De Novo Lipogenesis and Insulin Sensitivity in Obese
Condition: Insulin Resistance; Obesity
MeSH terms: Insulin Resistance
Study type: Interventional

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.
    

Intervention name(s): Fasting/refeeding; Fasting/refeeding; Ketogenic diet/ fasting
Intervention type(s): Behavioral; Behavioral; Behavioral
Intervention description(s): 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).; 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).; 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).
Other intervention name(s): FAST lean; FAST obese; KETO obese
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Basic Science
Keywords: adipose tissue; insulin resistance; obesity; ketogenic diet; de novo lipogenesis