Clinical trial NCT04260542: De Novo Lipogenesis and Insulin Sensitivity in Obese
Official title: The Role of De Novo Lipogenesis in Regulation of Insulin Sensitivity in Adipose Tissue in Obese
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Insulin Resistance
Obesity
Keywords: adipose tissue
insulin resistance
obesity
ketogenic diet
de novo lipogenesis
Lead sponsor: Charles University, Czech Republic
Sponsor class: OTHER
Collaborators: name: Faculty Hospital Kralovske Vinohrady
name: Institut National de la Santé Et de la Recherche Médicale, France
First posted: 2020-02-07
Enrollment: 66
Sex: FEMALE
Minimum age (years): 25
Maximum age (years): 45
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: BASIC_SCIENCE

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.

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

Primary outcomes:
measure: Insulin sensitivity
timeFrame: through study completion, an average of 1 year
measure: De Novo Lipogenesis in adipose tissue
timeFrame: through study completion, an average of 1 year
Secondary outcomes:
measure: gene expression profiling of adipose tissue
timeFrame: through study completion, an average of 1 year
Other outcomes:
measure: Exploratory outcome into adipose tissue lipolysis
timeFrame: through study completion, an average of 1 year
measure: Exploratory outcome into liver lipogenesis
timeFrame: through study completion, an average of 1 year
Locations:
city: Prague
country: Czechia
facility: Charles University
city: Prague
country: Czechia
facility: Faculty Hospital Kralovske Vinohrady
Study officials:
affiliation: Charles University
name: Michaela Siklova, PhD
role: PRINCIPAL_INVESTIGATOR
References: