Apple/Pear: Cellular Dynamics of Subcutaneous Fat Distribution in Obese Women

• Sponsor: Pennington Biomedical Research Center (Other)
• Overall Status: Completed
• CT.gov ID: NCT01748994
• Collaborator: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (NIH)
• Enrollment: 63
• Locations: 2
• Arms: 2
• Duration (Months): 70
• Patients Per Site: 31.5
• Patients Per Site Per Month: 0.5

Study Details

Study Description

Brief Summary

The body shape of obese women varies between having the majority of fat either above the waist ("apple" shape) or below the waist ("pear" shape). The study will investigate what restricts: apple"-shaped women from being "pear"-shaped at the cellular level. Since "pear" shaped women tend to have better health, this study will open the door to future research in regulating body shape and thus improving health.

Condition or Disease	Intervention/Treatment	Phase
Obesity; Metabolic Syndrome	Drug: Pioglitazone; Drug: Placebo	N/A

Detailed Description

Adipose tissue expandability and the distribution of stored fat in the body are stronger predictors of health risk. A better understanding of the factors that determine regional fat mass growth may lead to developing new strategies for prevention or treatment of metabolic complications of obesity. The objective of this proposal is to study the responsiveness of different fat depots to adipogenic stimulation in upper-body and lower-body obese women.

Study Design

• Study Type: Interventional
• Actual Enrollment: 63 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Single (Participant)
• Primary Purpose: Basic Science
• Official Title: Cellular Dynamics of Subcutaneous Fat Distribution in Obese Women
• Study Start Date: Feb 1, 2011
• Actual Primary Completion Date: Dec 1, 2016
• Actual Study Completion Date: Dec 1, 2016

Arms and Interventions

Arm	Intervention/Treatment
Placebo Comparator: Placebo Administration of placebo to upper- and lower-body obese women	Drug: Placebo
Active Comparator: Drug Administration of pioglitazone to upper- and lower-body obese women	Drug: Pioglitazone; 30mg per day for four months; Other Names: Actos

Outcome Measures

Primary Outcome Measures

1. In Vivo Adipose Cell Formation (Adipogenesis) [Change from baseline in adipogenesis at 16 weeks]

   Following the consumption of water labeled with the stable isotope deuterium (2H2O; heavy water), adipose tissue biopsies from the subcutaneous abdominal and femoral (thigh) depots will be collected. The 2H from the heavy water is enriched into the DNA of newly synthesized cells. Measures of DNA synthesis (obtained via gas chromatography and mass spectrometry analysis of 2H-enrichment) denote new adipose cell formation, or adipogenesis. The primary outcome is to assess the change (from baseline) in adipose cell formation rates (i.e. adipogenesis) in response to 16-weeks of pioglitazone versus the control group.

Secondary Outcome Measures

1. Visceral Adipose Tissue (Percentage of Total Abdominal Adipose Tissue) [Change from baseline in visceral fat at 16 weeks]

   The volume of fat tissue around the internal organs in the abdomen (visceral adipose tissue; VAT) and underneath the skin (subcutaneous abdominal adipose tissue; scABD) will be determined by Magnetic Resonance Imaging (MRI) of the abdominal region. VAT:total abdominal AT (TAT) reflects the percentage of abdominal fat that is VAT and is calculated as VAT/(scABD AT + VAT).

2. Lipid Accretion in the Liver (Intra-hepatic Lipid; IHL) [Change from Baseline in intra-hepato-cellular lipid at 16 weeks]

   Lipid accretion in the liver cells will be measured using 1H-MRS of the liver.

3. Matsuda Index (Measure of Insulin Sensitivity) [Change from Baseline in Matsuda Index at 16 weeks]

   Insulin sensitivity (glucose tolerance) will be assessed using an oral 75 g oral glucose tolerance test (OGTT) after an overnight fast. Blood samples will be collected at 0, 30, 60, 90, and 120 min after glucose administration to measure serum glucose and insulin. Insulin sensitivity was calculated using the Matsuda insulin sensitivity index [10,000/ √(glucose 0' x insulin 0') X (mean glucose OGTT x mean insulin OGTT)]. A higher value denotes increased insulin sensitivity.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 40 Years
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: Yes

Inclusion Criteria:

• You are a pre-menopausal woman between 18-40 years of age

• Your Body Mass Index (BMI, weight-to-height2 ratio) is 27 - 38 kg/m2, inclusive

• The ratio of your waist-to-hip circumferences is either >0.84 ("apple"-type body shape) or <0.77 ("pear"-type body shape)

• You are willing to undergo a drug intervention for 16 weeks

• You are willing to drink heavy water [similar to the ordinary water that is highly enriched in the naturally occurring stable (non-radioactive) form of hydrogen, deuterium; also called deuterium-labeled water] for 8 weeks before the beginning and during the second half of the drug intervention; you will need 24-hours access to a refrigerator for storage of the water.

