De Novo Lipogenesis and Insulin Sensitivity in Obese

  • STATUS
    Recruiting
  • End date
    Dec 11, 2022
  • participants needed
    60
  • sponsor
    Charles University, Czech Republic
Updated on 11 September 2021
insulin
fasting
insulin sensitivity
fats
dietary modification

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.

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.

Details
Condition Insulin Resistance, adiposity, Obesity
Treatment Fasting/refeeding, Ketogenic diet/ fasting
Clinical Study IdentifierNCT04260542
SponsorCharles University, Czech Republic
Last Modified on11 September 2021

Eligibility

Yes No Not Sure

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
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