title: HIV-1 Vpr induces adipose dysfunction in vivo through reciprocal effects on PPAR/GR co-regulation.
abstract: Viral infections, such as HIV, have been linked to obesity, but mechanistic evidence that they cause adipose dysfunction in vivo is lacking. We investigated a pathogenic role for the HIV-1 accessory protein viral protein R (Vpr), which can coactivate the glucocorticoid receptor (GR) and co-repress peroxisome proliferator-activated receptor γ (PPARγ) in vitro, in HIV-associated adipose dysfunction. Vpr circulated in the blood of most HIV-infected patients tested, including those on antiretroviral therapy (ART) with undetectable viral load. Vpr-mediated mechanisms were dissected in vivo using mouse models expressing the Vpr transgene in adipose tissues and liver (Vpr-Tg) or infused with synthetic Vpr. Both models demonstrated accelerated whole-body lipolysis, hyperglycemia and hypertriglyceridemia, and tissue-specific findings. Fat depots in these mice had diminished mass, macrophage infiltration, and blunted PPARγ target gene expression but increased GR target gene expression. In liver, we observed blunted PPARα target gene expression, steatosis with decreased adenosine monophosphate-activated protein kinase activity, and insulin resistance. Similar to human HIV-infected patients, Vpr circulated in the serum of Vpr-Tg mice. Vpr blocked differentiation in preadipocytes through cell cycle arrest, whereas in mature adipocytes, it increased lipolysis with reciprocally altered association of PPARγ and GR with their target promoters. These results delineate a distinct pathogenic sequence: Vpr, released from HIV-1 in tissue reservoirs after ART, can disrupt PPAR/GR co-regulation and cell cycle control to produce adipose dysfunction and hepatosteatosis. Confirmation of these mechanisms in HIV patients could lead to targeted treatment of the metabolic complications with Vpr inhibitors, GR antagonists, or PPARγ/PPARα agonists.
authors.affiliation: Translational Metabolism Unit, Diabetes Research Center, Division of Diabetes, Endocrinology and Metabolism, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Neeti
authors.initials: N
authors.lastname: Agarwal
authors.forename: Dinakar
authors.initials: D
authors.lastname: Iyer
authors.forename: Sanjeet G
authors.initials: SG
authors.lastname: Patel
authors.forename: Rajagopal V
authors.initials: RV
authors.lastname: Sekhar
authors.forename: Terry M
authors.initials: TM
authors.lastname: Phillips
authors.forename: Ulrich
authors.initials: U
authors.lastname: Schubert
authors.forename: Toni
authors.initials: T
authors.lastname: Oplt
authors.forename: Eric D
authors.initials: ED
authors.lastname: Buras
authors.forename: Susan L
authors.initials: SL
authors.lastname: Samson
authors.forename: Jacob
authors.initials: J
authors.lastname: Couturier
authors.forename: Dorothy E
authors.initials: DE
authors.lastname: Lewis
authors.forename: Maria C
authors.initials: MC
authors.lastname: Rodriguez-Barradas
authors.forename: Farook
authors.initials: F
authors.lastname: Jahoor
authors.forename: Tomoshige
authors.initials: T
authors.lastname: Kino
authors.forename: Jeffrey B
authors.initials: JB
authors.lastname: Kopp
authors.forename: Ashok
authors.initials: A
authors.lastname: Balasubramanyam
mesh_terms: D041721:3T3-L1 Cells; D000818:Animals; D002855:Chromatography, Thin Layer; D004797:Enzyme-Linked Immunosorbent Assay; D016336:Gene Products, vpr / Q000235:genetics / Q000378:metabolism*; D015497:HIV-1 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D015151:Immunoblotting; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D047493:PPAR alpha / Q000819:agonists / Q000378:metabolism; D047495:PPAR gamma / Q000378:metabolism; D011965:Receptors, Glucocorticoid / Q000819:agonists / Q000378:metabolism*
chemical_list: D016336:Gene Products, vpr; D047493:PPAR alpha; D047495:PPAR gamma; D011965:Receptors, Glucocorticoid