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Main aim: Study the anthropometric, metabolic, cardiovascular and neurocognitive and gut microbiota changes of different approaches for the weight reduction that increase the ketone bodies in a different proportion in relation to the classic hypocaloric diet.
Objective 1: Study the effect of hypocaloric diets that increase the ketone bodies on gut microbiota and its relationship with anthropometric changes and of the Brown adipose tissue, Objective 2: with the metabolic and inflammatory changes, Objective 3: on the cardiovascular system, Objective 4: on the neurocognition, Objective 5: if they are associated to epigenetic changes that may explain the changes found in the other objectives. Objective 6: Determine the safety of the diets that increase the ketone bodies compared to the classic hypocaloric diet, Objective 7: if the effects of the different dietary approaches are maintained during the medium time, and Objective 8: Verify in experimental models (microbiota transplants from humans with different diets to germ-free mice, ketosis dietary models, and ketone bodies administration) the causality of the gut microbiota of these findings.
Methodology: Model 1: Dietary intervention in humans with 4 types of diet with a different increase of the ketone bodies: classic hypocaloric diet (DH); diet with 8h of feeding and 16h of starving in periods of 24h (D16); diet with intermittent caloric restriction (DA); and normal in protein and low in carbohydrates hypocaloric ketogenic diet (DC).
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Standard hypocaloric diet | Experimental | Mediterranean diet based on olive oil as main fat and regular consumption of vegetables (2 daily rations), fruits 3 daily rations), legumes (3 weekly rations), fish (3 weekly rations), with low consumption of red meat and meat products (less than twice a week), dairy foods (less than once a week) and no sweets, pastries or sugary drinks. Diet will produce a 600 kcal per day caloric deficit, according to the Harris-Benedict equation for each subject. Diet will include 45% carbohydrates, 35% fat, 20% protein distributed in at least 4 meals (breakfast, lunch, afternoon snack and dinner). |
|
| Intermittent fasting 16/8 (early fasting) | Experimental | Diet will produce a 600 kcal per day caloric deficit, according to the Harris-Benedict equation for each subject. Diet will include 45% carbohydrates, 35% fat, 20% protein, but it will be consumed for 8 hours a day (from 12 am. to 8 pm.), maintaining 16 fasting hours (from 8 pm. to 12 am. the following day). |
|
| Intermittent fasting 16/8 (late fasting) | Experimental | Diet will produce a 600 kcal per day caloric deficit, according to the Harris-Benedict equation for each subject. Diet will include 45% carbohydrates, 35% fat, 20% protein, but it will be consumed for 8 hours a day (from 8 am. to 4 pm.), maintaining 16 fasting hours (from 4 pm. to 8 am. the following day). |
|
| Alternate-day fasting | Experimental |
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Standard hypocaloric die | Other | Standard hypocaloric diet |
| |
| Measure | Description | Time Frame |
|---|---|---|
| Changes in gut microbiota composition | To evaluate changes in gut microbiota composition from baseline using different strategies for weight loss which increase ketone bodies in comparison to a standard hypocaloric diet. Change from baseline in 16S rRNA amplicons of fecal community DNA at 3 months and 6 months | Baseline, 12 weeks |
| Measure | Description | Time Frame |
|---|---|---|
| Changes in weight | To analyze the effect of hypocaloric diets which increase ketone bodies on anthropometric parameters in comparison to a standard hypocaloric diet | Baseline, 12 weeks |
| Changes in body mass index. |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Francisco J. Tinahones, PhD | Instituto de Investigacion Biomedica de Malaga | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Virgen de la Victoria Hospital | Málaga | 29010 | Spain |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 40598397 | Derived | Martinez-Montoro JI, Bandera B, Gutierrez-Bedmar M, Gomez-Perez AM, Macias-Gonzalez M, Moreno-Indias I, Tinahones FJ. Effect of a ketogenic diet, time-restricted eating, or alternate-day fasting on weight loss in adults with obesity: a randomized clinical trial. BMC Med. 2025 Jul 1;23(1):368. doi: 10.1186/s12916-025-04182-z. | |
| 40335161 |
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| ID | Term |
|---|---|
| D009765 | Obesity |
| D007662 | Ketosis |
| ID | Term |
|---|---|
| D050177 | Overweight |
| D044343 | Overnutrition |
| D009748 | Nutrition Disorders |
| D009750 | Nutritional and Metabolic Diseases |
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| ID | Term |
|---|---|
| D055423 | Diet, Ketogenic |
| ID | Term |
|---|---|
| D050528 | Diet, Carbohydrate-Restricted |
| D004035 | Diet Therapy |
| D044623 | Nutrition Therapy |
| D013812 | Therapeutics |
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In this diet subjects alternate norm caloric diet during 24 h (according to Harris-Benedict equation) and a diet including only 25% of caloric requirements the following 24 h (this day diet will include 5 % carbohydrates, 65% fat and 30% high biological value protein).
