Skip to main content

Advertisement

SpringerLink
Log in

Designer Adiponectin Receptor Agonist Stabilizes Metabolic Function and Prevents Brain Injury Caused by HIV Protease Inhibitors

  • ORIGINAL ARTICLE
  • Published:
Journal of Neuroimmune Pharmacology Aims and scope Submit manuscript

Abstract

HIV protease inhibitors (PI) are fundamental to combination antiretroviral therapy, which has revolutionized HIV clinical care and produced significant reductions in HIV-associated morbidity and mortality. However, PI administration is frequently associated with severe metabolic impairment, including lipodystrophy, dyslipidemia, and insulin resistance; all of which can contribute to cardiovascular and neurologic co-morbidities. Experimental and epidemiological data support a potentially important role for the adipokine adiponectin in both metabolic and neurologic physiology. This study examined if ADP355, a novel, peptide-based adiponectin receptor agonist, could neutralize the detrimental effects of PI treatment in experimental animal models. Adult male C57BL/6 mice were subjected to a clinically relevant, 4-week regimen of lopinavir/ritonavir, with daily injections of ADP355 administered only during the final 2 weeks of PI exposure. Comprehensive metabolic, neurobehavioral, and biochemical analyses revealed that ADP355 administration partially reversed PI-induced loss of subcutaneous adipose tissue, attenuated PI-induced hyperinsulinemia, hypertriglyceridemia, and hypoadiponectinemia, and prevented PI-induced cognitive impairment and brain injury. Collectively, these data reinforce the link between metabolic co-morbidities and cognitive impairment and suggest that pharmacological reactivation of adiponectin pathways could remediate key aspects of PI-induced metabolic syndrome in clinical settings. Furthermore, therapeutic targeting of adiponectin receptors could show utility in reducing the prevalence and/or severity of HIV-associated neurocognitive disorders.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  • Ances BM, Ellis RJ (2007) Dementia and neurocognitive disorders due to HIV-1 infection. Semin Neurol 27:86–92

    Article  PubMed  Google Scholar 

  • Anuurad E, Semrad A, Berglund L (2009) Human immunodeficiency virus and highly active antiretroviral therapy-associated metabolic disorders and risk factors for cardiovascular disease. Metab Syndr Relat Disord 7:401–410

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Arai Y, Takayama M, Abe Y, Hirose N (2011) Adipokines and aging. J Atheroscler Thromb 18:545–545

    Article  CAS  PubMed  Google Scholar 

  • Arama V, Tiliscan C, Streinu-Cercel A, Ion D, Mihailescu R, Munteanu D, Hristea A, Arama SS, group. S-As (2013) Insulin resistance and adipokines serum levels in a caucasian cohort of hiv-positive patients undergoing antiretroviral therapy: a cross sectional study. BMC Endocr Disord 13:4

    Article  PubMed Central  PubMed  Google Scholar 

  • Bandaru VV, McArthur JC, Sacktor N, Cutler RG, Knapp EL, Mattson MP, Haughey NJ (2007) Associative and predictive biomarkers of dementia in HIV-1-infected patients. Neurology 68:1481–1487

    Article  CAS  PubMed  Google Scholar 

  • Barbaro G (2007) Visceral fat as target of highly active antiretroviral therapy-associated metabolic syndrome. Curr Pharm Des 13:2208–2213

    Article  CAS  PubMed  Google Scholar 

  • Chen B, Liao WQ, Xu N, Xu H, Wen JY, Yu CA, Liu XY, Li CL, Zhao SM, Campbell W (2009) Adiponectin protects against cerebral ischemia-reperfusion injury through anti-inflammatory action. Brain Res 1273:129–137

    Article  CAS  PubMed  Google Scholar 

  • de Waal R, Cohen K, Maartens G (2013) Systematic review of antiretroviral-associated lipodystrophy: lipoatrophy, but not central fat gain, is an antiretroviral adverse drug reaction. PLoS One 8:e63623

    Article  PubMed Central  PubMed  Google Scholar 

  • Duntas LH, Popovic V, Panotopoulos G (2004) Adiponectin: novelties in metabolism and hormonal regulation. Nutr Neurosci 7:195–200

    Article  CAS  PubMed  Google Scholar 

  • Foley J, Ettenhofer M, Wright MJ, Siddiqi I, Choi M, Thames AD, Mason K, Castellon S, Hinkin CH (2010) Neurocognitive functioning in HIV-1 infection: effects of cerebrovascular risk factors and age. Clin Neuropsychol 24:265–285

