Mentor: Abhimanyu Garg, M.D.
Department: Internal Medicine

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Project title: Mechanisms of Lipodystrophy in HIV-Infected Patients
Brief Description of Project 1:
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 title: Genetic and metabolic basis of familial lipodystrophies
Brief Description of Project 2:
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 title: Therapeutic Interventions in HIV-associated Lipodystrophy
Brief Description of Project 3:

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 HAART.