Impact of Exogenous Ketones on Indices of Keto-Adaptation in Obese Subjects on Weight Reducing Diets. (STAK)

Strategies to Augment Ketosis: Impact of Exogenous Ketones on Indices of Keto-Adaptation in Obese Subjects on Weight Reducing Diets.

This project will be a three-group controlled 6-wk feeding study where all meals are prepared and provided to obese participants. All participants will be fed a 25% energy-restricted diet. Two diets will be very low in carbohydrate (i.e., ketogenic diets) designed to induce nutritional ketosis and fat loss. Another diet will be low in fat and saturated fat but contain the same total calories. Participants will be randomly assigned to a Ketone Supplement group who are provided an exogenous pre-formed source of beta-hydroxybutyrate (BOHB) or a Control group that only receives the standard ketogenic diet. Randomization will be stratified based on insulin resistance, sex, and body composition to ensure balanced group assignment. Because of timing of recruitment (i.e., after most of the ketogenic groups have already completed the study), the low-fat group will not be randomized. Outcome measurements will be made at various intervals over the 6-wk intervention.

Study Overview

• Status: Completed
• Conditions: Weight Loss; Ketogenic Diet
• Intervention / Treatment: Other: Body Composition; Other: Diet; Biological: Blood Draw; Biological: Ketone/Glucose Monitoring; Biological: Urine Analysis; Behavioral: Neuropsychological Measures - ANAM

Detailed Description

This project will be a three-group controlled 6-wk feeding study where all meals are prepared and provided to obese participants. All participants will be fed a 25% energy-restricted diet. Two diets will be very low in carbohydrate (i.e., ketogenic diets) designed to induce nutritional ketosis and fat loss. Another diet will be low in fat and saturated fat but contain the same total calories. Participants will be randomly assigned to a Ketone Supplement group (n=12) who are provided an exogenous pre-formed source of beta-hydroxybutyrate (BOHB) or a Control group (n=12) that only receives the standard ketogenic diet. Randomization will be stratified based on insulin resistance, sex, and body composition to ensure balanced group assignment. Because of timing of recruitment (i.e., after most of the ketogenic groups have already completed the study), the low-fat group will not be randomized. Outcome measurements will be made at various intervals over the 6-wk intervention. Key outcome variables will include: 1) Markers of Ketosis/Keto-Adaptation: a. Daily measures of BOHB (capillary blood) b. Fasting serum BOHB and total ketones (venous blood) c. Diurnal capillary blood ketones and urinary loss of BOHB and total ketones 2) Energy Balance and Body Composition: a. Body mass (scale) b. Whole body and regional composition (DXA) c. Nitrogen balance (daily nitrogen intake - 24-hr urinary nitrogen loss) d. Resting energy expenditure and substrate oxidation (indirect calorimetry) e. Adiposity (myocardial/epicardial fat, liver fat, visceral fat, skeletal muscle fat by MRI) f. Microbiome (stool collection to observe microbiota and the response to diet alteration) 3) Cognitive and Behavioral: a. Computer-based cognitive function (ANAM) b. Behavioral responses (surveys) 4) Cardio-Metabolic Risk: a. Metabolic panel b. Circulating lipid panel (total cholesterol, LDL-C, HDL-C, TG) c. Glucose, insulin, HOMA

• Study Type: Interventional
• Enrollment (Actual): 37
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • Ohio
    • Columbus, Ohio, United States, 43210
      • The Ohio State University

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• BMI >27 and =35 kg/m2

Exclusion Criteria:

• have diabetes, liver, kidney, or other metabolic or endocrine dysfunction, or using diabetic medications.
• Currently consuming a low-carbohydrate diet
• Weight loss of >10% in past 6 months -Currently pregnant or nursing, or planning to become pregnant during the study
• Major psychiatric disorder (e.g., schizophrenia, bipolar disorder)
• Excessive alcohol intake (acute or chronic) defined as average consumption of 3 or more alcohol-containing beverages daily or consumption of more than 14 alcoholic beverages per week

