. It encourages insulin sensitivity (meaning a given molecule of insulin will cause a cell to uptake more sugar) and fat storage. 

I used the phrase “hormone X does Y” a lot, but it’s kind of misleading. Hormones are more or less arbitrary molecules, their shape doesn’t mean anything, just like the word “toast” doesn’t inherently mean “bread exposed to high, dry heat” or “raise a glass to”. Hormones’ meaning comes from the receptors they activate.  Hormone receptors are molecules that straddle the membranes of cells. 

The “outside” end of a receptor waits to be activated by a hormone molecule. When it does, the “inside” end of the receptor does… something. That something can depend on the activating molecule, the cell type, conditions inside the cell, phase of the moon…

[adapted from]

Hormones are often described as a “lock and key” model. The problem is that locks and keys are precision instruments.

[adapted from]

….whereas hormones and receptors are blobs. Some blobs don’t fit together at all, some fit as well as a key in a lock (strong affinity), and some fit together like puzzle pieces that don’t quite interlock, but are close enough  (weak affinity). Receptors are much less specific than locks, and don’t have a 1:1 relationship with hormones even when they are named after one. E.g. GLP-1 Receptor (GLP1R) has strong affinity for GLP1 but also weak affinity for glucagon, because their blob shapes are close enough to each other. 

[glucagon (red) and glucagon receptor (blue)] [adapted from]

I bring this up because some drugs referred to as GLP-1s hit more than one receptor, and this is important for understanding GLP-1s. 

How do GLP-1 Medications Work?

So GLP-1 the peptide hormone works by activating receptors that tell your brain you’ve eaten and don’t need more food. How do GLP-1s, the class of medication, work?

Semaglutide (aka Ozempic and Wegovy) activates only GLP1Receptor. We’ve covered why that helps, but often comes at the cost of fatigue.

Tirzepatide (Zepbound) activates GLP1R and GIPR, and no one is sure why the latter helps but it seems to.

Retatrutide (no retail name) activates GLP1R, GIPR, and glucagon receptor. The glucagon receptors encourage the breakdown of glycogen and fat, which your body will use as energy. You might hope this would cause weight loss on its own, but in practice it doesn’t. Even if it did, permanently elevated glucagon would raise blood sugar to undesirable levels for undesirable periods of time. But GLP-1 is great at managing blood sugar. If only there was a way to keep it from making you tired… 

So glucagon’s and GLP-1’s positive effects (burn more energy/eat less food) are synergistic, but their negative effects (elevated blood sugar/fatigue) cancel out. It’s elegant at a level rarely seen in biochemistry.

Just taking these hormones won’t help much, because all three have a half-life of less than 10 minutes. You’d need to be on a 24/7 IV infusion for them to maintain levels long enough to be useful. 

This is where big pharma pulls its weight. All three medications feature minor edits to the chemical structure of the hormone that don’t affect its work as a key but do slow your body’s ability to digest it (which they can get away with because key fit is fuzzy, not precise). Tirzepatide and retatrutide are further modified to fit the extra receptor(s) they target. This is easier because all three of GLP-1, glucagon, and GIP are peptide hormones, meaning they’re made up of amino acids, and it’s easy to substitute one amino acid for another (well, easy compared to modifying other kinds of hormones).

Then chemists attach that altered peptide hormone molecule to a chain of fatty acids. The acids are slowly picked off over days: when the last one is removed the remaining molecule briefly fits into its locks/receptors, before being digested (but not as quickly as if it were the unmodified hormone). Because this removal happens at a slow, predictable pace, it spaces out the availability of the molecule, getting you the same effect as an IV drip with a lower dosage each day. And thus fat is the instrument of its own undoing. 

The Side Effects 

Reminder that I am some lady who reads stuff on the internet and writes it down and the fact that I couldn’t find a better version of this should make everyone involved feel bad. That said.

The common side effects of all three GLP-1s are digestive distress and injection site reactions. The former makes sense- GLP-1s screw with your digestion, so you’d expect the side effects to show up there. The latter might be a combination of the volume and pH level of the injection.

Fatigue is another common side effect (it’s reported at only 7%, compared to 3% for placebo, but anecdotally seems worse). It’s unclear if this stems directly from the medication or the body’s normal protective reaction to a calorie deficit. There’s no data yet, but retatrutide’s 3rd mechanism of action (imitating glucagon) may counteract fatigue or even give people more energy (trip report from one such lucky person).

There’s no data on this either, but if GLP-1s cause fatigue due to calorie deficit, I wonder what they do to the immune system, which is among the first of your systems to suffer from energetic budget cuts. 

People who lose weight often lose muscle as well as fat. This might happen at slightly higher rates for people losing weight through GLP-1s, or they might just be selected for not exercising much. Weight lifting and protein consumption help (note that this may require planning to fit into your new, lower calorie budget).

In rodent studies, semaglutide and tirzepatide were both found to increase the rate of thyroid tumors. There’s no data on retatrutide yet but no reason to expect it to be different. It’s even less clear than usual if this rat finding will transfer to humans, because the rodents have several factors making them much more susceptible to thyroid cancer. If you have a family history of thyroid cancer or something called MEN2, GLP-1s probably aren’t for you. 

Another concern is drug interactions. GLP-1s will obviously interact with other drugs that affect blood sugar, so be cautious around that. So far as we know they don’t affect the production of liver enzymes that digest medications, which precludes a major source of drug interactions. However they will lead medication to sit in your gut longer, which might increase their effective dose. And any drug that’s highly sensitive to body weight, like warfarin or lithium, will need monitoring as you lose weight. 

Conclusion

I don’t like the idea of everyone being on a compound to mitigate a problem that modernity caused, forever, any more than anyone else does. But I’m unexpectedly impressed with the elegance of this solution (in a way I’m not for antidepressants, which have great empirical results but give us only the vaguest idea of how they work). It’s not clear this should make me feel better, but it does. 

*Osmotically unstable means that there’s a semi-permiable barrier and for some reason water will cross the barrier more in one direction that the other. In this case, the inside and outside of the cell “want” to have the same percentage sugar, but if a cell is stuffed full of sugar that will attract too much water and the cell will burst. If the cell has less sugar than the environment, it will leak and potentially dehydrate to death; this is one reason bacteria struggle to live on honey.