|
| Ketogenic diet | Experimental | Diet will produce a 600 kcal per day caloric deficit, according to the Harris-Benedict equation for each subject. Diet will include 5 % carbohydrates, 65% fat and 30% high biological value protein. |
|
| Intermittent fasting 16/8 (early fasting) |
| Other |
Intermittent fasting 16/8 (early fasting) |
|
| Intermittent fasting 16/8 (late fasting) | Other | Intermittent fasting 16/8 (late fasting) |
|
| Alternate-day fasting | Other | Alternate-day fasting |
|
| Ketogenic diet | Other | Ketogenic diet |
|
To analyze the effect of hypocaloric diets which increase ketone bodies on body mass index in comparison to a standard hypocaloric diet
| Baseline, 12 weeks |
| Changes in waist circumference. | To analyze the effect of hypocaloric diets which increase ketone bodies on the waist circumference in comparison to a standard hypocaloric diet | Baseline, 12 weeks |
| Changes in body composition. | To analyze the effect of hypocaloric diets which increase ketone bodies on anthropometric parameters in comparison to a standard hypocaloric diet measured by bioelectrical impedance analysis | Baseline, 12 weeks |
| Changes in brown adipose tissue. | To analyze the effect of hypocaloric diets which increase ketone bodies on brown adipose tissue in comparison to a standard hypocaloric diet, measured by Positron emission tomography with 18F-fluorodeoxyglucose (18F-FDG PET). | Baseline, 12 weeks |
| Changes in uncoupling protein 1 (UCP1) | To analyze the effect of hypocaloric diets which increase ketone bodies on brown adipose tissue UCP1 in comparison to a standard hypocaloric diet using a sample of subcutaneous white adipose tissue assessed by mRNA qPCR. | Baseline, 12 weeks |
| Changes in physical activity. | To analyze the effect of hypocaloric diets which increase ketone bodies on physical activity in comparison to a standard hypocaloric diet measured by accelerometry | Baseline, 12 weeks |
| Changes in blood pressure | To analyze the effect of hypocaloric diets which increase ketone bodies over the cardiovascular system in comparison to a standard hypocaloric diet based on blood pressure | Baseline, 12 weeks |
| Changes in the punctuation in neurocognitive test | To analyze the effect of hypocaloric diets which increase ketone bodies on neurocognition, in comparison to a standard hypocaloric diet, measured by neurocognitive test | Baseline, 12 weeks |
| Changes in heart rate | To analyze the effect of hypocaloric diets which increase ketone bodies on heart function measured by heart rate in comparison to a standard hypocaloric diet, measured by Holter. | Baseline, 12 weeks |
| Mela V, Heras V, Iesmantaite M, Garcia-Martin ML, Bernal M, Posligua-Garcia JD, Subiri-Verdugo A, Martinez-Montoro JI, Gomez-Perez AM, Bandera B, Moreno-Indias I, Tinahones FJ. Microbiota fasting-related changes ameliorate cognitive decline in obesity and boost ex vivo microglial function through the gut-brain axis. Gut. 2025 Oct 8;74(11):1828-1846. doi: 10.1136/gutjnl-2025-335353. |
| D001835 |
| Body Weight |
| D012816 | Signs and Symptoms |
| D013568 | Pathological Conditions, Signs and Symptoms |
| D000138 | Acidosis |
| D000137 | Acid-Base Imbalance |
| D008659 | Metabolic Diseases |
| D004032 |
| Diet |
| D009747 | Nutritional Physiological Phenomena |
| D000066888 | Diet, Food, and Nutrition |
| D010829 | Physiological Phenomena |