Obesity

Metabolic and Orexin-A Responses to Ketogenic Diet and Intermittent Fasting: A 12-Month Randomized Trial in Adults with Obesity

A 12-month randomized trial examined the effects of three dietary interventions on body weight, metabolic health, and Orexin-A – a neuropeptide involved in energy balance and glucose regulation – in adults with obesity. The interventions included a hypocaloric ketogenic diet (KD), time-restricted feeding (TRF 16:8), and ADF 5:2, a modified form of alternate-day fasting.

Thirty participants with obesity (BMI ≥30 kg/m²) were randomly assigned to one of the following groups:

• KD: Very low carbohydrate intake (≤50 g/day), designed to induce nutritional ketosis
• TRF 16:8: A daily eating window limited to 8 hours, without calorie restriction
• ADF 5:2: A modified version of alternate-day fasting, consisting of two non-consecutive low-calorie days per week and five days of normal eating

Measurements were taken every three months, including body composition, fasting glucose, lipid profile, inflammation, and plasma Orexin-A levels. Diet adherence was monitored throughout.

Results / Key Findings

Body Composition:

• BMI decreased most with the ketogenic diet (−4.3 kg/m²), followed by time-restricted feeding 16:8 (−3.3 kg/m²), with smaller changes in the 5:2 approach (−0.8 kg/m²).

• Fat mass declined across all groups, with the largest reduction seen in the ketogenic diet (−5.8%), followed by 16:8 (−4.6%) and 5:2 (−2.3%).

Metabolic Markers:

• Fasting glucose decreased in all groups, with the greatest reduction in the ketogenic diet (−21 mg/dL), followed by 16:8 (−15 mg/dL) and the 5:2 approach (−6 mg/dL).

• Total cholesterol fell significantly in the ketogenic diet group (−56 mg/dL), with significant reductions also observed in the other two groups.

Orexin-A Levels:

• Orexin-A increased across all interventions, rising most with the ketogenic diet (+1.3 ng/mL), followed by 16:8 (+1.0 ng/mL) and 5:2 (+0.5 ng/mL).

• Higher Orexin-A levels were associated with lower BMI, fat mass, fasting glucose, and total cholesterol, suggesting a link between neuroendocrine signaling and metabolic improvement.

Conclusion

The ketogenic diet produced the strongest improvements in body weight, glucose regulation, lipid profile, and Orexin-A levels, followed by the 16:8 time-restricted feeding approach. The modified ADF 5:2 protocol resulted in more modest effects. Importantly, Orexin-A emerged as a potentially meaningful neuroendocrine mediator of dietary impact on metabolic health. These findings suggest that nutritional strategies which elevate Orexin-A – particularly through nutritional ketosis – may enhance metabolic flexibility and support long-term obesity management.