Insulin Regulation of Lipolysis and Lipolysis Proteins

Study Overview
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Brief Summary
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These studies will define the abnormalities in the adipocyte proteins that are involved in the failure of insulin to suppress lipolysis normally in humans with upper body obesity and will help discover the mechanism by which pioglitazone, a medication used to treat type 2 diabetes and improve insulin resistance, improves insulin-regulation of adipocyte fatty acid metabolism.

Detailed Description
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The investigators will determine whether impaired insulin-induced suppression of lipolysis (as measured by IC50) is related to the above mentioned lipolysis proteins in groups of volunteers known to vary widely with regards to abdominal adipocyte size and regulation of adipose tissue lipolysis. The investigators will determine whether the improved insulin regulation of lipolysis resulting from treatment with the PPARγ agonist pioglitazone, with or without weight loss, can be linked to specific changes in sets of PPARγ-responsive adipocyte lipolysis proteins in UBO adults.

Official Title
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Insulin Regulation of Lipolysis and Lipolysis Proteins

Conditions
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Obesity

Intervention / Treatment
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* Behavioral: Immediate weight loss
* Drug: Pioglitazone
* Behavioral: Deferred weight loss
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Men and Women between the ages of 18 and 55. Women will be premenopausal Non obese adults BMI between 18-25 Obese BMI 30-38 Exclusion Criteria, Pioglitazone package insert of contraindications for use: Initiation in patients with established New York Heart Associations (NYHA) class III or IV Heart failure. Use in patients with known hypersensitivity to pioglitazone or any other component of ACTOSE.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: immediate weight loss (placebo) will be compared with deferred weight loss (placebo) to determine the effects of weight loss alone immediate weight loss placebo will be compared with deferred weight loss pioglitazone to determine the effects of weight loss vs. pioglitazone deferred weight loss placebo will be compared with deferred weight loss pioglitazone to determine the effects of pioglitazone alone deferred weight loss placebo will be compared with deferred weight loss pioglitazone to determine the effects of weight loss alone vs. previous exposure to pioglitazone immediate weight loss placebo and deferred weight loss placebo will be pooled to create a larger group to determine the effects of weight loss on outcome variables
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Immediate weight loss - placebo<br>Upper body obese participants randomized to this group; all will begin their immediate participation in a comprehensive lifestyle obesity treatment program after completion of baseline studies. Half of the volunteers will be randomized to placebo during this period. | Behavioral: Immediate weight loss<br>* Upper body obese subjects will undergo behavioral intervention with a life coach and a physical activity program of their choice for 4 months.<br>Drug: Placebo<br>* Upper body obese subjects will be block randomized to pioglitazone or placebo at enrollment.<br>|
| Placebo Comparator: Deferred control group - placebo<br>After baseline studies, UBO participants randomized to this group will wait without any intervention for 4 months, with continued monitoring to assure weight stability - this group will be the half of volunteers randomized to deferred weight loss intervention that are also randomized to placebo. At the end of this 'wait' period they will be enrolled in the same comprehensive lifestyle obesity treatment program for 4 months, but without placebo. | Behavioral: Deferred weight loss<br>* Upper body obese subjects will complete a weight-stable period of 4 months and subsequently undergo behavioral intervention with a life coach and a physical activity program of their choice for 4 months.<br>Drug: Placebo<br>* Upper body obese subjects will be block randomized to pioglitazone or placebo at enrollment.<br>|
| Active Comparator: Immediate weight loss - pioglitazone<br>Upper body obese participants randomized to this group; all will begin their immediate participation in a comprehensive lifestyle obesity treatment program after completion of baseline studies. Half of the volunteers will be randomized to pioglitazone during this period. | Behavioral: Immediate weight loss<br>* Upper body obese subjects will undergo behavioral intervention with a life coach and a physical activity program of their choice for 4 months.<br>Drug: Pioglitazone<br>* Upper body obese subjects will be block randomized to pioglitazone or placebo at enrollment.<br>|
| Active Comparator: Deferred group - pioglitazone<br>After baseline studies, UBO participants randomized to this group will wait without any intervention for 4 months, with continued monitoring to assure weight stability - this group will be the half of volunteers randomized to deferred weight loss intervention that are randomized to pioglitazone. They will be monitored to prevent the usual but modest weight gain associated with pioglitazone. They will be on pioglitazone during the 'wait' period. At the end of this 'wait' period they will be enrolled in the same comprehensive lifestyle obesity treatment program for 4 months, but without pioglitazone. | Drug: Pioglitazone<br>* Upper body obese subjects will be block randomized to pioglitazone or placebo at enrollment.<br>Behavioral: Deferred weight loss<br>* Upper body obese subjects will complete a weight-stable period of 4 months and subsequently undergo behavioral intervention with a life coach and a physical activity program of their choice for 4 months.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adipocyte response to insulin - perilipin 1 and FSP27 relative to HSL and ATGL | In response to weight maintenance vs. weight loss with pioglitazone vs. placebo, insulin regulation of lipolysis in upper body obese as measured by insulin IC50 for palmitate flux and compared to adipocyte perilipin 1 and FSP27 relative to HSL and ATGL. | 4-9 months | 
| Adipocyte response to insulin - adipocyte G0S2 relative to ATGL. | In response to weight maintenance vs. weight loss with pioglitazone vs. placebo, insulin regulation of lipolysis in upper body obese as measured by insulin IC50 for palmitate flux and compared to adipocyte G0S2 relative to ATGL. | 4-9 months | 
| Adipocyte response to insulin - adipocyte CGI-58 relative to ATGL | In response to weight maintenance vs. weight loss with pioglitazone vs. placebo, insulin regulation of lipolysis in upper body obese as measured by insulin IC50 for palmitate flux and compared to adipocyte CGI-58 relative to ATGL. | 4-9 months | 
| Adipocyte response to insulin - perilipin 1, ATGL and HSL phosphorylation | In response to weight maintenance vs. weight loss with pioglitazone vs. placebo, insulin regulation of lipolysis in upper body obese as measured by insulin IC50 for palmitate flux and compared to adipocyte perilipin 1, ATGL and HSL phosphorylation in response to insulin. | 4-9 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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adipose tissue