Update: Game of Hormones and Enzymes

Addendum: A Few Important Corrections

  • Calories still determine the long-term scoreboard.
    • Hormones influence when fuel is stored, released, and burned.
    • But long-term fat gain or loss still requires a net energy surplus or deficit.
  • Fat release is not the same as fat loss.
    • Lipolysis = fat is released from the fat cell.
    • Fat oxidation = that fat is actually burned for energy.
    • Fat loss = over time, more fat leaves storage than returns to it.
    • Released fatty acids can be re-stored, so activating HSL does not automatically mean losing body fat.
  • HSL is not the only fat-release enzyme.
    • ATGL begins triglyceride breakdown.
    • HSL continues it.
    • MGL completes it.
    • Think of them as the offensive line for fat mobilization, rather than HSL acting alone.
  • Insulin remains a major brake on lipolysis.
    • Higher insulin strongly suppresses release of stored fat.
    • Lower insulin makes fat mobilization easier.
    • But this does not mean lower insulin automatically produces greater net fat loss.
  • Low-carb diets increase fat burning, but fat burning ≠ fat loss.
    • Lower carbohydrates generally mean lower insulin and higher fat oxidation.
    • However, if you are also eating more fat, some of that burned fat may simply be dietary fat.
    • The important question remains: is stored body fat decreasing over time?
  • My original equation
    Δ Fat = C × (Calories In − Calories Out)
    was too simplistic.
    • There is no useful constant C that simply falls when carbohydrate intake falls.
    • Macronutrients affect satiety, thermic effect, hormones, substrate use, and behavior, but they do not create a simple carb multiplier.

Exercise Is Even More Interesting Than I Originally Thought

  • Muscle contraction can activate GLUT4 without insulin.
    • Exercise gives muscle a second key to the glucose door.
    • This temporarily bypasses part of the problem of insulin resistance.
  • Exercise also:
    • increases GLUT4 expression
    • activates AMPK
    • increases energy demand
    • improves subsequent insulin sensitivity
    • helps preserve/build muscle mass
  • My statement that exercise is the ONLY way to improve insulin sensitivity was wrong.
    • Weight loss, calorie restriction, sleep, medications, and other interventions can also improve insulin sensitivity.
    • Exercise is special because it can increase glucose uptake independently of insulin while also improving later insulin response.

Insulin Resistance Is More Complicated

  • I originally imagined insulin resistance as:
    • insulin yelling louder
    • cells ignoring it
    • fat becoming permanently locked away
  • That is incomplete.
  • In adipose insulin resistance, fat cells can also become resistant to insulin’s ability to suppress lipolysis.
    • That can mean too much fatty acid release at the wrong time.
    • Those fatty acids can then accumulate in places like the liver and muscle.
  • So insulin resistance can involve both:
    • high insulin
    • and poor control over fat release

Add Ghrelin: The Hunger Signal

  • Ghrelin belongs in the game, but not directly on Team Storage or Team Liberation.
  • Ghrelin is closer to:
    • “We need more fuel. Go find food.”
  • Ghrelin generally:
    • rises during fasting
    • increases hunger
    • increases food-seeking/reward
    • falls after eating
    • stimulates growth hormone
  • This creates an interesting situation during fasting:
    • Insulin falls
    • fat mobilization rises
    • ghrelin rises
    • therefore the body is simultaneously saying:
      • “Use stored energy.”
      • and “Please go acquire more energy.”

The Updated NFL Model

  • Scoreboard: long-term energy balance
  • Insulin: favors storage and suppresses fat withdrawal
  • Catecholamines: encourage fuel mobilization
  • Ghrelin: tells you to go acquire more fuel
  • Leptin: signals longer-term energy reserves
  • GLP-1 / PYY / CCK: help signal that food has arrived
  • ATGL / HSL / MGL: execute fat mobilization
  • GLUT4: moves glucose into cells
  • Muscle: a huge metabolic sink for glucose and energy
  • Exercise: changes both the immediate play and how well the team performs afterward

The cleanest way I now think about the whole system is:

Calories determine the long-term scoreboard. Hormones determine how the game is played.

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