The role of PPAR-* in familial partial lipodystrophy

Familial partial lipodystrophy (FPLD) is a rare autosomal dominant disorder
characterized by abnormal distribution of subcutaneous fat accompanied by a
variable degree of metabolic derangements. FPLD is a heterogeneous disorder
with several distinct phenotypes and a number of genetic defects underlying
these clinical entities have been described including mutations in PPARG (FPLD
type 3). Peroxisome proliferator-activated receptor (PPAR)-* is a member of the
nuclear hormone receptor superfamily that is known to play a critical role in
the differentiation of pre-adipocytes to mature fat cells and in the regulation
of inflammation and lipid and glucose metabolism. PPAR-y has become the subject
of medical interest because the thiazolidinedione (TZD) group of drugs, now
widely used as insulin-sensitizing agents in the treatment of type 2 diabetes
and the metabolic syndrome, is a high-affinity ligand for this receptor. The
description of subjects with FPLD in whom heterozygous mutations in PPAR-* were
found provided the first genetic evidence to support a role for the PPAR-*
receptor in adipogenesis and the control of glucose metabolism in humans.
However the exact mechanism of action of PPARy is unclear. We therefore propose
a study to investigate the effect of PPARy treatment in patients with PPARy
mutations on clinical features of FPLD. But also to investigate the effects of
PPAR-y on the inflammatory phenotype and adipocyte function.

To study:

The effect of treatment with PPAR-* agonists on clinical features of FPLD

To compare the monocytic (M1/M2) phenotype (peripheral and adipose tissue) of
patients with FPLD
- to controls
- before and after treatment with PPAR* agonists.

To compare adipokine profile in patients with FPLD
- to controls
- before and after treatment with PPAR-* agonists.

To compare the histological aspects (macrophages, lymphocytes, adipocyte cell
size) of abdominal subcutaneous fat of patients with FPLD
- to controls
- before and after treatment with PPAR-* agonists.

This study consists of a case-control and an observational part.
To investigate the effects of PPAR-* agonists administration for 4 months in
patients with FPLD due to PPAR-* mutations we use an observational design.
Since PPAR* agonists treatment will be prescribed by the patients own physician
at the out patient*s clinic under terms of routine patient care, this study is
not an intervention trial.
To asses differences in inflammatory phenotype and aspects of subcutaneous fat
between PPAR-* mutants and healthy volunteers we use a case-control design.

FPLD subjects will visit the AMC in Amsterdam on 3 different occasions for a
time period ranging from 1 to 4 hours. Subjects should fast overnight prior to
all these 3 visits. A DEXA scan will be performed during the first and last
visit. The radiation hazard of the DEXA is 0.0026 milliSievert per total body
measurement. Total radiation exposure in this study is therefore 0.0052
milliSievert. For comparison: background radiation is 2 milliSievert per year
for every person.
1HMRS spectroscopy of the liver will be made twice. This spectroscopy is not
considered to be potentially harmful to subjects.
During the heparin LPL test a drip will be placed. This as well as veni
puncture carry the risk of developing thromboflebitis, hematoma and pain.
Theoretically administration of heparin carries the risk of bleeding, including
the formation of hematoma at the place of injection, thrombocytopenia,
reversible hair loss, collapse and vascular cramps. Since we administer 50
Units/kg we do not expect any complications. In fact, the heparin-LPL test has
been performed in HTG patients for more than 5 years in our hospital now. We
have not witnessed any adverse event following a single heparin bolus. Due to
the rapid half life of heparin, all anticoagulant effect will have disappeared
within 2 hours following heparin administration.
During every visit blood will be drawn for the assessment of glucose, insulin,
Hba1c, HOMA-index, lipids, ALT, AST, FFA and NEFA. During the baseline visit
and during the last visit, additional blood will be drawn for storage,
adipokine and adipocytokines and isolation of CPBM. Since the total volume of
blood withdrawn during the baseline visit and the last visit is less than 125
ml, no side effects are to be expected.
A fat biopsy at the thigh and abdomen will be performed twice. The risks of
this procedure are overall minimal. There can be some mild discomfort or
pressure during the needle insertion and afterwards the area may feel tender or
bruised. There is a slight risk of infection and there is also a minor risk of
bruising or slight bleeding for several days.

Controls will visit the study centre once in the morning after an overnight
fast. They will undergo a physical examination and we will measure weight and
blood pressure. Blood will be drawn (< 125 ml) and a fatbiopsy of abdominal and
thigh subcutaneous fat will be performed. Risks of these procedures are
described above.