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Ketogenic Diet; Participants will have all their meals prepared in the Instructional Kitchen in the Ohio Union, irrespective of group assignment. They will receive a daily caloric intake equal to 75% of their estimated requirement to maintain weight, which should result in weight loss over the 6-week period. For those in the ketogenic groups, daily macronutrient intake will consist of 35 g of carbohydrates and moderate protein calculated as 1.5 g/kg of reference weight. The remaining caloric intake will consist of fat. A wide range of whole foods will be incorporated into the meals, including non-starchy vegetables, meats, nuts and seeds, oils, cheese, butter, cream, and eggs. The menu will be shared with participants prior to enrolling in the study so they know what to expect in terms of the meal plans.	Other: Body Composition; DEXA Scanning will be done pre-, mid-, and post- intervention.; Other: Diet; The diet intervention will start after all baseline testing is complete; Biological: Blood Draw; Blood samples will be collected biweekly.; Biological: Ketone/Glucose Monitoring; Hand-held glucometer will be used daily to monitor dietary intervention adherence.; Biological: Urine Analysis; 24 hour urine collection will be done biweekly.; Behavioral: Neuropsychological Measures - ANAM; The first cognitive assessment will be done via Automated Neuropsychological Assessment Metrics (ANAM). This cognitive battery is a library of computer-based tests of domains including attention, concentration, reaction time, memory, processing speed, decision-making, and executive function.
Experimental: Ketogenic Diet + Ketone Salt; Participants will have all their meals prepared in the Instructional Kitchen in the Ohio Union, irrespective of group assignment. They will receive a daily caloric intake equal to 75% of their estimated requirement to maintain weight, which should result in weight loss over the 6-week period. For those in the ketogenic groups, daily macronutrient intake will consist of 35 g of carbohydrates and moderate protein calculated as 1.5 g/kg of reference weight. The remaining caloric intake will consist of fat. A wide range of whole foods will be incorporated into the meals, including non-starchy vegetables, meats, nuts and seeds, oils, cheese, butter, cream, and eggs. The menu will be shared with participants prior to enrolling in the study so they know what to expect in terms of the meal plans. This group will also be provided a ketone salt supplement to take x2 daily.	Other: Body Composition; DEXA Scanning will be done pre-, mid-, and post- intervention.; Other: Diet; The diet intervention will start after all baseline testing is complete; Biological: Blood Draw; Blood samples will be collected biweekly.; Biological: Ketone/Glucose Monitoring; Hand-held glucometer will be used daily to monitor dietary intervention adherence.; Biological: Urine Analysis; 24 hour urine collection will be done biweekly.; Behavioral: Neuropsychological Measures - ANAM; The first cognitive assessment will be done via Automated Neuropsychological Assessment Metrics (ANAM). This cognitive battery is a library of computer-based tests of domains including attention, concentration, reaction time, memory, processing speed, decision-making, and executive function.
Active Comparator: Low Fat Diet +Placebo; The low-fat comparison group will also be provided all their food. Their diet will also be restricted in calories and have the same level of protein, but it will be lower in fat and higher in carbohydrate. The low-fat diet will consist of approximately 25% fat, with the remaining calories coming from carbohydrates (approximately 55% after accounting for protein at around 20%). Added sugars will be kept relatively low (less than 25 g/day) with a focus on unprocessed carbohydrate-rich foods. Saturated fat will be limited to less than 10% of total energy, with a focus on unsaturated fat sources.	Other: Body Composition; DEXA Scanning will be done pre-, mid-, and post- intervention.; Other: Diet; The diet intervention will start after all baseline testing is complete; Biological: Blood Draw; Blood samples will be collected biweekly.; Biological: Ketone/Glucose Monitoring; Hand-held glucometer will be used daily to monitor dietary intervention adherence.; Biological: Urine Analysis; 24 hour urine collection will be done biweekly.; Behavioral: Neuropsychological Measures - ANAM; The first cognitive assessment will be done via Automated Neuropsychological Assessment Metrics (ANAM). This cognitive battery is a library of computer-based tests of domains including attention, concentration, reaction time, memory, processing speed, decision-making, and executive function.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Daily Ketone/Glucose Monitoring	Daily fasting glucose/ketones will be assessed using capillary finger stick lancing. A small drop of blood will be obtained once daily, while fasting, using enzymatic strips fitted for a handheld analyzer (KetoMojo). All the data will be stored in the device's internal memory.	Up to 6 weeks
Cholesterol (mg/dl)	Fasting venous blood will be collected biweekly to measure cholesterol.	up to six weeks
Insulin (mIU/L)	Fasting venous blood will be collected biweekly.	up to six weeks
Glucose (mg/dL)	Fasting venous blood will be collected biweekly.	up to six weeks
Lean Mass (kg)	DEXA Scanning will be biweekly to assess lean mass	up to six weeks
Fat Mass (kg)	DEXA Scanning will be biweekly to assess fat mass	up to six weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Neuropsychological Outcome 1 - Reaction time (Throughput)	The first cognitive assessment will be done via Automated Neuropsychological Assessment Metrics (ANAM). Measures SRT by presenting the user with a series of "*" symbols to which they must respond as quickly as possible each time the symbol appears. Results are measured by throughput.	up to six weeks
Neuropsychological Outcome 1 - Visual Short Term Memory (Throughput)	The first cognitive assessment will be done via Automated Neuropsychological Assessment Metrics (ANAM). Measures verbal short-term memory by having the users memorize a set of characters and then indicate as single characters are presented on the screen whether the character was part of the memory set. Results are measured by throughput.	up to six weeks
Neuropsychological Outcome 1 - Spatial Processing (Throughput)	The first cognitive assessment will be done via Automated Neuropsychological Assessment Metrics (ANAM). Measures visual spatial skills and mental rotation by having the users compare the equivalence of two 4-bar histograms, the first of which is displayed upright and the second of which is displayed after a 90° rotation either clockwise or counterclockwise. Results are measured by Throughput.	up to six weeks
Urine Chemistries	24 hour urine will be collected biweekly and analyzed for urine chemistries	up to 6 weeks

