Lipodystrophy in HIV type-1 (HIV-1)-infected patients is the consequence of effects originating from antiretroviral treatment and HIV-1 infection. We have studied adipose tissues and circulating parameters in mice bearing the HIV-1 transgene as a model to provide insight into the role of HIV-1-infection-related events in fat alterations.
Methods
Heterozygous transgenic mice expressing a 7.7 kb HIV-1 construct (Tg26+/-) were used. Cytokine and adipokine levels were quantified using multiplex procedures. Gene expression and mitochondrial DNA abundance in visceral and subcutaneous white adipose tissues and in brown fat were determined using quantitative real-time PCR.
Results
The amount of visceral, but not subcutaneous, adipose depot was lower in Tg26+/- mice. Serum proinflammatory cytokine levels were increased in Tg26+/-mice, whereas adiponectin and leptin levels were reduced. Gene expression of monocyte chemoattractant protein-1 was induced in visceral and subcutaneous fat, whereas tumour necrosis factor-α and interleukin-6 were induced in visceral and subcutaneous white adipose tissues, respectively. Adiponectin and leptin gene expression was repressed in all white fat depots, in concert with reduced expression of peroxisome proliferator-activated receptor γ, a master controller of adipogenesis. In brown fat, a coordinate induction in the expression of thermogenesis marker genes was observed.
Conclusions
HIV-1 transgene expression in mice causes changes in adipose tissue reminiscent of those in patients with HIV-1 lipodystrophy, particularly early pretreatment changes. These data support a role for HIV-1-infection-related events in eliciting adipose tissue dysfunction. The Tg26+/- mouse appears as a promising model to assess the effects of HIV-1 infection on adipose tissue and for determining the effects of antiretroviral drugs on an HIV-1-infected background.
References
1.
VillarroyaF., DomingoP., GiraltM.Lipodystrophy in HIV 1-infected patients: lessons for obesity research.Int J Obes (Lond)2007; 31: 1763–1776.
2.
GiraltM., DomingoP., GuallarJ.P.HIV-1 infection alters gene expression in adipose tissue, which contributes to HIV-1/HAART-associated lipodystrophy.Antivir Ther2006; 11: 729–740.
3.
VisnegarwalaF., RaghavanS.S., MullinC.M.Sex differences in the associations of HIV disease characteristics and body composition in antiretroviral-naive persons.Am J Clin Nutr2005; 82: 850–856.
4.
PeckM.D., Mantero-AtienzaE., Miguez-BurbanoM.J.The esterified plasma fatty acid profile is altered in early HIV-1 infection.Lipids1993; 28: 593–597.
5.
GoetzmanE.S., TianL., NagyT.R.HIV protease inhibitor ritonavir induces lipoatrophy in male mice.AIDS Res Hum Retroviruses2003; 19: 1141–1150.
6.
ProtM., HeripretL., Cardot-LecciaN.Long-term treatment with lopinavir-ritonavir induces a reduction in peripheral adipose depots in mice.Antimicrob Agents Chemother2006; 50: 3998–4004.
7.
BalasubramanyamA., MersmannH., JahoorF.Effects of transgenic expression of HIV-1 Vpr on lipid and energy metabolism in mice.Am J Physiol Endocrinol Metab2007; 292: E40–E48.
8.
KlotmanP.E., RappaportJ., RayP.Transgenic models of HIV-1.AIDS1995; 9: 313–324.
9.
DeS.K., DevadasK., NotkinsA.L.Elevated levels of tumor necrosis factor alpha (TNF-alpha) in human immunodeficiency virus type 1-transgenic mice: prevention of death by antibody to TNF-alpha.J Virol2002; 76: 11710–11714.
10.
AddyC.L., GavrilaA., TsiodrasS., BrodoviczK., KarchmerA.W., MantzorosC.S.Hypoadiponectinemia is associated with insulin resistance, hypertriglyceridemia, and fat redistribution in human immunodeficiency virus-infected patients treated with highly active antiretroviral therapy.J Clin Endocrinol Metab2003; 88: 627–636.
11.
NagyG.S., TsiodrasS., MartinL.D.Human immunodeficiency virus type 1-related lipoatrophy and lipohypertrophy are associated with serum concentrations of leptin.Clin Infect Dis2003; 36: 795–802.
12.
HommesM.J., RomijnJ.A., EndertE., Eeftinck SchattenkerkJ.K., SauerweinH.P.Insulin sensitivity and insulin clearance in human immunodeficiency virus-infected men.Metabolism1991; 40: 651–656.
13.
JanV., CerveraP., MaachiM.Altered fat differentiation and adipocytokine expression are inter-related and linked to morphological changes and insulin resistance in HIV-1-infected lipodystrophic patients.Antivir Ther2004; 9: 555–564.
14.
VillarroyaJ., Gallego-EscuredoJ.M., DomingoJ.C.Differential alterations of gene expression in visceral versus subcutaneous adipose tissue from HIV-1-infected, HAART-treated patients with lipodystrophy: a pilot study.Antivir Ther2008; 13 Suppl 4: A3.
15.
CintiS.Transdifferentiation properties of adipocytes in the adipose organ.Am J Physiol Endocrinol Metab2009; 297: E977–E986.
DomingoP., GuallarJ.P., Gallego-EscuredoJ.M.Genome-wide transcriptomic analysis reveals distinct patterns of altered gene expression in subcutaneous adipose tissue associated with HIV-1-infection, antiretroviral treatment and lipodystrophy.Antivir Ther2008; 13 Suppl 4: A25.
18.
CeliF.S.Brown adipose tissue - when it pays to be inefficient.N Engl J Med2009; 360: 1553–1556.
19.
GuallarJ.P., Gallego-EscuredoJ.M., DomingoJ.C.Differential gene expression indicates that ‘buffalo hump’ is a distinct adipose tissue disturbance in HIV-1-associated lipodystrophy.AIDS2008; 22: 575–584.
20.
RayP.E., TassiE., LiuX-H, WellsteinA.Role of fibroblast growth factor-binding protein in the pathogenesis of HIV-associated hemolytic uremic syndrome.Am J Physiol Regul Integr Comp Physiol2006; 290: R105–R113.
