GoKawiilOn 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
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