Clock Gene Mutations and Metabolic Phenotypes

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How the body's internal circadian clocks regulate metabolism, energy balance, and health.

TOPICS DISCUSSED:

• Master circadian clock in the brain: Light detection via retina entrains the suprachiasmatic nucleus, which coordinates body-wide rhythms; intrinsic period slightly deviates from 24 hours, allowing seasonal flexibility.
• Peripheral clocks in organs: Nearly all cells have autonomous clocks; liver and fat clocks rapidly adjust to feeding time, while brain clock aligns more tightly to light.
• Clock mutations and metabolism: Disrupting core clock genes (e.g., CLOCK, BMAL1) causes obesity, liver fat accumulation, and impaired insulin secretion without hyperinsulinemia.
• Timing of food intake: Eating the same high-fat calories during rest phase causes more weight gain than during active phase due to differences in energy dissipation.
• Modern disruptions (jet lag, shift work, blue light): Create desynchrony between brain and peripheral clocks, contributing to metabolic issues; late-night eating impairs glucose handling.
• Critical illness & feeding: Tube feeding at night (opposite natural cycle) induces rapid insulin resistance, highlighting mismatch costs.
• Hormone rhythms: Testosterone, glucocorticoids, and others peak at specific times; misalignment affects stress, reproduction, and metabolism.
• Weight loss drugs & maintenance: GLP-1 drugs reduce intake effectively, but regain involves neuroendocrine adaptations tied to brain clock pathways.

ABOUT THE GUEST: Joseph Bass, MD, PhD is Chief of Endocrinology, Metabolism and Molecular Medicine at Northwestern University Feinberg School of Medicine, Director of the Center for Diabetes and Metabolism, and a leading researcher who pioneered the link between circadian clock genes and metabolic disorders including obesity and diabetes.

RELATED EPISODE:

• M&M 237 | Circadian Biology: Genetics, Behavior, Metabolism, Light, Oxygen & Melatonin | Joseph Takahashi

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