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The Ketogenic Diet: Effects on Human Metabolism and Brain Health

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Dear Colleagues,

The ketogenic diet (KD), traditionally used in the treatment of refractory epilepsy, has emerged as a powerful metabolic intervention with wide-ranging effects on human health. This Special Issue explores the expanding scientific landscape of the KD, focusing on its impact across metabolic and neurological domains. By shifting the body’s primary fuel source from glucose to ketone bodies, KD induces profound changes in energy metabolism, insulin sensitivity, lipid regulation, and inflammatory status. Beyond its metabolic benefits, KD has shown promise in supporting neurological function, with implications for conditions such as epilepsy, Alzheimer’s disease, Parkinson’s disease, and mood disorders. Key molecular mediators—including orexin, which is involved in sleep–wake regulation and energy balance, and adiponectin, a hormone associated with insulin sensitivity and anti-inflammatory activity—are highlighted as central to the diet’s systemic and neuroprotective effects. This Special Issue brings together cutting-edge research and clinical insights to examine the mechanisms, therapeutic applications, and potential limitations of KD. By bridging metabolic and neurobiological perspectives, these collected works aim to deepen our understanding of how leveraging dietary strategies can promote brain health and systemic homeostasis.

Prof. Dr. Rita Polito
Prof. Dr. Giovanni Messina
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18 pages, 1167 KB

Open AccessEditor’s ChoiceArticle

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

by Antonietta Monda, Maria Casillo, Salvatore Allocca, Fiorenzo Moscatelli, Marco La Marra, Vincenzo Monda, Girolamo Di Maio, Paride Vasco, Marcellino Monda, Rita Polito, Giovanni Messina and Antonietta Messina

Nutrients 2026, 18(2), 238; https://doi.org/10.3390/nu18020238 - 12 Jan 2026

Viewed by 1663

Abstract

Background/Objectives: Intermittent fasting and ketogenic dietary approaches are increasingly investigated for their potential metabolic benefits in obesity. However, their long-term neuroendocrine effects—particularly those involving Orexin-A, a peptide implicated in energy regulation—remain poorly understood. The objective of this study was to compare the long-term metabolic, inflammatory, and orexinergic responses to different dietary strategies in adults with obesity. Methods: In this 12-month randomized, three-arm trial, 30 adults with obesity (BMI ≥ 30 kg/m²) were randomly assigned (1:1:1) to a hypocaloric ketogenic diet (KD), a 16:8 time-restricted eating regimen (TRF16:8), or a 5:2 intermittent fasting protocol (ADF5:2). Anthropometric parameters, body composition, fasting glucose, lipid profile, inflammatory cytokines (CRP, IL-6, TNF-α, IL-10), and plasma Orexin-A levels were assessed at baseline and every 3 months. Dietary adherence was monitored through structured logs and monthly assessments. Statistical analyses included repeated-measures models with sensitivity analyses adjusted for age and sex. Results: All participants completed the intervention. The ketogenic diet produced the largest sustained reductions in BMI, fat mass, fasting glucose, and total cholesterol over 12 months. TRF16:8 elicited more rapid early metabolic improvements and showed the most consistent longitudinal increase in Orexin-A levels. The ADF5:2 protocol resulted in moderate improvements across outcomes. In all groups, increases in Orexin-A were associated with markers of improved metabolic flexibility and reduced inflammation; however, mediation analyses were exploratory and non-causal. Between-group differences remained significant for fat mass, glucose, and Orexin-A trajectories after correction for multiple comparisons. Conclusions: The ketogenic diet was associated with the most pronounced long-term metabolic improvements, whereas 16:8 time-restricted eating yielded faster early responses and the most stable enhancement in Orexin-A levels. These findings indicate distinct metabolic and neuroendocrine adaptation profiles across dietary strategies. Given the small sample size, results should be interpreted cautiously, and larger trials are warranted to clarify the role of Orexin-A as a potential biomarker of dietary response in obesity. Full article

(This article belongs to the Special Issue The Ketogenic Diet: Effects on Human Metabolism and Brain Health)

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