Mentor: Dr. Abhimanyu Garg
Department: Internal Medicine
Room number: K5.214
Mail Code: 8537
Phone number: 214-648-2895
E-mail:abhimanyu.garg@utsouthwestern.edu
Project title:
Two projects: Genetic and Metabolic basis of familial lipodystrophies.
Therapeutic Interventions in HAART-Associated Lipodystrophies
Human subjects IRB approved project number (where applicable):
# 1093-375, # 0102-049, # 0902-491
Animal subjects IRB approved project number (where applicable):
# 0975-05-01-3
Project Type (patient-based research, animal-based research, or basic research;
this characterization is only to permit a general classification for grouping
similar types of projects) Project one is Patient-based but with animal and
basic research components.
Project two is patient-based.
Project one:
Project title: Genetic and metabolic basis of familial lipodystrophies
Brief Description of Project 1:
Obesity is a major health problem in the U.S. However, how adipose tissue disorders
cause insulin resistance and related metabolic diseases is not known. Study
of single gene disorders of adipose tissue may elucidate the mechanisms involved
in these processes. Congenital generalized lipodystrophy (CGL) is an autosomal
recessive disorder that results in almost complete absence of adipose tissue.
Familial partial lipodystrophy, Dunnigan variety (FPLD) is an autosomal dominant
disorder characterized by gradual loss of subcutaneous adipose tissue in both
the upper and lower extremities during early adolescence, and excessive adipose
tissue on the face and neck. Other common features include insulin resistance,
diabetes mellitus, hypertriglyceridemia, low levels of high-density lipoprotein,
acanthosis nigricans and in some women, hirsutism and menstrual abnormalities.
The project therefore has two aims: 1) to characterize metabolic abnormalities
in patients with CGL and FPLD and 2) to identify the molecular basis of these
disorders. To accomplish these aims, we have collected a number of well-characterized
pedigrees. We will study body fat distribution by anthropometry and whole body
magnetic resonance imaging and will measure insulin sensitivity, plasma lipoproteins,
free fatty acids, glycerol and other metabolic variables. We have localized
the FPLD gene to chromosome 1q21-22 by genome-wide linkage analysis. Recently,
several missense mutations have been identified in Lamin A/C (LMNA) gene in
FPLD. The gene for CGL has been localized to chromosome 9q34. Recently, a gene
for CGL (BSCL2) was found on chromosome 11q13, however, the gene on chromosome
9q34 remains to be identified. Following chromosomal localization and fine mapping,
candidate genes, already mapped or identified by positional cloning into these
regions will be examined for mutations using the single strand conformation
polymorphism (SSCP), denaturing high performance liquid chromatography (DHPLC)
or direct sequencing. The identification of gene defects will allow us to define
the normal role of these genes in insulin action and body fat distribution and
will lead to a better understanding of how common adipose tissue disorders such
as obesity cause insulin resistance and other metabolic complications.
Project two:
Project title: Therapeutic Interventions in HIV-associated Lipodystrophy
Brief Description of Project 2:
Management of lipodystrophy and its metabolic complications pose a therapeutic
challenge. We propose to investigate potentially safe therapeutic lifestyle
changes as well as novel therapies for its management. The project therefore
has the following aims: 1) to compare acceptability and metabolic effects of
diets rich in carbohydrates and cis-monounsaturated fats, 2) to compare effects
of a supervised aerobic exercise regimen and dietary advice to dietary advice
alone on metabolic variables and body fat distribution, 3) to compare lipid-lowering
effects of n-3 polyunsaturated fats alone and in combination with Sitostanol
and 4) to study efficacy and safety of recombinant methionyl leptin (r-metHuleptin)
in improving insulin sensitivity, dyslipidemia and body fat distribution in
patients with HAART-induced lipodystrophy and metabolic complications. To accomplish
these aims, we will enroll ~124 patients with HAART-induced lipodystrophy or
metabolic complications in randomized, crossover studies (aims 1 and 3) and
randomized, parallel design studies (aims 2 and 4). We will study body fat distribution
by anthropometry, dual energy X-ray absorptiometry and magnetic resonance imaging
and will measure insulin sensitivity (aims 2 and 4). We will study plasma lipoproteins,
glucose tolerance, and other metabolic variables (all aims). Our results may
help in designing therapeutic approaches to HAART-induced lipodystrophy and
its metabolic complications. Additionally, the study may help prevent these
problems in HIV-infected patients being initiated on PI-containing regimen.
Previous Research Activities or Publications with Housestaff:
Simha V, Jacob, KL, Szczepaniak L, Garg A. Marked reduction in skeletal muscle
mass with long-term leptin replacement therapy in congenital generalized lipodystrophy.
88th Annual meeting of the Endocrine Society, Boston, MA June 2006.
O'Neal B, Simha V, Kotha V, Al-Gazali LI and Garg A. Body fat distribution and
metabolic variables in patients with neonatal progeroid (Wiedemann-Rautenstrauch)
syndrome associated lipodystrophy. "Lipodystrophy and the Metabolic Consequences
of Altered Fat Deposition Workshop", National Institutes of Health, Bethesda,
MD, November 2006.
Simha, V, Sousay AB, Dos Santos H, Agarwal AK, Garg A. Face-sparing Congenital
Generalized Lipodystrophy due to combined AGPAT2 and 21-hydroxylase deficiency.
The Lipodystrophies and the Metabolic Consequences of Altered Fat Deposition
Workshop, NIH, Bethesda, MD, 2006
Subramanyam L, Kotha V, Crow Y, Agarwal AK, Garg A. Wide spectrum of lipodystrophies
and progeroid features in atypical progeria syndrome due to heterozygous missense
LMNA mutations. The Lipodystrophies and the Metabolic Consequences of Altered
Fat Deposition Workshop, NIH, Bethesda, MD, 2006.
Dinges WL, Witherspoon SR, Itani KM, Garg A, Peterson DM. Blepharoptosis and
external ophthalmoplegia associated with chronic antiretroviral therapy (ART).
Infectious Disease Society of America 45th Meeting, San Diego, CA, 2007.
Simha V, Rao S, Garg A. Prolonged thiazolidinedione (TZD) therapy does not reverse
subcutaneous fat loss for lipodystrophic areas in patients with Familial Partial
Lipodystrophy, Dunnigan variety (FPLD). Submitted to the 90th Annual meeting
of the Endocrine Society, San Francisco, CA 2008.
Subramanyam L, Simha V, Garg A. Autosomal dominant familial partial lipodystrophy,
Dunnigan variety (FPLD) and severe cardiomyopathy associated with a novel heterozygous
Asp192Val Lamin A/C (LMNA) mutation. Submitted to the 90th Annual meeting of
the Endocrine Society, San Francisco, CA 2008.