Thread by @JUNIUS_64

I watched a tedx talk today on the biophysics and energetics of weight loss

it made me realize, holy shit, unless you’ve gone to college for a biology degree and taken biochemistry, most people don’t understand what “burning fat” really means

so I wanna make a thread about it

this might take a minute for me to put together so bear with me

but this first part, the tedx talk brought up- most people have no idea where fat really goes!

the most common answers people give are “it turns to energy”, “turns to muscle”, “disappears”

all of those are wrong

Where does fat go?

through metabolic processes which we’ll now discuss, it turns into H2O and CO2. You breathe it out, sweat it out, pee it out

But I’m getting ahead of myself, first let’s start with: what is fat?

the best way I’ve ever heard an adipocyte- a fat cell- described is “like a raw egg plopped on top of a beach ball”

This itty bitty nucleus and sparing amount of cytosol are stretched around an ENORMOUS fat droplet

Well, that describes white fat, the type we put on as excess

Brown and beige adipocytes are a whole nother matter, we’ll save that for another day

we need to zoom in on that great big white adipocyte lipid droplet. what’s inside there, chemically?

2 main really important things:
- triglycerides
- cholesteryl esters

cholesteryl esters, to put it briefly, are a storage form of cholesterol, and you NEED that shit (not too much of it though)

cholesterol keeps your cell membranes strong but flexible, not too hard/brittle and not too soft/melty

but triglycerides are more relevant to this thread

Here’s an example of a triglyceride. All of them have 3 long chain fatty acids, attached to a glycerol backbone

The purpose of this is efficient energy storage. It’s much easier to wrangle a lot of fatty acids in one place when they’re in this reduced nonpolar form

i wont linger too long on explaining triglycerides but you can find a more thorough explanation of their function for storage here ncbi.nlm.nih.gov/books/NBK22369/

point is: the bulk of energy we derive from fat comes from those fatty acids, which are stored in threes in these molecules

Triglycerides are great for long term energy storage, but getting your energy out of storage is a bit convoluted

I‘ll skip over how we get energy straight from the fats in our food, they take their own fascinating but complex journey. We’ll assume we’re just using our stored fat

Hormones are EVERYTHING here. When your blood glucose gets low, the levels of the hormones epinephrine and glucagon rise.

Those hormones activate an enzyme called adenylyl cyclase, and in turn, adenylyl cyclase produces a signaling molecule called cyclic-AMP (cAMP)

(I could spend a full hour just talking about adenylyl cyclase. it’s the most polyphyletic enzyme known to science, nearly everything alive has some form of it, it works as a biochemical signal transducer in SO many different regulatory systems

...BUT I’VE GOTTA STAY ON TOPIC)

when cAMP levels rise in response to glucagon and epinephrine rising, the cAMP activates a protein called cAMP-dependent-PKA

cAMP-dependent-PKA tacks a phosphate group onto another protein, perilipin A

(I love signaling cascades, they’re like nature’s Rube Goldberg machines)

perilipin A is like a club bouncer, standing outside and judging what gets into/out of the lipid droplets

When cAMP-dependent-PKA sticks that phosphate group onto it, our bouncer steps aside and lets the VIP in- another protein, hormone-sensitive lipase

VIP
Very Important Protein
heheheh

hormone-sensitive lipase is a VIP, it’s the first one in this cascade to do something other than pass the signal on!

it enters into the lipid droplet surface and starts chopping up triglycerides left and right-

now we have fatty acids which have been cut off their glycerol backbone by lipase

you can’t let them into the bloodstream willy-nilly. that’s very dangerous, it promotes insulin resistance, and research also suggests a link between free fatty acid spikes and sudden heart attacks

So we have carriers for those fatty acids- namely, the protein called serum albumin. The carrier dumps the fatty acids into specific transporters on the surface of cells that need fuel for energy- muscles, heart, brain, what have you

THIS IS COMPLICATED SHIT

in my mind i didn't realize how long-winded it'd be to properly explain, but whoops, now we're on this ride together

here's a diagram from my most favorite textbook of all time, Lehninger's Principles of Biochemistry, showing you where we're at rn

Also, nothing is wasted in breaking down those triglycerides! The glycerol backbone gets reused, or converted into glyceraldehyde-3-phosphate in a series of enzymatic steps

glyceraldehyde-3P is a key feedstock into central metabolic pathways, namely, glycolysis

This is a key tenet of biochemistry and metabolism that you should take to heart: central metabolic pathways tie EVERYTHING together

you get from catabolism to anabolism and vice-versa by going back through those core processes that generate energy and precursor metabolites

we’ll come back to central metabolism

BECAUSE WE INEVITABLY ALWAYS DO

but our fatty acids have a little more traveling to do first

for us animals, we must take fatty acids to the mitochondria of the heart/skeletal muscle/brain/whatever cell in order to use them as fuel (don’t even let me start talking about the evolution of mitochondria, I’ll never stop)

so beep beep bitch here comes the carnitine shuttle

This is the process bottleneck (we say “rate-limiting step”) in burning fatty acids for fuel

fatty acids (excepting some short little ones) can’t get into the mitochondria by themselves. a molecule called carnitine carries them in. There’s more to say but I’ll leave it at that

To shuttle fatty acids via carnitine, you need to attach coenzyme A to the fatty acid first, then switch CoA for carnitine. it’s inefficient, but the thermodynamics won’t allow direct transfer

the fatty acids have made it into the mitochondria, and we start breakdown in earnest

this whole process of squeezing all the energy out of fatty acids via multiple pathways, comes back to oxidation- taking off electrons

a gasoline fire is loud, hard, and fast oxidation

fatty acid catabolism is tidy, orderly, delicate oxidation

end product of both? H2O and CO2

NADH and FADH2 are electron carriers. ATP stores energy in phosphate bonds

As you break the fatty acid down, first chopping off 2 carbons at a time via beta-oxidation, then feeding those 2 carbon pieces into the citric acid cycle, you make lots of those three things

Your electron carriers can then be used to make MORE ATP, by way of dumping their electrons into a process called oxidative phosphorylation

ATP is the energetic currency of life- when a given biochemical reaction needs more energy to proceed, its usually what provides the push

When all is said and done these three processes combined: beta-oxidative cleavage, the citric acid cycle, and oxidative phosphorylation, oxidize your fatty acid fully into CO2, and shunt its hydrogens into H2O. That’s what you’re left with

anyways if you’ve made it this far you’re almost as crazy as me and I love you, thanks for listening

....if you need a biochemistry tutor my rates are reasonable