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| Name | Class |
|---|---|
| Faculty Hospital Kralovske Vinohrady | OTHER_GOV |
| Institut National de la Santé Et de la Recherche Médicale, France | OTHER_GOV |
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Disturbances of de novo lipogenesis (DNL) are one of the features of dysfunction of adipose tissue (AT). Disturbances of DNL play a role in development of metabolic complications of obesity. The goal of this project is to investigate novel pathways of DNL regulation. DNL will be studied during nutritional interventions in healthy and obese subjects in exposure to 2-days high carbohydrate diet preceded by a) 2-days fasting b) several weeks´ ketogenic diet. This nutritional protocol creates conditions for the study of prominent changes in DNL: suppression of DNL during fasting or ketogenic diet followed by stimulation during high-carbohydrate diet. Systemic phenotypic features and molecular indices of DNL regulation in AT will be followed during the protocols. Specific attention will be paid to newly reported pathway- hormone sensitive lipase and transcription factor ChREBP. The results will contribute to development of pharmacological approaches in the treatment of metabolic complications of obesity, targeted selectively to AT, without side effects in other tissues.
The main goal of the proposed project is to characterize the regulation of de novo lipogenesis in AT, a pathway strongly associated with insulin sensitivity in humans. The project should provide information that will bring proof-of-concept for the development of AT DNL-targeting therapeutic strategies to decrease the metabolic risk in obese individuals. Two protocols in lean and obese women to modulate (inhibit/induce) DNL will be implemented: 1) two days of fasting followed by two days of high-carbohydrate diet refeeding (FAST/RF) in lean and obese women; 2) "fasting-mimicking" intervention in obese women with high fat low carbohydrate ketogenic diet followed by two days of high-carbohydrate diet refeeding (KETO/RF). KETO diet should provide long lasting AT DNL inhibition, and as such it should further highlight the processes necessary for DNL activation in the refeeding phase. The unique protocols proposed in the application will allow to investigate in humans the relationship between AT DNL and whole body insulin sensitivity and glucose tolerance. Moreover, the state of the art experimental methodologies applied for the analyses of AT samples should uncover the possible mechanisms of regulation of DNL by ChREBP, HSL and other factors as well as the related AT secretory capacity in humans. The findings obtained in lean subjects will be compared to obese subjects, as the deregulated response of these pathways might be expected. The project will provide a proof-of-principle for the role of AT DNL in the regulation of insulin sensitivity in lean and obese individuals. The results will indicate novel pathways for future development of drugs targeting the relevant sites in AT in the context of treatment of obesity-induced insulin resistance and associated disorders.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| FAST Lean | Active Comparator | Short-term fasting (FAST), comparator group of lean subjects |
|
| FAST Obese | Experimental | Short-term fasting (FAST), experimental group of obese subjects |
|
| KETO Obese | Experimental | Medium-term ketogenic diet intervention (KETO), experimental group of obese subjects |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Fasting/refeeding | Behavioral | 2-days fasting followed by 2-days of refeeding. During the fasting period the subjects will be hospitalized to control their state of health and ensure fasting compliance. During refeeding the standardized meals will be provided to cover individual daily requirements (60% carbohydrates, 15% protein, 25 % fat). |
| Measure | Description | Time Frame |
|---|---|---|
| Insulin sensitivity | Change in insulin sensitivity index (ΔiAUC insulin/ΔiAUC glucose from OGTT) | through study completion, an average of 1 year |
| De Novo Lipogenesis in adipose tissue | Change in mRNA expression of lipogenic genes and by targeted and non-targeted lipid analysis (ΔCT) | through study completion, an average of 1 year |
| Measure | Description | Time Frame |
|---|---|---|
| gene expression profiling of adipose tissue | Change in long non-coding RNA analysis by microarrays (ΔCT) | through study completion, an average of 1 year |
| Measure | Description | Time Frame |
|---|---|---|
| Exploratory outcome into adipose tissue lipolysis | Change in glycerol, FFA concentration in AT explants | through study completion, an average of 1 year |
| Exploratory outcome into liver lipogenesis | Change in amount of liver fat and VLDL-TG composition |
Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Michaela Siklova, PhD | Charles University, Czech Republic | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Charles University | Prague | 100 00 | Czechia | |||
| Faculty Hospital Kralovske Vinohrady |
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| ID | Term |
|---|---|
| D007333 | Insulin Resistance |
| D009765 | Obesity |
| ID | Term |
|---|---|
| D006946 | Hyperinsulinism |
| D044882 | Glucose Metabolism Disorders |
| D008659 | Metabolic Diseases |
| 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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| Fasting/refeeding | Behavioral | 2-days fasting followed by 2-days of refeeding. During the fasting period the subjects will be hospitalized to control their state of health and ensure fasting compliance. During refeeding the standardized meals will be provided to cover individual daily requirements (60% carbohydrates, 15% protein, 25 % fat). |
|
|
| Ketogenic diet/ fasting | Behavioral | 1 month of fasting-mimicking ketogenic diet and subsequent 2-days of refeeding. The subjects will be instructed by nutritional specialist to follow isocaloric ketogenic diet consisting of 6% carbohydrates, 17 % of proteins and 77% fat to cover individual energy demand. During refeeding the standardized meals will be provided to cover individual daily requirements (60% carbohydrates, 15% protein, 25 % fat). |
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| through study completion, an average of 1 year |
| Prague |
| Czechia |
| D050177 | Overweight |
| D044343 | Overnutrition |
| D009748 | Nutrition Disorders |
| D001835 | Body Weight |
| D012816 | Signs and Symptoms |
| D013568 | Pathological Conditions, Signs and Symptoms |
| D004032 |
| Diet |
| D009747 | Nutritional Physiological Phenomena |
| D000066888 | Diet, Food, and Nutrition |
| D010829 | Physiological Phenomena |