The Causal Role of Ketone Bodies in Obesity-associated Disease Prevention - Combining Genetic Epidemiology With a Randomised Trial to Infer Causality (KETO-GENETIC)

The Causal Role of Ketone Bodies in Obesity-Associated Disease Prevention - Combining Genetic Epidemiology With a Randomised Trial to Infer Causality

Excess weight increases the risk of several diseases including cardiovascular disease, type 2 diabetes, kidney disease and various cancers. There is a need for preventative strategies for obesity-associated disease, especially for people in the overweight and moderately obese ranges where pharmacological intervention may not be suitable.

Low-carbohydrate (ketogenic) diets are popular for weight control. Ketogenic diets increase circulating ketones, which can have favourable effects on cardiometabolic health markers. However, the ketogenic diet has a nutrient composition associated with harms (high-saturated fat/red meat, and low-fibre). The net effects of ketogenic diets on long-term health are unclear. Ketone supplements can increase circulating ketones and could provide benefits of ketosis without needing to adhere to a potentially harmful diet.

Establishing causality between complex exposures (e.g., diet) and long-term outcomes (e.g., disease), is challenging. The MRC & NIHR Review of Nutrition and Human Health Research (2017) highlighted an "overreliance (as opposed to reasonable reliance) on observational studies" as a key barrier to progression in the field of nutrition and health. Randomised controlled trials (RCTs) facilitate causal inference, but for long-term outcomes are expensive, time-consuming, and often suffer from waning adherence. Mendelian randomization (MR) can estimate causal effects subject to key assumptions. A challenge to these assumptions includes complex behavioural exposures (e.g., diet), which could be intercorrelated with causal factors.

Our proposal will address these limitations with a novel combination of study designs to establish causal effects of ketosis (via diet and supplementation) on obesity-associated disease risk in humans.

The investigators will combine a tightly controlled, short-term RCT, with MR to link short-term responses to long-term endpoints. The investigators will examine the circulating (blood) and tissue-specific (adipose) transcriptomic and proteomic responses in the fasted and postprandial state in response to our dietary interventions and translate these to MR by identifying single-nucleotide polymorphisms from genome wide association studies. This approach overcomes limitations of RCTs and MR, as adherence to diets will be confirmed with controlled feeding, and intermediate molecular traits as exposure for MR are less likely to be intercorrelated with causal traits.

Study Overview

• Status: Recruiting
• Conditions: Nutrition; Obesity and Overweight
• Intervention / Treatment: Dietary supplement: Ketone Monoester (KE); Behavioral: Ketogenic diet

• Study Type: Interventional
• Enrollment (Estimated): 69
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Javier Gonzalez; Phone Number: +441225385518; Email: j.t.gonzalez@bath.ac.uk
• Study Contact Backup: Name: Sophie L Russell, PhD; Phone Number: +44 7966 975316; Email: slr79@bath.ac.uk

Study Locations

• United Kingdom
  • Bath, United Kingdom, BA2 7AY
    • Recruiting
    • University of Bath
    • Contact: Javier Gonzalez, PhD; Phone Number: +441225385518; Email: j.t.gonzalez@bath.ac.uk

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

• Body mass index: 25-45 kg/m2
• Waist circumference >93.9 (males) or >79.9 (females)

Exclusion Criteria:

• Glucose or lipid lowering medication
• Diagnosis of cardiovascular disease, renal failure, liver disease or type 2 diabetes
• Contraindications to a ketogenic diet (e.g., pancreatitis, liver failure, disorders of fat metabolism, primary carnitine deficiency, carnitine palmitoyltransferase deficiency, carnitine translocase deficiency, porphyrias, or pyruvate kinase deficiency)
• Unable to understand English language

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
No Intervention: CONTROL
Active Comparator: KETONE ESTER	Dietary supplement: Ketone Monoester (KE); 25g ketone ester 3x/day. The ketone ester will be a beta-hydroxybutyrate monoester [(R)-3-hydroxybutyl (R)-3-hydroxybutyrate].
Experimental: KETOGENIC DIET	Behavioral: Ketogenic diet; Ketogenic diet (<50 g carbohydrate per day)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Plasma proteome	Plasma proteome at week 4 adjusted for baseline values	From baseline to week 4
Transcriptome of peripheral blood mononuclear cells	Transcriptome of peripheral blood mononuclear cells at week 4 adjusting for baseline values	From baseline to week 4
Transcriptome of adipose tissue	Transcriptome of subcutaneous abdominal adipose tissue at week 4 adjusting for baseline values	From baseline to week 4

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Apolipoprotein B concentrations	Plasma apolipoprotein B concentrations at week 4 adjusted for baseline values.	From baseline to week 4
Fasting glucose concentrations	Plasma fasting glucose concentrations at week 4 adjusting for baseline values	From baseline to week 4
Urinary albumin concentrations	Urinary albumin concentrations at week 4 adjusting for baseline values	From baseline to week 4

Collaborators and Investigators

• Sponsor: University of Bath
• Collaborators: Imperial College London; University of Bristol

Study record dates

Study Major Dates

• Study Start (Actual): May 6, 2025
• Primary Completion (Estimated): May 6, 2027
• Study Completion (Estimated): January 1, 2030

Study Registration Dates

• First Submitted: October 30, 2024
• First Submitted That Met QC Criteria: October 30, 2024
• First Posted (Actual): October 31, 2024

Study Record Updates

• Last Update Posted (Actual): July 31, 2025
• Last Update Submitted That Met QC Criteria: July 28, 2025
• Last Verified: July 1, 2025

More Information

Terms related to this study

• Keywords: Ketogenic diet
• Additional Relevant MeSH Terms: Nutrition Disorders; Overnutrition; Body Weight; Overweight; Obesity
• Other Study ID Numbers: 23-09665

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No