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Dysfunctional Subcutaneous Fat With Reduced Dicer and Brown Adipose Tissue Gene Expression in HIV-Infected Patients
Martin Torriani1, Suman Srinivasa1, Kathleen V Fitch1
1Program in Nutritional Metabolism (M.T., S.S., K.V.F., K.W., E.P., S.K.G.) and Division of Musculoskeletal Imaging and Intervention (M.T.), Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114; Section on Integrative Physiology and Metabolism (T.T., C.R.K., A.M.C.), Joslin Diabetes Center and Harvard Medical School, Boston, Massachusetts 02215; and Translational Physiology Section, Diabetes, Endocrinology, and Obesity Branch, National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Diseases (A.M.C.), Bethesda, Maryland 20892.
Context:
HIV patients are at an increased risk for cardiometabolic disease secondary to depot-specific alterations in adipose function, but mechanisms remain poorly understood.
Objective:
The endoribonuclease Dicer has been linked to the modulation of brown and white adipocyte differentiation. We previously demonstrated that Dicer knockout mice undergo transformation of brown adipose tissue to white adipose tissue and develop a lipodystrophic phenotype. We hypothesized reduced Dicer and brown adipose tissue gene expression from nonlipomatous sc fat among HIV patients with a lipodystrophic phenotype.
Design:
Eighteen HIV (nine with and without lipodystrophic changes in fat distribution, characterized by excess dorsocervical adipose tissue [DCAT]) and nine non-HIV subjects underwent punch biopsy of abdominal sc fat to determine expression of Dicer and other adipose-related genes.
Results:
HIV subjects with long-duration antiretroviral use demonstrated excess DCAT vs non-HIV subjects (9.8 ± 1.0 vs 6.6 ± 0.8 cm(2), P = .02) with similar body mass index. Dicer expression was decreased in abdominal sc fat of HIV vs non-HIV (4.88 [1.91, 11.93] vs 17.69 [10.72, 47.91], P = .01), as were PPARα, ZIC1, PRDM16, DIO2, and HSP60 (all P ≤ .03). Moreover, the expression of Dicer (2.49 [0.02, 4.88] vs 11.20 [4.83, 21.45], P = .006), brown fat (PPARα [P = .002], ZIC1 [P = .004], LHX8 [P = .03], PRDM16 [P = .0008], PAT2 [P = .008], P2RX5 [P = .02]), beige fat (TMEM26 [P = .004], CD137 [P = .008]), and other genes (DIO2 [P = .002], leptin [P = .003], HSP60 [P = .0004]) was further decreased in abdominal sc fat comparing HIV subjects with vs without excess DCAT. Down-regulation of Dicer in the abdominal sc fat correlated with the down-regulation of all brown and beige fat genes (all P ≤ .01).
Conclusion:
Our results demonstrate dysfunctional sc adipose tissue marked by reduced Dicer in relationship to the down-regulation of brown and beige fat-related genes in lipodystrophic HIV patients and may provide a novel mechanism for metabolic dysregulation. A strategy to increase browning of white adipose tissue may improve cardiometabolic health in HIV.
Insights
Human immunodeficiency virus (HIV) patients with lipodystrophy show reduced Dicer expression and brown/beige fat genes in subcutaneous fat. This suggests a novel mechanism for metabolic issues, potentially treatable by increasing white adipose tissue browning.
Area of Science:
- Adipose tissue biology
- Molecular mechanisms of metabolic disease
- HIV-associated comorbidities
Background:
- HIV patients exhibit increased cardiometabolic disease risk due to altered adipose tissue function.
- Mechanisms underlying these adipose tissue changes in HIV are not well understood.
- The endoribonuclease Dicer plays a role in adipocyte differentiation.
Purpose of the Study:
- To investigate the role of Dicer and brown adipose tissue (BAT) gene expression in HIV patients with lipodystrophy.
- To test the hypothesis that reduced Dicer and BAT gene expression in subcutaneous (sc) fat is associated with lipodystrophy in HIV patients.
Main Methods:
- Biopsies of abdominal sc fat were obtained from 18 HIV patients (9 with and 9 without lipodystrophy) and 9 non-HIV controls.
- Gene expression levels of Dicer, brown fat markers, beige fat markers, and other related genes were quantified.
- Dorsocervical adipose tissue (DCAT) was measured to assess lipodystrophy.
Main Results:
- HIV patients with lipodystrophy had significantly higher DCAT compared to non-HIV controls.
- Dicer expression was significantly decreased in the sc fat of HIV patients compared to non-HIV subjects.
- Expression of multiple brown and beige fat-related genes (e.g., PPARα, ZIC1, PRDM16, DIO2) was significantly reduced in HIV patients, particularly those with excess DCAT.
- Reduced Dicer expression strongly correlated with the down-regulation of brown and beige fat genes.
Conclusions:
- Dysfunctional sc adipose tissue, characterized by reduced Dicer and down-regulated brown/beige fat genes, is evident in lipodystrophic HIV patients.
- This provides a potential novel mechanism for metabolic dysregulation in HIV.
- Therapeutic strategies aimed at increasing white adipose tissue browning may improve cardiometabolic health in HIV patients.
