Metabolism, Feeding & Chrononutrition

1. Circadian Metabolism in Health

Healthy human physiology displays marked daily rhythmicity:

• Cortisol: peaks 30–45 min after waking (CAR, cortisol awakening response); falls through the day.
• Melatonin: rises ~2 h before habitual sleep onset (DLMO, dim-light melatonin onset); falls after waking.
• Core body temperature: trough at ~4 am, peak at ~4–6 pm, ~1°C swing.
• Glucose tolerance: best in morning, worst in evening. Same carbohydrate load produces higher glucose excursion at night.
• Insulin sensitivity: higher in morning, lower in evening.
• Lipolysis and lipid oxidation: peak in the fasted state during sleep.

2. Feeding as a Peripheral Zeitgeber

Damiola 2000 showed that restricting nocturnal mouse feeding to daytime hours reverses the liver clock phase within 48 hours, while the SCN remains entrained to light. Feeding is the dominant Zeitgeber for peripheral metabolic tissues. In humans, the same principle holds: meal timing shifts liver, pancreatic, and gut clocks more potently than small adjustments in light exposure. Critical implication: late-night meals desynchronise peripheral clocks from the central SCN, producing internal circadian misalignment.

Consequences observed experimentally: week-long simulated shift-work protocols (eating at night, sleeping by day) cause insulin resistance, elevated CRP, altered cortisol rhythms, and reduced leptin — within days. These perturbations explain why shift workers have 2× elevated risk of type-2 diabetes (meta-analysis, Gan 2015).

3. NAD⁺, SIRT1, and Metabolic Sensors

The clock and metabolism interlock molecularly. NAMPT, the rate-limiting enzyme of NAD⁺ salvage, is a CLOCK/BMAL1 target gene. NAD⁺ thus oscillates with ~24 h period. NAD⁺ drives SIRT1deacetylase activity, which deacetylates BMAL1 and PER2 proteins, feeding back onto the clock. The Asher & Sassone-Corsi loop: NAD⁺-SIRT1 connects metabolic state to clock phase, so that metabolic stress (low NAD⁺) can shift the clock.

4. Time-Restricted Eating

Time-restricted eating (TRE)— also called time-restricted feeding in rodent studies — confines calorie intake to a ~6–10 h window while keeping daily calories constant. Satchidananda Panda’s Salk lab showed that TRE in mice protects against diet-induced obesity, insulin resistance, and fatty liver independent of calorie restriction (Hatori 2012).

Human clinical trials:

• 10-h TRE for 12 weeks in metabolic-syndrome patients (Wilkinson 2020): weight loss, improved HbA1c, blood pressure, cholesterol.
• Ramadan fasting studies (which are essentially ~14 h overnight TRE in reverse) show metabolic improvements but also sleep disruption.
• Early TRE (eating 8 am–5 pm) outperforms late TRE (eating 11 am–8 pm) for glucose control (Sutton 2018) — consistent with evening glucose intolerance.

Chrononutrition maxims supported by data: eat your largest meal when your clock expects it (breakfast-heavy), finish eating 2–3 h before bed, avoid blue light at night (suppresses melatonin, further disrupting glucose metabolism).

5. REV-ERB & ROR Drug Targets

REV-ERBα/β nuclear receptors are haem- and ligand-modulated. Synthetic agonists (SR9009, SR9011, developed by Burris) shift the clock, boost exercise capacity, reduce adiposity, and improve glucose tolerance in rodent studies (Solt 2012). Enthusiasm was tempered by the finding that SR9009 produces many of these phenotypes through off-target effects (Dierickx 2019), highlighting difficulty of targeting nuclear receptors selectively. Newer REV-ERB-specific agonists and RORα antagonists continue in preclinical development as chronometabolic drug candidates for obesity, NASH, and diabetes.