De Novo Lipogenesis and Insulin Sensitivity in Obese

NCT ID: NCT04260542

Last Updated: 2023-02-15

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: NA
• Total Enrollment: 66 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2019-05-01
• Study Completion Date: 2022-03-11

Brief Summary

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.

Detailed Description

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.

Conditions

Insulin Resistance; Obesity

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: BASIC_SCIENCE
• Blinding Strategy: NONE

Study Groups

FAST Lean

Short-term fasting (FAST), comparator group of lean subjects

Group Type: ACTIVE_COMPARATOR

Fasting/refeeding

Intervention Type: 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).

FAST Obese

Short-term fasting (FAST), experimental group of obese subjects

Group Type: EXPERIMENTAL

Fasting/refeeding

Intervention Type: 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).

KETO Obese

Medium-term ketogenic diet intervention (KETO), experimental group of obese subjects

Group Type: EXPERIMENTAL

Ketogenic diet/ fasting

Intervention Type: 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).

Interventions

Fasting/refeeding

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).

Intervention Type: BEHAVIORAL

Fasting/refeeding

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).

Intervention Type: BEHAVIORAL

Ketogenic diet/ fasting

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).

Intervention Type: BEHAVIORAL

Other Intervention Names

FAST lean; FAST obese; KETO obese

Eligibility Criteria

Inclusion Criteria

• sedentary premenopausal women
• lean (n=20-25, age 25-40 years, BMI 20-25 kg/m2)
• obese (n=20-25, age 25-40 years, BMI 30-40 kg/m)

Exclusion Criteria

• diagnosed cancer
• diabetes (T1DM and T2DM)
• liver and renal diseases
• major cardiovascular event
• bariatric surgery
• allergy to lidocaine
• positive serology for hepatitis (B and C) and HIV
• smoking above 10 cigarettes/day, alcohol consumption above 66g/day
• sleep apnea
• poor venous status
• weight-change more than 3kg in last 3 months
• untreated hyper- or hypo-thyroidism
• long term use of medication and/or steroids
• shift workers and individuals with abnormal sleep/wake pattern

• Minimum Eligible Age: 25 Years
• Maximum Eligible Age: 45 Years
• Eligible Sex: FEMALE
• Accepts Healthy Volunteers: Yes

Sponsors

Faculty Hospital Kralovske Vinohrady

OTHER_GOV

Sponsor Role: collaborator

Institut National de la Santé Et de la Recherche Médicale, France

OTHER_GOV

Sponsor Role: collaborator

Charles University, Czech Republic

OTHER

Sponsor Role: lead

Responsible Party

Michaela Siklova

Deputy head of adipose tissue physiology lab

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Michaela Siklova, PhD

Role: PRINCIPAL_INVESTIGATOR

Charles University

Locations

Charles University

Prague, , Czechia

Faculty Hospital Kralovske Vinohrady

Prague, , Czechia

Countries

Czechia

Other Identifiers

NV19-01-00263

Identifier Type: -

Identifier Source: org_study_id