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Reduced Adipogenic Gene Expression in Thigh Adipose Tissue Precedes Human Immunodeficiency Virus-Associated Lipoatrophy

Department of Medicine, Divisions of Metabolism, Endocrinology, and Nutrition (M.K., P.A.B., K.M.U., S.E.K., D.S.W.), Allergy and Infectious Diseases (K.K.T.), Obstetrics and Gynecology (D.B.C.), Gerontology and Geriatric Medicine (M.Y.), University of Washington, Seattle, Washington 98109; the Department of Biostatistics (J.P.H.), the Diabetes Endocrinology Research Center, Molecular and Genetics Core (E.A.R., B.V.Y.), the Veterans Affairs Puget Sound Health Care System (K.M.U., S.E.K.), Seattle, Washington 98108; and Department of Medicine, Division of Endocrinology, Diabetes, and Clinical Nutrition (J.Q.P.), Oregon Health and Science University, Portland, Oregon 97239

Address all correspondence and requests for reprints to: Dr. Mario Kratz, Fred Hutchinson Cancer Research Center, Cancer Prevention Program, Mail stop M4-B402, 1100 Fairview Avenue North, Seattle, Washington 98109. E-mail: mkratz{at}fhcrc.org.

Context: The expression of adipogenic genes in sc adipose tissue has been reported to be lower among patients with HIV-associated lipoatrophy than HIV-uninfected controls. It is unclear whether this is a result or cause of lipoatrophy.

Objective: The objective of the study was to investigate the temporal relationships among changes in adipogenic gene expression in sc adipose tissue and changes in body fat distribution and metabolic complications in HIV-infected subjects on antiretroviral therapy.

Design: This was a prospective longitudinal study.

Setting: The study was conducted at HIV clinics in Seattle, Washington.

Participants: The study population included 31 HIV-infected and 12 control subjects.

Interventions: Subjects were followed up for 12 months after they initiated or modified their existing antiretroviral regimen.

Main Outcome Measures: Changes in body composition, plasma lipids, insulin sensitivity, and gene expression in sc abdominal and thigh adipose tissue.

Results: Subjects who developed lipoatrophy (n = 10) had elevated fasting triglycerides [3.16 (SD 2.79) mmol/liter] and reduced insulin sensitivity as measured by frequently sampled iv glucose tolerance test [1.89 (SD 1.27) x 10^–4 min^–1/µU·ml] after 12 months, whereas those without lipoatrophy (n = 21) did not show any metabolic complications [triglycerides 1.32 (SD 0.58) mmol/liter, P = 0.01 vs. lipoatrophy; insulin sensitivity 3.52 (SD 1.91) x 10^–4 min^–1/µU·ml, P = 0.01 vs. lipoatrophy]. In subjects developing lipoatrophy, the expression of genes involved in adipocyte differentiation, lipid uptake, and local cortisol production in thigh adipose tissue was significantly reduced already at the 2-month visit, several months before any loss of extremity fat mass was evident.

Conclusions: In HIV-infected subjects, lipoatrophy is associated with elevated fasting triglycerides and insulin resistance and might be caused by a direct or indirect effect of antiretroviral drugs on sc adipocyte differentiation.

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