The Metabolic Classroom with Dr. Ben Bikman

Episode Summary: The Hidden Power of Ketones: Fueling + Signaling

Date: January 5, 2026
Host: Dr. Ben Bikman
Podcast by: Insulin IQ

Overview

In this episode, Dr. Ben Bikman reveals the emerging science around ketone bodies—particularly beta-hydroxybutyrate (BHB)—and their roles far beyond being an alternative fuel source. Traditionally viewed as a metabolic “Plan B,” ketones are now recognized as powerful signaling molecules that influence gene expression, inflammation, and mitochondrial protection. Dr. Bikman explains how BHB uniquely links energy use, immune modulation, and cellular resilience, highlighting specific receptors and molecular pathways behind these effects.

Key Discussion Points and Insights

1. Ketones: More Than a Backup Fuel

• Historical Perspective:
  • For decades, ketones were considered “metabolic garbage” or, at best, a backup fuel for when glucose is scarce.
  • Modern research now recognizes BHB as not only a nutrient but also a signaling molecule with diverse biological effects.
  • Memorable analogy:
    “It’s like discovering that gasoline doesn’t just power your car’s engine, but it also unlocks the doors.”
    (Dr. Ben Bikman, 03:15)

2. What is Beta-Hydroxybutyrate (BHB)?

• Composition:
  • BHB is the most abundant ketone (about 70% of circulating ketones).
  • Other ketones: acetoacetate and acetone.
• Production:
  • Synthesized in the liver mitochondria during high rates of fatty acid oxidation.
  • Exists in two mirror-image forms (enantiomers): D-BHB (R-BHB) and L-BHB (S-BHB).
  • The body predominantly produces the D form; L-BHB is less understood but present at ~10%.

3. Ketone Concentration Dynamics (06:45)

• Baseline:
  • During normal feeding, BHB levels are very low (often <0.1 mM).
• Fasting/Ketogenic Diet:
  • Levels rise to 0.3–4 mM.
• Diabetic Ketoacidosis:
  • Can reach up to 20 mM (much higher, not relevant unless type 1 diabetic).
• Key Point:
  • Most signaling effects occur at physiological levels (1–2 mM).

4. Ketone Metabolism Pathway (08:00)

• Absorbed into cells via MCT1/MCT2 transporters.
• Converted back to acetoacetate, then acetyl-CoA, and fed into the Krebs (citrate) cycle to produce ATP.
• Interesting fact:
  • The liver produces but does not consume ketones due to lacking certain enzymes.

5. BHB as a Signaling Molecule

a. GPR109A (HCAR2) Receptor (09:37)

• Role:

  • Discovered first as the receptor for niacin, it also binds BHB.
  • Present on immune cells (macrophages, neutrophils, microglia) and in tissues like retina and brain.
  • Actions:
    • BHB binding inhibits adenylyl cyclase via Gi proteins, reducing cAMP and Protein Kinase A activity.
    • Inhibits inflammation, creates a neuroprotective environment.

• Research Highlights:

  • Mice without GPR109A lose the anti-inflammatory and neuroprotective benefits of BHB.
  • Both D and L enantiomers can activate the receptor, but D-BHB has higher affinity at physiologically relevant levels.

• Memorable quote:
  “A metabolite produced during fasting could directly communicate with cells through a receptor pathway.”
  (Dr. Ben Bikman, 10:54)

b. FFAR3 (GPR41) Receptor (15:05)

• Role:

  • Originally a receptor for short-chain fatty acids (SCFAs, e.g., acetate, butyrate).
  • BHB activates FFAR3 in sympathetic neurons, leading to dampened sympathetic outflow—a potential mechanism for reduced stress responses during fasting or ketosis.

• Cancer Connection:

  • In some cancers (e.g., non-small cell lung cancer), BHB’s anti-cancer effects require FFAR3 signaling.

• Notable insight: “These findings suggest there’s something more direct. It’s not just about the indirect use of fuel, but rather the signaling itself.”
  (Dr. Ben Bikman, 17:58)

c. NLRP3 Inflammasome Inhibition (18:30)

• Role:

  • BHB directly (not via a receptor) inhibits the NLRP3 inflammasome, a major innate immune system complex.
  • NLRP3 activation triggers highly inflammatory cytokines (interleukin 1β and 18).

• Disease Connection:

  • Overactive NLRP3 linked to type 2 diabetes, atherosclerosis, gout, Alzheimer’s, MS, and autoimmunity.

• Mechanism:

  • BHB prevents potassium efflux and “oligomerization” of ASC, blocking inflammasome assembly and activity.
  • Both D- and L-BHB forms are equally effective—important for the ketone supplement market.

• Clinically:

  • Lower BHB in Alzheimer’s patients may contribute to chronic brain inflammation.

