Fat Loss Decoded: Part 3 · Castore: Built to Adapt

Fat Loss Decoded: Part 3

How Your Body Chooses Fuel (And How to Tilt the Odds Toward Fat)

By now, you’ve mobilized fat from storage (Part 1) and learned how to support the mitochondria so they can burn it efficiently (Part 2). But here’s the question that matters most:

How does your body decide whether to burn fat or sugar?

The answer isn’t random—it’s governed by tightly regulated signaling systems. And if you understand how they work, you can bias your metabolism toward fat oxidation without starving yourself or overtraining.

At any given time, your body can use glucose, fatty acids, or ketones for fuel. Protein can be used too, but that's not ideal unless you’re undernourished or extremely glycogen-depleted. The fuel you burn depends on your internal environment mainly energy status, hormone levels, and cellular signaling.

The primary switch that tilts metabolism toward fat burning is AMPK (AMP-activated protein kinase). AMPK is activated when energy is low like during fasting, exercise, or calorie deficits. It tells the cell: “We’re short on energy. Start breaking down fat, stop building things, and prioritize survival.”

When AMPK is activated, several things happen:

It increases fatty acid uptake and oxidation
It downregulates mTOR (the growth/building pathway)
It enhances mitochondrial biogenesis and function
It inhibits anabolic processes like fat storage and protein synthesis

This is the environment where fat is preferred over sugar as a fuel source.

On the flip side, mTOR (mechanistic Target of Rapamycin) is a nutrient-sensing signal that turns on when energy and nutrients especially amino acids and insulin are abundant. It tells the body: “We’re good on energy. Let’s build, grow, and repair.” That’s great for hypertrophy or recovery but it shuts down fat oxidation. mTOR and AMPK work in opposition. You can't fully activate both at once.

This is why timing matters. If you activate mTOR right after waking up with a large carb-heavy meal, you blunt the AMPK-driven fat-burning window you had from fasting overnight. But if you train fasted or push your first meal later (and keep it moderate in carbs), you extend the AMPK window and shift fuel use toward fat.

There are also transcription factors and nuclear receptors that push this balance further:

PPAR-alpha and PPAR-delta (Peroxisome Proliferator-Activated Receptors) regulate the genes involved in fatty acid transport and oxidation. Activating PPARs improves your body’s ability to use fat for fuel, especially during endurance exercise and fasting.

ERRα (Estrogen-Related Receptor Alpha) is a master regulator of mitochondrial oxidative genes. This is the receptor activated by SLU-PP-332. When ERRα is upregulated, the mitochondria become more efficient and flexible in choosing fat as fuel, especially under energy stress.

Hormones also matter:

Insulin suppresses lipolysis and promotes glucose uptake and storage.
Glucagon, adrenaline, growth hormone, and cortisol all promote fat mobilization and, when balanced, support a fat-burning state.
Thyroid hormone (especially T3) increases mitochondrial activity and raises the basal metabolic rate, supporting fat oxidation when calories are sufficient.
Leptin and ghrelin, your hunger signals, also feed back into this system to influence energy use vs. storage.

Now let’s look at interventions that can bias these signals toward fat metabolism:

MOTS-c – This mitochondrial peptide activates AMPK, especially under metabolic stress, and improves fat oxidation by increasing mitochondrial resilience and substrate use efficiency.
SLU-PP-332 – As mentioned, this ERRα agonist enhances mitochondrial gene expression, particularly those involved in fat oxidation. It doesn’t just help the mitochondria burn fat it tells them to prefer it.
Berberine – Activates AMPK, improves insulin sensitivity, and suppresses hepatic glucose output, making the internal environment more favorable for fat use over sugar.
Ketone esters – Using ketones like βHB (beta-hydroxybutyrate) shifts the body into fat-burning mode by reducing the need for glucose. They also inhibit glycolysis at the enzymatic level and provide a clean-burning alternative fuel.
Telmisartan – Activates PPAR-delta and enhances fatty acid metabolism while improving insulin sensitivity. It also has a mild AMPK-activating effect.
Fast mimicking protocols – Short-term fasting or strategic carbohydrate restriction can increase AMPK and reduce insulin, tipping the metabolic scales toward fat oxidation.
Zone 2 cardio – Not only supports mitochondrial density (as discussed in Part 2) but consistently pushes the body to use fat over sugar during sustained low-to-moderate intensity work.
Thyroid optimization – Ensuring optimal free T3 levels can improve basal metabolic rate and mitochondrial function, indirectly supporting fuel flexibility and fat loss.
Cold exposure – Increases norepinephrine and activates brown fat, which burns fatty acids and glucose to produce heat without shivering a process called non-shivering thermogenesis.

The key takeaway here is that your body doesn’t randomly choose what fuel to burn. It follows a logic based on energy needs, hormonal environment, and cellular signaling.

If you want to burn fat consistently and efficiently, your goal is to create the right signal and reinforce it with the right tools.

In Part 4, we’ll bring in training, recovery, and real-time feedback. You’ll learn how to integrate everything you've built so far into a sustainable rhythm one that adapts with you and doesn’t leave your body in a burned-out state.

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