• You agree to use a double barrier method as a form of birth control to prevent pregnancy. Oral contraceptives (birth control pills) are not allowed in the study. Acceptable methods of birth control are condoms, spermicide, IUD (intrauterine device, must be hormone free - see list in clinic), diaphragm and abstinence. An example of a double barrier method would be condoms plus spermicide, etc.

Exclusion Criteria:

• You have gained or lost more than 4.5 lb (2 kg) in the last 3 months

• You have had significant changes in the diet or level of physical activity within the past month

• You have a blood sugar of greater than 100 or a diagnosis of diabetes.

• You have abnormal liver enzyme values from your blood work

• You have a history of heart, kidney, lung, liver, and thyroid disease

• You have an average blood pressure >140/90 at your screening visit

• Have you had a positive test for human immunodeficiency virus (HIV), hepatitis B or hepatitis C?

• You require chronic use of medications including diuretics, steroids, thyroid hormones, and adrenergic-stimulating agents (bronchodilators, nasal decongestants)

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Pennington Biomedical Research Center	Baton Rouge	Louisiana	United States	70808
2	Pennington Biomedical Research Center	Baton Rouge	Louisiana	United States	70809

Sponsors and Collaborators

• Pennington Biomedical Research Center
• National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Investigators

• Principal Investigator: Eric Ravussin, PhD, Pennington Biomedical Research Center

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Eric Ravussin, Principal Investigator, Pennington Biomedical Research Center
• ClinicalTrials.gov Identifier: NCT01748994
• Other Study ID Numbers: PBRC 10039; 5R01DK090607
• First Posted: Dec 13, 2012
• Last Update Posted: Apr 30, 2021
• Last Verified: Apr 1, 2021

• Keywords provided by Eric Ravussin, Principal Investigator, Pennington Biomedical Research Center: Obesity; Fat distribution; Adipogenesis; Adipocyte; Preadipocyte; Ectopic fat
• Additional relevant MeSH terms: Metabolic Syndrome; Pioglitazone

Study Results

Participant Flow

Arm/Group Title	Placebo	Drug
Arm/Group Description	Administration of placebo to upper- and lower-body obese women Placebo	Administration of pioglitazone to upper- and lower-body obese women Pioglitazone: 30mg per day for four months
Period Title: Overall Study
STARTED	31	32
COMPLETED	23	26
NOT COMPLETED	8	6

Baseline Characteristics

Arm/Group Title	Placebo	Drug	Total
Arm/Group Description	Administration of placebo to upper- and lower-body obese women Placebo	Administration of pioglitazone to upper- and lower-body obese women Pioglitazone: 30mg per day for four months	Total of all reporting groups
Overall Participants	20	21	41
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	20 100%	21 100%	41 100%
>=65 years	0 0%	0 0%	0 0%
Sex: Female, Male (Count of Participants)
Female	20 100%	21 100%	41 100%
Male	0 0%	0 0%	0 0%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%	0 0%	0 0%
Not Hispanic or Latino	20 100%	21 100%	41 100%
Unknown or Not Reported	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	10 50%	10 47.6%	20 48.8%
White	10 50%	11 52.4%	21 51.2%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%
Region of Enrollment (participants) [Number]
United States	20 100%	21 100%	41 100%

Outcome Measures

1. Primary Outcome

Title	In Vivo Adipose Cell Formation (Adipogenesis)
Description	Following the consumption of water labeled with the stable isotope deuterium (2H2O; heavy water), adipose tissue biopsies from the subcutaneous abdominal and femoral (thigh) depots will be collected. The 2H from the heavy water is enriched into the DNA of newly synthesized cells. Measures of DNA synthesis (obtained via gas chromatography and mass spectrometry analysis of 2H-enrichment) denote new adipose cell formation, or adipogenesis. The primary outcome is to assess the change (from baseline) in adipose cell formation rates (i.e. adipogenesis) in response to 16-weeks of pioglitazone versus the control group.
Time Frame	Change from baseline in adipogenesis at 16 weeks

Outcome Measure Data

Analysis Population Description

Of the 23 participants in the Placebo group, N=3 did not have adipose tissue biopsy data, and of the 26 participants in the Drug group, N=5 did not have adipose tissue biopsy data. Therefore, the Primary Outcome Analysis only included N=20 and N=21, respectively.