• Memorable quote:
  “This was a landmark paper... BHB specifically inhibits the NLRP3 inflammasome... not dependent on the GPR109A receptor... a direct action of the BHB molecule itself.”
  (Dr. Ben Bikman, 21:03)

6. Epigenetic Regulation: Histone Deacetylase (HDAC) Inhibition (22:27)

• BHB and Gene Expression:

  • Inhibits Class 1 HDACs (HDAC1, HDAC2, HDAC3) at physiologic concentrations.
  • Leads to increased acetylation of histones, making DNA more accessible for protective gene expression.
  • Upregulates antioxidants like FoxO3A and MT2, helping cells withstand oxidative stress.
  • Additional Layer:
    • BHB can directly beta-hydroxybutyrylate proteins, a novel epigenetic mechanism.

• Practical Impact:

  • Enhances mitochondrial resilience and reduces damage from oxidative stress, especially in brain/heart tissue.

• Quote:
  “By inhibiting HDACs, BHB promotes histone acetylation and enables the transcription of specific gene programs.”
  (Dr. Ben Bikman, 23:22)

Effects on Three Key Fronts

1. Mitochondrial Efficiency and Protection

• BHB is a highly efficient fuel, may produce ATP with greater efficiency than glucose.
• Its metabolism yields NADH and FADH₂ for energy production and supports mitochondrial activity even when glucose is low.

2. Inflammation Reduction

• Inhibits the NLRP3 inflammasome, thereby reducing production of pro-inflammatory cytokines like IL-1β.
• Protects cells from chronic, low-level inflammation associated with metabolic and neurodegenerative diseases.

3. Gene Expression and Oxidative Stress

• Through HDAC inhibition, BHB encourages the cell to produce more antioxidants and become more resilient to cellular stress and damage.

Practical & Clinical Applications (30:38)

• Beyond Diets:

  • Exogenous BHB supplements (e.g., GoBHB) can achieve therapeutic ketone levels without strict fasting or carbohydrate restriction.

• Therapeutic Potential:

  • Under investigation for Alzheimer’s (to compensate for impaired glucose metabolism in the brain).
  • May serve as a “superfuel” for weak hearts in heart failure patients.
  • Potentially useful in autoimmune or chronic inflammatory diseases.

• Closing Wisdom:

  • BHB is both an energy source and a critical signaling molecule, helping synchronize energetic and protective responses across the body.

• Quote:
  “This is not one drug hitting one target. It's a fundamental metabolic signal that orchestrates cellular resilience.”
  (Dr. Ben Bikman, 28:37)

Notable Quotes & Memorable Moments

• On rewiring ketone reputation:
  “For decades, biochemistry textbooks treated ketones as metabolic garbage. Then they were finally upgraded to a backup fuel... But we now understand that this view was far too limited.”
  (Dr. Ben Bikman, 02:55)

• On BHB’s unique status:
  “Most signaling molecules… don't provide calories or any energy at all. And most nutrients… are not considered signaling molecules in any classic sense. But BHB blurs these boundaries completely.”
  (Dr. Ben Bikman, 03:32)

• The BHB effect in disease:
  “The downstream effects—reduced interleukin 1 beta, increased FoxO3A, enhanced antioxidant capacity—are precisely what we'd want to protect against the chronic diseases of our time like diabetes, neurodegeneration, cardiovascular disease, certain cancers, and more.”
  (Dr. Ben Bikman, 33:33)

• Final take-home:
  “BHB is a signaling metabolite that connects our eating patterns to our inflammatory status, our gene expression, and the very health of our mitochondria.”
  (Dr. Ben Bikman, 33:57)

Key Timestamps

• Intro and recap of the “old” ketone science: 02:27–05:45
• BHB chemistry, forms, and levels: 05:45–08:00
• Cellular metabolism of ketones: 08:00–09:37
• The GPR109A receptor and neuro/immune effects: 09:37–15:05
• The FFAR3 receptor and systemic effects (including on cancer): 15:05–18:30
• NLRP3 inflammasome inhibition and anti-inflammatory benefits: 18:30–22:27
• Epigenetic actions and HDAC inhibition: 22:27–27:30
• Summary of mechanisms and mitochondrial protection: 27:30–28:43
• Therapeutic directions and final conclusions: 30:38–33:57

Tone & Style

Throughout, Dr. Bikman is clear, engaging, and didactic—using analogies, examples, and practical applications to convey complex science accessibly. He maintains a "guest professor" vibe, striving for clarity and everyday significance.

For Listeners Who Missed the Episode

This episode goes far beyond the ketogenic diet hype, offering a deep scientific dive into how ketones—specifically BHB—work as both a universal fuel and a master regulator of immune, genetic, and cellular health. The discovery that a molecule produced during fasting or low-carb eating can tell your cells to lower inflammation, enhance antioxidant defenses, and shift gene activity has powerful implications for therapies against metabolic, cardiovascular, neurodegenerative, and autoimmune diseases. BHB is not just plan B fuel; it’s a molecular master key for resilience.