AMPK Removes the Brake on Fat Oxidation

What is T2, and why have researchers been investigating its effects on metabolism?

In this episode of the Optimal Protein Podcast, I'm welcoming back Dr. Amie Hornaman to explore 3,5-diiodothyronine, commonly called T2—a lesser-known thyroid hormone derivative studied for its effects on energy expenditure, fatty acid oxidation, and mitochondrial function.

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We walk through research on liver cells, skeletal muscle, and brown fat, unpacking the machinery that helps fatty acids enter the mitochondria and a process called mitochondrial uncoupling, in which energy is released as heat.

We also explore possible connections with ketogenic diets and the question that matters so much to us here: what could these findings mean for losing body fat while preserving muscle?

Much of the research discussed comes from animal studies. We examine a small human report involving just two participants, and Amie shares observations from an uncontrolled group of 14 women who used her T2-containing product. These findings raise interesting questions, but they do not establish that supplemental T2 is a safe or effective approach to fat loss.

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In this episode, we discuss:

• What T2 is and how it relates to the better-known thyroid hormones T3 and T4.
• The 2005 rat study reporting less fat accumulation and greater liver fatty acid oxidation.
• How the carnitine shuttle helps transport long-chain fatty acids into the mitochondria.
• AMPK, ACC, and malonyl-CoA—and their roles in regulating fat oxidation.
• Mitochondrial uncoupling, ATP production, and thermogenesis.
• Research on T2 and brown fat in animals with low thyroid function.
• Potential overlaps with ketogenic metabolism.
• The limited human evidence and the need for larger, controlled studies.
• Why increased fat burning, lower body weight, and muscle preservation are different outcomes.
• Protein, resistance training, and body composition during weight loss.

Important context for interpreting the research

The approximately 50% lower fat mass reported in the 2005 rat study was a comparison with the untreated high-fat-diet group. It does not mean the animals lost half of their starting body fat.

The 2011 human report described approximately 4% lower body weight, not proof that all weight lost was fat. Neither that report nor the uncontrolled 14-woman project establishes long-term safety or that T2 caused the reported changes.

Changes in muscle-cell fuel use do not establish muscle preservation during weight loss. Shared metabolic pathways also do not establish that combining keto and T2 provides additional benefits.

Studies discussed

• Lanni and colleagues, 2005: T2, fat accumulation, and liver fatty acid oxidation in rats receiving a high-fat diet. ⁠Read the study
• Lombardi and colleagues, 2009: T2, skeletal muscle fatty acid oxidation, AMPK signaling, and thermogenesis in rats. ⁠Read the study
• Antonelli and colleagues, 2011: Preliminary human report on T2, resting metabolic rate, and body weight in two participants. ⁠Read the study
• Cavallo and colleagues, 2013: Rapid effects of T2 on fatty acid oxidation and mitochondrial function in liver cells from hypothyroid rats. ⁠Read the study
• Lombardi and colleagues, 2015: T2 and brown adipose tissue thermogenesis in hypothyroid rats. ⁠Read the study

Additional safety references

• Padron and colleagues, 2014: T2 administration, central hypothyroidism, and effects on thyroid-sensitive tissues in rats. ⁠Read the study
• Jonas and colleagues, 2015: T2's effects on thyroid regulation, body composition, energy metabolism, and heart weight in mice. ⁠Read the study

Thank you so much for listening! If you enjoyed exploring the science with us, please share this episode with a friend who loves learning about metabolism and body composition.

Join me on Friday for my solocast recap, where I'll revisit the key mechanisms, clarify what the studies do and don't show, and connect the discussion to practical takeaways for supporting muscle and metabolic health.

Guest disclosure and medical disclaimer

Dr. Amie Hornaman sells the T2-containing supplement discussed. This episode is educational and does not endorse or recommend purchasing or taking it. Some animal studies have raised concerns about thyroid suppression and heart effects; availability without a prescription does not establish safety.

Do not start T2, substitute it for prescribed treatment, or change your thyroid medication based on this episode. Consult a qualified healthcare professional about your individual circumstances.

Correction: In the mitochondrial uncoupling discussion, we meant DNP, not DMT.