Reduced adipogenic gene expression in thigh adipose tissue precedes human immunodeficiency virus-associated lipoatrophy

Abstract

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)x10(-4) min(-1)/microU.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)x10(-4) min(-1)/microU.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.

Figures

Figure 1

Changes in trunk and extremity fat mass in HIV-infected subjects on HAART (▪) and HIV-uninfected controls (○) over the 12 months of the study. The two lines indicate the mean change ± 1 sd in trunk fat mass (+23.8%) as well as the mean change −1 sd loss in extremity fat mass (−18.7%) observed in controls. HIV-infected subjects who gained more than 23.8% of trunk fat mass were defined as having developed central lipohypertrophy; HIV-infected subjects who lost more than 18.7% of extremity fat mass were defined as having developed peripheral lipoatrophy.

Figure 2

Changes in trunk (A) and extremity (B) fat mass in HIV-infected subjects developing lipohypertrophy (• and solid lines, n = 11), lipoatrophy (▴ and dashed lines, n = 9), and no lipodystrophy (▪ and broken lines, n = 10) during 12 months of antiretroviral therapy. Because the group definitions were based on these variables, no statistical tests were performed. Data represent means and se values.

Figure 3

Changes in plasma triglycerides (A), HDL-cholesterol (B), and insulin sensitivity (C) over the 12 months of the study in HIV-infected subjects developing lipoatrophy (▴ and dashed lines, n = 10) or not developing lipoatrophy (• and solid lines, n = 21 except for insulin sensitivity, where n = 19). *, P < 0.05 for comparison of the two groups at that time point. †, P < 0.05 for change within group over time (Friedman test). Data represent means and se values.

Figure 4

Absolute changes in mRNA concentrations of genes involved in adipocyte differentiation, lipid uptake, and local cortisol production as well as GAPDH in the 12-month study period in abdominal (A) and thigh (B) sc adipose tissue as well as in the first 2 months of the study in abdominal (C) and thigh (D) sc adipose tissue. Data are mRNA concentrations normalized for total RNA content (in nanograms of standard per nanograms total RNA in reaction). Error bars represent se values. ▪, No lipoatrophy group [n = 16 for abdominal and n = 15 for thigh adipose tissue data (A and B); n = 20 for abdominal and n = 21 for thigh adipose tissue (C and D)]; □, lipoatrophy group [n = 9 for abdominal and n = 8 for thigh adipose tissue (A and B); n = 10 for abdominal and n = 9 for thigh adipose tissue (C and D)]. *, P < 0.05 for comparison of mRNA concentrations at baseline and 12-month visit (A and B) and baseline and 2-month visit (C and D), respectively, within each group. **, P < 0.05; ***, P < 0.01 for comparison of change between the two groups.