title: Dysfunctional Subcutaneous Fat With Reduced Dicer and Brown Adipose Tissue Gene Expression in HIV-Infected Patients.
abstract: BACKGROUND
  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.
  
  
  METHODS
  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).
  
  
  CONCLUSIONS
  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.
authors.affiliation: Program 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.
authors.forename: Martin
authors.initials: M
authors.lastname: Torriani
authors.affiliation: Program 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.
authors.forename: Suman
authors.initials: S
authors.lastname: Srinivasa
authors.affiliation: Program 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.
authors.forename: Kathleen V
authors.initials: KV
authors.lastname: Fitch
authors.affiliation: Program 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.
authors.forename: Thomas
authors.initials: T
authors.lastname: Thomou
authors.affiliation: Program 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.
authors.forename: Kimberly
authors.initials: K
authors.lastname: Wong
authors.affiliation: Program 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.
authors.forename: Eva
authors.initials: E
authors.lastname: Petrow
authors.affiliation: Program 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.
authors.forename: C Ronald
authors.initials: CR
authors.lastname: Kahn
authors.affiliation: Program 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.
authors.forename: Aaron M
authors.initials: AM
authors.lastname: Cypess
authors.affiliation: Program 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.
authors.forename: Steven K
authors.initials: SK
authors.lastname: Grinspoon
mesh_terms: D050156:Adipogenesis / Q000235:genetics; D002001:Adipose Tissue, Brown / Q000378:metabolism* / Q000473:pathology; D052436:Adipose Tissue, White / Q000378:metabolism* / Q000473:pathology; D001415:Back; D050218:Body Fat Distribution; D016022:Case-Control Studies; D053487:DEAD-box RNA Helicases / Q000235:genetics* / Q000378:metabolism; D004734:Energy Metabolism / Q000235:genetics; D015870:Gene Expression; D015658:HIV Infections / Q000150:complications* / Q000235:genetics / Q000473:pathology; D015497:HIV-1; D039682:HIV-Associated Lipodystrophy Syndrome / Q000235:genetics* / Q000473:pathology; D006801:Humans; D008297:Male; D008875:Middle Aged; D009333:Neck; D043244:Ribonuclease III / Q000235:genetics* / Q000378:metabolism; D050151:Subcutaneous Fat / Q000378:metabolism* / Q000473:pathology
chemical_list: C408087:DICER1 protein, human; D043244:Ribonuclease III; D053487:DEAD-box RNA Helicases