The Game of Hormones and Enzymes – Insulin Resistance, Sensitivity and Fat metabolism

The Game of Hormones and Enzymes is an NFL game between Insulin and Catecholamines commanding Phosphoinositide 3-Kinase on one side and Hormone Sensitive Lipase on the other side to either store Fat or release Fat. The ultimate governor is Calorie Deficit / Surplus

1. Introduction
2. The Second Law of Thermodynamics reigns supreme
3. Setup for The Game of Hormones and Enzymes
4. How the Game is played
5. Who wins: Fat Storage or Fat Libration
6. How to make Fat Storage win
7. How to make Team Fat Liberation Win – the team I support
8. Insulin resistance – The Cells will hear the Coach Again! Exercise the ONLY play
9. How calorie deficit can lead to fat storage
10. Sleep
11. Alcohol – stops Fat Liberation from coming on the field
12. Expulsion of the fat

Introduction

This is going to be a fun blog post – a blog post I will refer to again and again. I am going to think about fat gain and loss as a game. I want to try to understand why I have been loosing at this game. A particular half of my body is winning against the other half. The question is why. I have often felt like my body is “broken”. I am just rephrasing that statement now. I am not special. It’s not like my body is particularly different from every other human being’s body. We know that human beings become fat and loose fat. I am trying to understand the basic mechanics of that as a game, so that I can “metaphorically feed” the side that will make me loose fat. Maybe this will be the blog post that ends all blog posts on insulin for me.

How do we Flip the Switch on this fat machine.

The Second Law of Thermodynamics reigns supreme

The Game of Hormones and Enzymes is tilted by one high level governing equation: Calories in – Calories Out.

delta Fat = C * ( calories in – calories out )

However, think about both the calories in and calories out. And remember that C is a factor that changes with the composition of the calories in. If, for instance, all the calories in are sugar, then C is 1. But you can reduce C by moving to less carbohydrates. But how is this mechanism actually working?

Setup for The Game of Hormones and Enzymes

There is a cabal of hormones and enzymes that are constantly playing a game.
– Hormones: the coaches of the game. The directors. The Instructors
– Enzymes: The executors of the vision. The players. The actors
– Calorie Delta: The governor. The fans. Who to favor?
– Muscle and Fat cells: The field where this game is played.

Team Fat Storage	Team Fat Liberation
*** Calorie Surplus ***	*** Calorie Deficit ***
* Insulin * Estrogen * Chronic Cortisol	* Catecholamines (Epinephrine, Norepinephrine) * Glucagon * Growth Hormone
* Phosphoinositide 3-Kinase * GLUT4 (cells)	* GLUT4 (muscles)

What does insulin do?
– Tell cell: suppress Hormone Sensitive Lipasis (HSL) which locks the door to fat liberation
– Tell cell: activate Phosphoinositide 3-Kinase which opens the door to glucose, starting fat storage
– Tell cell: activate GLUT4 which also opens the door

Insulin is always moving around in your body. Remember that the body is robust. It needs to survive. And fat is the way it saves energy. It is a battery for the body. By default, you need the body to keep the fat locked in somewhat so it keeps HSL suppressed. Otherwise, you have runaway fat loss.

What does Catecholamines (adrenaline, epinephrine, norepinephrine) do?
– Tell cell: activate Hormone Sensitive Lipasis (HSL) which will open door to fat liberation
– Tell liver: dump your stored Glucose
– Tell pancreas: bro, SUPPRESS INSULIN
– Tell muscles: you can active GLUT4 (note that fat cells did not get activated)

How the Game is played

The game begins. You are at a default state. You have not eaten anything in a while. Things are chill.

FOOD enters the system. Team Fat Storage takes the field, and starts to ramp up insulin. This suppresses HSL and it opens GLUT4 for muscles and cells. But if you EXERCISE or let it fast, then Fat Liberation takes the field and reduces the insulin.

Who wins: Fat Storage or Fat Libration

There are Three environments in which Fat Storage wins. And Five environments in which Fat Liberation wins:

• Fat Storage: Calorie Surplus, high Insulin, chronic stress / sleep
• Fat Liberation: Calorie Deficit, high Catecholamines, muscle mass, fasting

How to make Fat Storage win

It’s fairly easy to make this team win. When you eat more, the insulin goes up. Low exercise will reduce the catecholamines, which will not suppress the insulin.

How to make Team Fat Liberation Win – the team I support

• Get HSL working
  • Increase cyclic AMP with fasting and exercise
  • Reduce insulin circulating in the system:
    • Calorie deficit – drops insulin, increases glucagon
    • Less carbs less incoming glucose – reduces insulin response
      • Muscle mass allows GLUT4 to scoop up the Glucose
    • Fasting – naturally reduces insulin
    • Catecholamines – they suppress insulin secretion
    • Increase glucagon – suppresses insulin
    • Sleep reduces insulin
• Avoid muscle breakdown
  • activate mTOR by building muscle
  • suppress proteolysis (muscle breakdown)
• Keep it on the field
• Keep the game going uninterrupted – alcohol (these are the TV ads in the NFL game)

The key is to give the advantage to Team Liberation. Push them on the field with Fasting. Start making them effecting using activity Catecholamines. Use Sleep to keep Team Storage away from the field.

Insulin resistance – The Cells will hear the Coach Again! Exercise the ONLY play

The coach (insulin) is yelling, but the players (muscle and fat cells) aren’t listening. GLUT4 stays inside the cell. Glucose builds up in the blood. HSL stays benched. Insulin remains high. This reduces metabolic flexibility.

The key — Activate GLUT4 without needing insulin. This becomes a powerful vacuum cleane

The cells will hear the coach again

Player	Game Effect
Muscle Contraction	Opens GLUT4 channels without needing insulin. Glucose gets used efficiently. This bypasses insulin resistance temporarily.
GLUT4 Expression Increases	Over time, your muscle builds more GLUT4 and keeps it closer to the surface, ready to respond to future insulin signals.
AMPK (AMP-activated protein kinase)	Acts like an internal “fuel sensor.” When muscle contracts, AMPK tells the cell: “We’re burning fuel, keep pulling in glucose and fat.”
HSL Activation	Catecholamines rise → HSL turns on → fat is released and burned for energy.
Insulin Sensitivity Improves	After exercise, insulin’s signal becomes stronger and more effective for hours to days. Cells “hear the coach” again.

Holy shit: Exercise is the ONLY way to improve insulin sensitivity

How calorie deficit can lead to fat storage

• Cortisol locks fat in cells, body can start burning muscle
• Bad sleep same thing
• Insulin resistance and sedentary can lead to muscle loss, fat locked.
• Usually, 48 hours on deficit will lead to fat loss. Takes time

Sleep

• Reduces cortisol
• Reduces insulin!

Alcohol – stops Fat Liberation from coming on the field

Amount	Game Effect
1–2 drinks occasionally	Mild disruption — small pause for Team Fat Release
Binge or frequent use	Full sabotage — Team Fat Storage runs wild, fat loss stalls, muscle breaks down

Expulsion of the fat

You will exhale most of your fat. 85% of it. The rest is water.