    Article  PubMed Central  PubMed  Google Scholar 

  • Fruebis J, Tsao TS, Javorschi S, Ebbets-Reed D, Erickson MR, Yen FT, Bihain BE, Lodish HF (2001) Proteolytic cleavage product of 30-kDa adipocyte complement-related protein increases fatty acid oxidation in muscle and causes weight loss in mice. Proc Natl Acad Sci U S A 98:2005–2010

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Fry M, Smith PM, Hoyda TD, Duncan M, Ahima RS, Sharkey KA, Ferguson AV (2006) Area postrema neurons are modulated by the adipocyte hormone adiponectin. J Neurosci 26:9695–9702

    Article  CAS  PubMed  Google Scholar 

  • Gil A, Olza J, Gil-Campos M, Gomez-Llorente C, Aguilera CM (2011) Is adipose tissue metabolically different at different sites? Int J Pediatr Obes 6(Suppl 1):13–20

    Article  PubMed  Google Scholar 

  • Guaraldi G, Zona S, Alexopoulos N, Orlando G, Carli F, Ligabue G, Fiocchi F, Lattanzi A, Rossi R, Modena M, Esposito R, Palella F and Raggi P (2009) Coronary aging in HIV-infected patients. 49:1756–1762

  • Gupta S, Knight AG, Losso BY, Ingram DK, Keller JN, Bruce-Keller AJ (2012) Brain injury caused by HIV protease inhibitors: role of lipodystrophy and insulin resistance. Antiviral Res 95:19–29

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Gutierrez AD, Balasubramanyam A (2012) Dysregulation of glucose metabolism in HIV patients: epidemiology, mechanisms, and management. Endocrine 41:1–10

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Han S, Hong S, Lee D, Lee MH, Choi JS, Koh MJ, Sun W, Kim H, Lee HW (2012) Altered expression of synaptotagmin 13 mRNA in adult mouse brain after contextual fear conditioning. Biochem Biophys Res Commun 425:880–885

    Article  CAS  PubMed  Google Scholar 

  • Harvey J (2007) Leptin regulation of neuronal excitability and cognitive function. Curr Opin Pharmacol 7:643–647

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Jiménez-Nácher I, Alvarez E, Morello J, Rodriguez-Nóvoa S, de Andrés S, Soriano V (2011) Approaches for understanding and predicting drug interactions in human immunodeficiency virus-infected patients. Expert Opin Drug Metab Toxicol 7:457–477

    Article  PubMed  Google Scholar 

  • Jung TW, Lee JY, Shim WS, Kang ES, Kim JS, Ahn CW, Lee HC, Cha BS (2006) Adiponectin protects human neuroblastoma SH-SY5Y cells against MPP + -induced cytotoxicity. Biochem Biophys Res Commun 343:564–570

    Article  CAS  PubMed  Google Scholar 

  • Kamogawa K, Kohara K, Tabara Y, Uetani E, Nagai T, Yamamoto M, Igase M, Miki T (2010) Abdominal fat, adipose-derived hormones and mild cognitive impairment: the J-SHIPP study. Dement Geriatr Cogn Disord 30:432–439

    Article  CAS  PubMed  Google Scholar 

  • Kinlaw WB, Marsh B (2004) Adiponectin and HIV-lipodystrophy: taking HAART. Endocrinology 145:484–486

    Article  CAS  PubMed  Google Scholar 

  • Kohli R, Shevitz A, Gorbach S, Wanke C (2007) A randomized placebo-controlled trial of metformin for the treatment of HIV lipodystrophy. HIV Med 8:420–426

    Article  CAS  PubMed  Google Scholar 

  • Kubota N, Yano W, Kubota T, Yamauchi T, Itoh S, Kumagai H, Kozono H, Takamoto I, Okamoto S, Shiuchi T, Suzuki R, Satoh H, Tsuchida A, Moroi M, Sugi K, Noda T, Ebinuma H, Ueta Y, Kondo T, Araki E, Ezaki O, Nagai R, Tobe K, Terauchi Y, Ueki K, Minokoshi Y, Kadowaki T (2007) Adiponectin stimulates AMP-activated protein kinase in the hypothalamus and increases food intake. Cell Metab 6:55–68

    Article  CAS  PubMed  Google Scholar 

  • Leszczyszyn-Pynka M, Pynka S, Boron-Kaczmarska A, Pilarska K (2005) Serum leptin and adiponectin concentrations in patients infected with human immunodeficiency virus type 1 (HIV-1) on antiretroviral therapy. Endokrynol Pol 56:19–24

