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

Not Applicable

Recruiting

• Conditions: Nutrition; Obesity and Overweight

• Registration Number: NCT06668168
• Lead Sponsor: University of Bath

Brief Summary

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.

Detailed Description

Not available

Study Timeline

• Study First Submitted: 2024-10-30
• Study First Submitted QC: 2024-10-30
• Study First Posted: 2024-10-31
• Study Start: 2025-05-06
• Status Verified: 2025-07
• Last Update Submitted: 2025-07-28
• Last Update Posted: 2025-07-31
• Primary Completion: 2027-05-06
• Study Completion: 2030-01-01

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 69

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 & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Primary Outcome Measures

Name	Time	Method
Plasma proteome	From baseline to week 4	Plasma proteome at week 4 adjusted for baseline values
Transcriptome of peripheral blood mononuclear cells	From baseline to week 4	Transcriptome of peripheral blood mononuclear cells at week 4 adjusting for baseline values
Transcriptome of adipose tissue	From baseline to week 4	Transcriptome of subcutaneous abdominal adipose tissue at week 4 adjusting for baseline values

Secondary Outcome Measures

Name	Time	Method
Apolipoprotein B concentrations	From baseline to week 4	Plasma apolipoprotein B concentrations at week 4 adjusted for baseline values.
Urinary albumin concentrations	From baseline to week 4	Urinary albumin concentrations at week 4 adjusting for baseline values
Fasting glucose concentrations	From baseline to week 4	Plasma fasting glucose concentrations at week 4 adjusting for baseline values

Trial Locations

Locations (1)

University of Bath; 🇬🇧 Bath, United Kingdom