Arm/Group Title	Placebo	Drug
Arm/Group Description	Placebo	Pioglitazone
Measure Participants	20	21
Abdominal	-0.3 (1.5)	1.8 (1.4)
Femoral	-1.2 (1.1)	2.1 (1.1)

2. Secondary Outcome

Title	Visceral Adipose Tissue (Percentage of Total Abdominal Adipose Tissue)
Description	The volume of fat tissue around the internal organs in the abdomen (visceral adipose tissue; VAT) and underneath the skin (subcutaneous abdominal adipose tissue; scABD) will be determined by Magnetic Resonance Imaging (MRI) of the abdominal region. VAT:total abdominal AT (TAT) reflects the percentage of abdominal fat that is VAT and is calculated as VAT/(scABD AT + VAT).
Time Frame	Change from baseline in visceral fat at 16 weeks

Outcome Measure Data

Analysis Population Description

Of the 23 participants in the Placebo group, N=3 did not have adipose tissue biopsy data, and of the 26 participants in the Drug group, N=5 did not have adipose tissue biopsy data. Therefore, the Secondary Outcome Analysis only included N=20 and N=21, respectively.

Arm/Group Title	Placebo	Drug
Arm/Group Description	Placebo	Pioglitazone
Measure Participants	20	21
Least Squares Mean (Standard Error) [percent]	0.5 (0.3)	-0.8 (0.3)

3. Secondary Outcome

Title	Lipid Accretion in the Liver (Intra-hepatic Lipid; IHL)
Description	Lipid accretion in the liver cells will be measured using 1H-MRS of the liver.
Time Frame	Change from Baseline in intra-hepato-cellular lipid at 16 weeks

Outcome Measure Data

Analysis Population Description

Of the 23 participants in the Placebo group, N=3 did not have adipose tissue biopsy data, and of the 26 participants in the Drug group, N=5 did not have adipose tissue biopsy data. Therefore, the Secondary Outcome Analysis only included N=20 and N=21, respectively.

Arm/Group Title	Placebo	Drug
Arm/Group Description	Placebo	Pioglitazone
Measure Participants	20	21
Least Squares Mean (Standard Error) [percent]	-0.7 (1.2)	-2.0 (1.2)

4. Secondary Outcome

Title	Matsuda Index (Measure of Insulin Sensitivity)
Description	Insulin sensitivity (glucose tolerance) will be assessed using an oral 75 g oral glucose tolerance test (OGTT) after an overnight fast. Blood samples will be collected at 0, 30, 60, 90, and 120 min after glucose administration to measure serum glucose and insulin. Insulin sensitivity was calculated using the Matsuda insulin sensitivity index [10,000/ √(glucose 0' x insulin 0') X (mean glucose OGTT x mean insulin OGTT)]. A higher value denotes increased insulin sensitivity.
Time Frame	Change from Baseline in Matsuda Index at 16 weeks

Outcome Measure Data

Analysis Population Description

Of the 23 participants in the Placebo group, N=3 did not have adipose tissue biopsy data, and of the 26 participants in the Drug group, N=5 did not have adipose tissue biopsy data. Therefore, the Secondary Outcome Analysis only included N=20 and N=21, respectively.

Arm/Group Title	Placebo	Drug
Arm/Group Description	Placebo	Pioglitazone
Measure Participants	20	21
Least Squares Mean (Standard Error) [index]	-0.39 (0.41)	0.80 (0.40)

Adverse Events

Arm/Group Title	Placebo		Drug
Arm/Group Description	Administration of placebo to upper- and lower-body obese women Placebo		Administration of pioglitazone to upper- and lower-body obese women Pioglitazone: 30mg per day for four months
All Cause Mortality
	Placebo		Drug
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Placebo		Drug
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/31 (0%)		0/32 (0%)
Other (Not Including Serious) Adverse Events
	Placebo		Drug
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	15/31 (48.4%)		15/32 (46.9%)
Gastrointestinal disorders
Gastrointestinal issues	4/31 (12.9%)		3/32 (9.4%)
Nervous system disorders
Vertigo (dizziness)	4/31 (12.9%)		6/32 (18.8%)
Skin and subcutaneous tissue disorders
Skin irritation	6/31 (19.4%)		6/32 (18.8%)
Skin hematoma	1/31 (3.2%)		0/32 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.