    PubMed  Google Scholar 

  • Masaki T, Anan F, Shimomura T, Fujiki M, Saikawa T and Yoshimatsu H (2012) Association between hippocampal volume and serum adiponectin in patients with type 2 diabetes mellitus. Metabolism. Epub ahead of print

  • McMurtray A, Nakamoto B, Shikuma C, Valcour V (2007) Small-vessel vascular disease in human immunodeficiency virus infection: the Hawaii aging with HIV cohort study. Cerebrovasc Dis 24:236–241

    Article  PubMed  Google Scholar 

  • Mulligan K, Yang Y, Wininger DA, Koletar SL, Parker RA, Alston-Smith BL, Schouten JT, Fielding RA, Basar MT, Grinspoon S (2007) Effects of metformin and rosiglitazone in HIV-infected patients with hyperinsulinemia and elevated waist/hip ratio. AIDS 21:47–57

    Article  CAS  PubMed  Google Scholar 

  • Nannipieri M, Bonotti A, Anselmino M, Cecchetti F, Madec S, Mancini E, Baldi S, Santini F, Pinchera A, Rossi M, Ferrannini E (2007) Pattern of expression of adiponectin receptors in human adipose tissue depots and its relation to the metabolic state. Int J Obes (Lond) 31:1843–1848

    Article  CAS  Google Scholar 

  • Oomura Y, Hori N, Shiraishi T, Fukunaga K, Takeda H, Tsuji M, Matsumiya T, Ishibashi M, Aou S, Li X, Kohno D, Uramura K, Sougawa H, Yada T, Wayner M, Sasaki K (2006) Leptin facilitates learning and memory performance and enhances hippocampal CA1 long-term potentiation and CaMK II phosphorylation in rats. Peptides 11:2738–2749

    Article  Google Scholar 

  • Otvos LJ, Haspinger E, La Russa F, Maspero F, Graziano P, Kovalszky I, Lovas S, Nama K, Hoffmann R, Knappe D, Cassone M, Wade J, Surmacz E (2011) Design and development of a peptide-based adiponectin receptor agonist for cancer treatment. BMC Biotechnol 11:90

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Ouchi N, Walsh K (2007) Adiponectin as an anti-inflammatory factor. Clin Chim Acta 380:24–30

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Ouedraogo R, Gong Y, Berzins B, Wu X, Mahadev K, Hough K, Chan L, Goldstein BJ, Scalia R (2007) Adiponectin deficiency increases leukocyte-endothelium interactions via upregulation of endothelial cell adhesion molecules in vivo. J Clin Invest 117:1718–1726

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Pajvani UB, Du X, Combs TP, Berg AH, Rajala MW, Schulthess T, Engel J, Brownlee M, Scherer PE (2003) Structure-function studies of the adipocyte-secreted hormone Acrp30/adiponectin. Implications fpr metabolic regulation and bioactivity. J Biol Chem 278:9073–9085

    Article  CAS  PubMed  Google Scholar 

  • Paruthi J, Gill N, Mantzoros CS (2013) Adipokines in the HIV/HAART-associated lipodystrophy syndrome. Metabolism 24:S0026–S0495

    Google Scholar 

  • Pistell PJ, Gupta S, Knight AG, Domingue M, Uranga RM, Ingram DK, Kheterpal I, Ruiz C, Keller JN, Bruce-Keller AJ (2010a) Metabolic and neurologic consequences of chronic lopinavir/ritonavir administration to C57BL/6 mice. Antiviral Res 88:334–342

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Pistell PJ, Morrison CD, Gupta S, Knight AG, Keller JN, Ingram DK, Bruce-Keller AJ (2010b) Cognitive impairment following high fat diet consumption is associated with brain inflammation. J Neuroimmunol 219:25–32

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Qi Y, Takahashi N, Hileman SM, Patel HR, Berg AH, Pajvani UB, Scherer PE, Ahima RS (2004) Adiponectin acts in the brain to decrease body weight. Nat Med 10:524–529

    Article  CAS  PubMed  Google Scholar 

  • Quinn TC (2008) HIV epidemiology and the effects of antiviral therapy on long-term consequences. AIDS Patient Care STDS 22(Suppl 3):S7–S12

    CAS  Google Scholar 

  • Reagan-Shaw S, Nihal M, Ahmad N (2007) Dose translation from animal to human studies revisited. FASEB J 22:659–661

    Article  PubMed  Google Scholar 

  • Rocha VZ, Libby P (2008) The multiple facets of the fat tissue. Thyroid 18:175–183

    Article  PubMed  Google Scholar 

  • Rodriguez-Pacheco F, Martinez-Fuentes AJ, Tovar S, Pinilla L, Tena-Sempere M, Dieguez C, Castaño JP, Malagon MM (2007) Regulation of pituitary cell function by adiponectin. Endocrinology 148:401–410

