Request for Funding

Medical Student Research Fellowship for Summer 2002

Mentor: Abhimanyu Garg,M.D.
Department: Internal Medicine
Room number: Y3.222
Mail Code: 9052
Phone number: 214-648-2895
E-mail: abhimanyu.garg@utsouthwestern.edu

Project 1

Project title: Genetic and Metabolic Basis of Familial Lipodystrophies

Human subjects IRB approved project number (where applicable): IRB File # 1093-37500

Animal subjects IRB approved project number (where applicable):

Project Type: Patient-based, molecular genetics
Brief Description of Project:

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. Recently, we have also identified a missense mutation in PPAR-? gene in Familial partial lipodystrophy ( non-Dunnigan variety). 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 2

Project Title: Mechanisms of Lipodystrophy in HIV-Infected Patients

Human subjects IRB approved project number (where applicable): IRB File # 0199-032

Animal subjects IRB approved project number (where applicable):

Project Type Patient-based, molecular biology.

Brief Description of Project:
This is an NIH funded grant intending to characterize the metabolic abnormalities and changes in body fat distribution related to protease inhibitor therapy.

Human immunodeficiency virus (HIV) infection is a major global health problem. Recently, combination therapy including HIV-1 protease inhibitors (PIs) has dramatically improved the long-term survival of HIV (+) patients. However, such therapy is associated with a lipodystrophy syndrome characterized by marked loss of subcutaneous (sc) fat from the face and extremities but excess of sc fat around the neck, dorsocervical region and trunk. Such patients have increased propensity to insulin resistance, diabetes mellitus and dyslipidemia. The metabolic and molecular basis of lipodystrophy syndrome in HIV-infected patients is not known. Whether besides PIs, other antiretroviral drugs, HIV infection and reduction in viral load contribute to the development of lipodystrophy syndrome is not clear. The project therefore has the following aims: 1) to characterize metabolic abnormalities and changes in body fat distribution, 2) to develop objective criteria for defining the syndrome and to ascertain prognostic indicators and 3) to elucidate the molecular basis of the lipodystrophy syndrome in HIV-infected patients. To accomplish these aims, we will conduct a 2-year long prospective, randomized, double blind, placebo-controlled study in 200 asymptomatic HIV (+) patients to compare two equally effective antiretroviral regimens, one with and the other without a PI. We will study body fat distribution by anthropometry and magnetic resonance imaging and will measure insulin sensitivity (in a subset of patients), plasma lipoproteins, glucose tolerance and other metabolic variables. We will study expression of an array of adipocyte specific proteins/transcription factors involved in adipocyte differentiation, insulin action and lipoprotein metabolism in fat biopsy samples obtained before and after institution of therapy. Identification of the metabolic and molecular basis of lipodystrophy syndrome in HIV (+) patients may lead to better understanding of role of adipocyte-specific genes in insulin action and body fat distribution and may lead to discovery of other antiretroviral drugs that do not cause the lipodystrophy syndrome. Additionally, the study may prove effectiveness and reduced toxicity of alternative antiretroviral regimens without a PI.

Project 3

Project Title: Identifying Autoantigens in Acquired Lipodystrophies

Human subjects IRB approved project number (where applicable): IRB File # 1093-37500

Animal subjects IRB approved project number (where applicable):

Project Type Patient-oriented, molecular research

Brief Description of Project:

Acquired generalized lipodystrophy (AGL), is a rare disorder characterized by onset of loss of subcutaneous fat throughout the body during childhood or adolescence.
It is three times more prevalent in women than men. Some patients with AGL have evidence of panniculitis and others have autoimmune diseases and serum autoantibodies such as antinuclear antibody. Therefore investigations were begun into identifying serum autoantibodies against adipocyte proteins in patients with AGL utilizing a western blot protocol. These investigations demonstrated that there were autoantibodies directed against adipocyte proteins in patients with AGL. The detection of the expression of autoantigen(s) in patients with AGL who had previously demonstrated autoantibodies supports the notion that AGL is an autoimmune disease. We will further characterize the autoantigens using molecular techniques. The detection and expression of autoantigens against which autoantibodies are directed in patients with AGL will help elucidate the molecular basis of autoimmunity in this rare disease.

Project 4

Project Title: Efficacy of leptin replacement in treatment of Lipodystrophy

Human subjects IRB approved project number (where applicable): IRB File # 0800-404

Animal subjects IRB approved project number (where applicable):

Project Type Patient-based

Brief Description of Project:

Lipodystrophies are disorders characterized by selective loss of adipose tissue. Patients with lipodystrophies are prone to insulin resistance, diabetes, dyslipidemia and fatty liver.
Leptin is a hormone that is primarily produced by the fat cells. It circulates in the blood and reflects the amount of fat tissue in the body. Leptin has been shown to play a role in regulating appetite. It also has other effects such as regulating the levels of various reproductive hormones and possible fuel metabolism. Patients with generalized lipodystrophy have marked reduction in body fat and low plasma leptin levels. In studying mice with lipoatrophy who have low leptin levels and have leptin therapy, dramatic improvement in their diabetes, insulin resistance, dyslipidemia and fatty liver has been observed. In this study, humans with clinically significant generalized lipodystrophy, low leptin levels and a metabolic derangement such as diabetes, hypertriglyceridemia, or insulin resistance will be treated with escalating leptin therapy after a comprehensive metabolic work-up. We will be analyzing differences in various parameters of euglycemic, hyperinsulinemic clamp studies in addition to insulin, lipoprotein and body fat distribution.

Previous Research Activities or Publications with Medical Students:

Body-Fat Distribution Assessment in HIV-Associated Lipodystrophy
Authors: Warren Dinges, D. Chen, A. Agyarko, and P. Weatherall,
Mentors: Abhimanyu Garg and Dolores Peterson

Assessment of Lipodystrophy in HIV-Infected Patients Using Magnetic Resonance
Afua Agyarko
Mentor: Abhimanyu Garg, M.D.

Detection of An Autoantigen In Acquired Generalized Lipodystrophy
Joseph Rossi Berger
Mentor: Abhaimnyu Garg, M.D.

Abstract submitted to International AIDS Conference, Barcelona, Spain. August, 2002
Body Composition Assessment of HIV-Associated Lipodystrophy
W. Dinges, A. Agyarko, D Chen, D Peterson, A Garg

Abstract presented at 39th Annual UT Southwestern Medical Student Reaserch Forum
Serum Autoantibodies Against Adipocyte Proteins In Acquired Generalized Lipodystrophy
Mentor: Abhimanyu Garg, M.D.
Joseph Rossi Berger

Abstract presented at 38TH Annual UT Southwestern Medical Student Research Forum
Magnetic Resonance Imaging (MRI) of Lipodystrophy in HIV-Infected Patients
Warren Dinges
Mentors: Dolores Peterson M.D., Ph.D., Abhimanyu Garg, M.D.

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