Collaborators and Investigators

• Sponsor: Ohio State University
• Investigators: Principal Investigator: Jeff Volek, PhD, Ohio State University

Publications and helpful links

General Publications

• Kackley ML, Brownlow ML, Buga A, Crabtree CD, Sapper TN, O'Connor A, Volek JS. The effects of a 6-week controlled, hypocaloric ketogenic diet, with and without exogenous ketone salts, on cognitive performance and mood states in overweight and obese adults. Front Neurosci. 2022 Sep 30;16:971144. doi: 10.3389/fnins.2022.971144. eCollection 2022.
• Belany P, Kackley ML, Zhao S, Kluwe B, Buga A, Crabtree CD, Nedungadi D, Kline D, Brock G, Simonetti OP, Volek JS, Joseph JJ. Effects of Hypocaloric Low-Fat, Ketogenic, and Ketogenic and Ketone Supplement Diets on Aldosterone and Renin. J Clin Endocrinol Metab. 2023 Jun 16;108(7):1727-1739. doi: 10.1210/clinem/dgad009.
• Buga A, Kackley ML, Crabtree CD, Bedell TN, Robinson BT, Stoner JT, Decker DD, Hyde PN, LaFountain RA, Brownlow ML, O'Connor A, Krishnan D, McElroy CA, Kraemer WJ, Volek JS. Fasting and diurnal blood ketonemia and glycemia responses to a six-week, energy-controlled ketogenic diet, supplemented with racemic R/S-BHB salts. Clin Nutr ESPEN. 2023 Apr;54:277-287. doi: 10.1016/j.clnesp.2023.01.030. Epub 2023 Feb 4.

Study record dates

Study Major Dates

• Study Start (Actual): July 5, 2018
• Primary Completion (Actual): March 1, 2019
• Study Completion (Actual): August 21, 2019

Study Registration Dates

• First Submitted: May 31, 2024
• First Submitted That Met QC Criteria: June 5, 2024
• First Posted (Actual): June 10, 2024

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: December 16, 2024
• Last Verified: December 1, 2024

More Information

Terms related to this study

• Keywords: weight loss; metabolism; ketones
• Additional Relevant MeSH Terms: Body Weight Changes; Weight Loss; Body Weight
• Other Study ID Numbers: 2017H0395

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No