    Article  CAS  PubMed  Google Scholar 

  • Schambelan M, Benson CA, Carr A, Currier JS, Dubé MP, Gerber JG, Grinspoon SK, Grunfeld C, Kotler DP, Mulligan K, Powderly WG, Saag MS, Society-USA. IA (2002) Management of metabolic complications associated with antiretroviral therapy for HIV-1 infection: recommendations of an International AIDS Society-USA panel. J Acquir Immune Defic Syndr 31:257–275

    Article  PubMed  Google Scholar 

  • Siasos G, Tousoulis D, Kollia C, Oikonomou E, Siasou Z, Stefanadis C, Papavassiliou AG (2012) Adiponectin and cardiovascular disease: mechanisms and new therapeutic approaches. Curr Med Chem 19:1193–1209

    Article  CAS  PubMed  Google Scholar 

  • Sivakumar T, Mechanic O, Fehmie DA, Paul B (2011) Growth hormone axis treatments for HIV-associated lipodystrophy: a systematic review of placebo-controlled trials. HIV Med 12:453–462

    Article  CAS  PubMed  Google Scholar 

  • Spooner LM, Olin JL (2012) Tesamorelin: a growth hormone-releasing factor analogue for HIV-associated lipodystrophy. Ann Pharmacother 46:240–247

    Article  PubMed  Google Scholar 

  • Takahashi T, Saegusa S, Sumino H, Nakahashi T, Iwai K, Morimoto S, Kanda T (2005) Adiponectin replacement therapy attenuates myocardial damage in leptin-deficient mice with viral myocarditis. J Int Med Res 33:207–214

    Article  CAS  PubMed  Google Scholar 

  • Tan IL, McArthur JC (2012) HIV-associated neurological disorders: a guide to pharmacotherapy. CNS Drugs 26:123–134

    Article  PubMed  Google Scholar 

  • Vachharajan IV, Cunningham C, Yoza B, Carson JJ, Vachharajani TJ, McCall C (2012) Adiponectin-deficiency exaggerates sepsis-induced microvascular dysfunction in the mouse brain. Obesity (Silver Spring) 20:498–504

    Article  Google Scholar 

  • Valcour VG, Sacktor NC, Paul RH, Watters MR, Selnes OA, Shiramizu BT, Williams AE, Shikuma CM (2006) Insulin resistance is associated with cognition among HIV-1-infected patients: the Hawaii aging with HIV cohort. J Acquir Immune Defic Syndr 43:405–410

    Article  PubMed  Google Scholar 

  • Valcour V, Maki P, Bacchetti P, Anastos K, Crystal H, Young M, Mack W, Cohen M, Golub E and Tien P (2011) Insulin resistance and cognition among HIV-infected and HIV-uninfected adult women—the women’s interagency HIV study. AIDS Res Hum Retroviruses. Epub ahead of print

  • van Wijk JP, Hoepelman AI, de Koning EJ, Dallinga-Thie G, Rabelink TJ, Cabezas MC (2011) Differential effects of rosiglitazone and metformin on postprandial lipemia in patients with HIV-lipodystrophy. Arterioscler Thromb Vasc Biol 31:228–233

    Article  PubMed  Google Scholar 

  • Veloso S, Escoté X, Ceperuelo-Mallafré V, López-Dupla M, Peraire J, Viladés C, Domingo P, Castro A, Olona M, Sirvent JJ, Leal M, Vendrell J, Richart C, Vidal F (2012) Leptin and adiponectin, but not IL18, are related with insulin resistance in treated HIV-1-infected patients with lipodystrophy. Cytokine 58:253–260

    Article  CAS  PubMed  Google Scholar 

  • Waki H, Yamauchi T, Kamon J, Ito Y, Uchida S, Kita S, Hara K, Hada Y, Vasseur F, Froguel P, Kimura S, Nagai R, Kadowaki T (2003) Impaired multimerization of human adiponectin mutants associated with diabetes. Molecular structure and multimer formation of adiponectin. J Biol Chem 278:40352–40363

    Article  CAS  PubMed  Google Scholar 

  • Wei W, Wan Y (2011) Thiazolidinediones on PPARγ: the roles in bone remodeling. PPAR Res 2011:867180

    Article  PubMed Central  PubMed  Google Scholar 

  • Wright EJ, Grund B, Robertson K, Brew BJ, Roediger M, Bain MP, Drummond F, Vjecha MJ, Hoy J, Miller C, de Oliveira AC P, Pumpradit W, Shlay JC, El-Sadr W, Price RW, Group. ISS (2010) Cardiovascular risk factors associated with lower baseline cognitive performance in HIV-positive persons. Neurology 75:864–873

