HIV Fat Redistribution and the Evaluation of Brown Fat

Among individuals infected with HIV, highly active antiretroviral therapy has reduced the
incidence of morbidity and mortality however, despite recent improvements in newer
antiretrovirals patients continue to exhibit secondary effects related to body composition
such as lipoatrophy of the periphery, increased adiposity of the trunk and lipomatosis,
especially of the dorsocervical spine. Changes in body composition have been reported in
40-50% of HIV-infected patients. Several studies have shown that antiretroviral therapy
contributes to changes in body composition and is coupled with increased dyslipidemia,
insulin resistance and diabetes.

Accumulation of fat over the dorsocervical spine, or "buffalo" has been reported in 2% to
13% of HIV-infected patients. Enlargement of adipose tissue in the dorsocervical region
involves subcutaneous fat and is therefore unique to fat accumulation of the abdominal area.
Guallar et al. examined dorsocervical adipose tissue after surgical removal and found that
adipose tissue in this area showed substantial levels of the marker gene of brown fat,
uncoupling protein 1 (UCP-1) suggesting there may be brown adipose tissue (BAT) in HIV
infected individuals with lipomatosis of the dorsocervical spine. Until recently, BAT was
known to be present in rodents throughout their lifetime and was thought to be present in
humans only during infancy and early childhood. However, recent studies using 18F-FDG PET-CT
have confirmed the presence of BAT in adults. Brown adipose tissue is known to affect
whole-body metabolism and may be related to insulin sensitivity as well as susceptibility to
weight gain.

Using 18F-FDG PET techniques, our group has evaluated HIV-infected subjects with lipoatrophy
and noted there was significantly increased glucose uptake into subcutaneous tissue which
may suggest presence of BAT in HIV-infected patients. However our previous study did not
specifically examine areas of BAT in the subjects. Therefore, using 18F-FDG PET-CT in
addition to fat biopsies we propose to explore the presence of BAT in fat depots among
HIV-infected patients with fat redistribution, focusing specifically in the cervical area.

Also, as recent studies suggest down regulation of Dicer, a major component of miRNA has an
important role in the differentiation and function of brown and white adipose tissue and may
contribute to lipodystrophy. We will perform subcutaneous fat biopsies of the dorsocervical
and abdominal fat in a subset of HIV-infected and non-HIV-infected men in order to explore
further the question of down regulation of Dicer and its implication on metabolic
abnormalities in this population.

Subject Selection and Enrollment:

Twenty male subjects comprised of four distinct groups will be recruited for the study.
Subjects will be matched by age and body-mass index. The four groups are:

Group 1: HIV infected with fat redistribution (lipohypertrophy) (n=5) Group 2: HIV
infected with fat redistribution (lipoatrophy) (n=5) Group 3: Healthy Controls (n=10)

Inclusion Criteria for HIV+ with fat redistribution (lipohypertrophy) subjects (Group 1)

1. Evidence of HIV infection

2. Age ≥ 20 and ≤ 60 years of age

3. BMI measurement between 25-29.9 kg/m2

4. HIV positive, on a stable HAART treatment regimen (including an NRTI) for > 12 months

5. Evidence of significant fat redistribution rated by the investigator, including 1)
significant fat atrophy of the face, arms or legs, and 2) significant increase in fat
accumulation of the neck.

Exclusion Criteria for HIV+ with fat redistribution (lipohypertrophy) (Group 1)

1. Hemoglobin < 10.0 g/dL

2. Diabetes or on medications for diabetes

3. Abnormal thyroid function

4. Therapy with medications such as beta blockers, alpha-blockers, sympatholytic drugs

5. Chronic adrenergic drug use (>3 months) and benzodiazepine use.

6. Therapy with glucocorticoids (oral and inhaled), growth hormone or other anabolic
agents currently or within the past 3 months

7. Current substance abuse, including alcohol, cocaine and/or heroin

8. Other serious or chronic diseases

9. New antiretroviral regimen in the past 12 months

10. Any new serious opportunistic infection within the past 6 weeks

Inclusion Criteria for HIV+ with fat redistribution (lipoatrophy) (Group 2)

1. Evidence of HIV infection

2. Age ≥ 20 and ≤ 60 years of age

3. BMI measurement between 18-24 kg/m2

4. HIV positive, on a stable HAART treatment regimen (including an NRTI) for > 12 months

5. No evidence of fat redistribution rated by the investigator.

Exclusion Criteria for HIV+ with fat redistribution (lipoatrophy) (Group 2)

1. Hemoglobin < 10.0 g/dL

2. Diabetes or on medications for diabetes

3. Abnormal thyroid function

4. Therapy with medications such as beta blockers, alpha-blockers, sympatholytic drugs

5. Chronic adrenergic drug use (>3 months) and benzodiazepine use.

6. Therapy with glucocorticoids (oral and inhaled), growth hormone or other anabolic
agents currently or within the past 3 months

7. Current substance abuse, including alcohol, cocaine and/or heroin

8. Other serious or chronic diseases

9. New antiretroviral regimen in the past 12 months

10. Any new serious opportunistic infection within the past 6 weeks

Inclusion Criteria for Healthy Controls (Group 3)

1. No history of HIV infection

2. Age ≥ 20 and ≤ 60 years of age

3. BMI measurement between 18-29.9 kg/m2

Exclusion Criteria for Healthy Controls (Group 3)

1. Hemoglobin <10.0 g/dL.

2. Diabetes or on medications for diabetes

3. Abnormal thyroid function.

4. Therapy with medications such as beta blockers, alpha-blockers, sympatholytic drugs

5. Chronic adrenergic drug use (>3 months) and benzodiazepine use.

6. Therapy with glucocorticoid (oral and inhaled), growth hormone or other anabolic
agents currently or within the past 3 months

7. Current substance abuse, including alcohol, cocaine and/or heroin

8. Any history of serious or chronic diseases -