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Xu A, Wang Y, Keshaw H, Xu LY, Lam KS, Cooper GJ (2003) The fat-derived hormone adiponectin alleviates alcoholic and nonalcoholic fatty liver diseases in mice. J Clin Invest 112:91–100

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Xu A, Yin S, Wong L, Chan KW, Lam KS (2004) Adiponectin ameliorates dyslipidemia induced by the human immunodeficiency virus protease inhibitor ritonavir in mice. Endocrinology 145:487–494

    Article  CAS  PubMed  Google Scholar 

  • Yamauchi T, Kamon J, Ito Y, Tsuchida A, Yokomizo T, Kita S, Sugiyama T, Miyagishi M, Hara K, Tsunoda M, Murakami K, Ohteki T, Uchida S, Takekawa S, Waki H, Tsuno N, Shibata Y, Terauchi Y, Froguel P, Tobe K, Koyasu S, Taira K, Kitamura T, Shimizu T, Nagai R, Kadowaki T (2003) Cloning of adiponectin receptors that mediate antidiabetic metabolic effects. Nature 423:762–769

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

The authors are grateful to Dr. Barry Robert for expert veterinary assistance related to lopinavir/ritonavir administration, and also thank Prof. John Wade (Florey Neuroscience Institutes, Melbourne, Australia) for peptide synthesis. This work was supported by a grant from the NIH (MH099944), and also used PBRC Core facilities (Animal Phenotyping) that are funded by the NIH (P20-RR021945 and P30-DK072476).

Conflict of Interest

The authors declare that they have no conflict of interest.

Author information

Authors and Affiliations

  1. Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge, LA, 70808, USA

    Jennifer K. Pepping, Sunita Gupta, Jeffrey N. Keller & Annadora J. Bruce-Keller

  2. Department of Pathobiological Sciences, School of Veterinary Medicine, Louisiana State University, Baton Rouge, LA, 70803, USA

    Jennifer K. Pepping

  3. Department of Biology, Temple University, Philadelphia, PA, 19122, USA

    Laszlo Otvos Jr.

  4. Sbarro Institute for Cancer Research and Molecular Medicine, Temple University, Philadelphia, PA, 19122, USA

    Eva Surmacz

  5. Inflammation and Neurodegeneration Laboratory, Pennington Biomedical Research Center/LSU, 6400 Perkins Road, Baton Rouge, LA, 70808, USA

    Annadora J. Bruce-Keller

Authors
  1. Jennifer K. Pepping
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Laszlo Otvos Jr.
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Eva Surmacz
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Sunita Gupta
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jeffrey N. Keller
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Annadora J. Bruce-Keller
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Annadora J. Bruce-Keller.

Electronic Supplementary Material

Below is the link to the electronic supplementary material.

Supplemental Figure 1

ADP355 does not affect circulating serum resistin or retroperitoneal fat in PI-treated mice. Male C57BL/6 mice were given daily administration of 10 % ethanol/15 % propylene glycol (vehicle; left bars) or 150 mg lopinavir/37.5 mg ritonavir/kg (PI; right bars) for 28 days. Additionally, randomly selected vehicle (open bars) and PI-treated mice (hatched bars) mice were also treated daily with ADP355 (1 mg/kg) or PBS via intraperitoneal injection for the final 14 days of PI exposure, after which all mice were euthanatized and serum and adipose deposits were harvested. (A) Effects of lopinavir/ritonavir with or without ADP355 on serum resistin concentration. Data are means ± S.E.M. of resistin expressed as ng/μl serum, and were analyzed by 1-way ANOVA, but significant differences between groups were not found. (B) Effects of lopinavir/ritonavir with or without ADP355 on retroperitoneal fat depot weight in vehicle and lopinavir/ritonavir-treated mice following administration of PBS or ADP355. * indicates significant (p < 0.05) decreases in weight of the retroperitoneal fat depot in lopinavir/ritonavir/PBS and lopinavir/ritonavir/ADP355 mice as compared to vehicle-treated mice, respectively (PDF 33 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Pepping, J.K., Otvos, L., Surmacz, E. et al. Designer Adiponectin Receptor Agonist Stabilizes Metabolic Function and Prevents Brain Injury Caused by HIV Protease Inhibitors. J Neuroimmune Pharmacol 9, 388–398 (2014). https://doi.org/10.1007/s11481-014-9529-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11481-014-9529-1

Keywords

Search

Navigation