title: Designer adiponectin receptor agonist stabilizes metabolic function and prevents brain injury caused by HIV protease inhibitors.
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.
authors.affiliation: Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge, LA, 70808, USA.
authors.forename: Jennifer K
authors.initials: JK
authors.lastname: Pepping
authors.forename: Laszlo
authors.initials: L
authors.lastname: Otvos
authors.forename: Eva
authors.initials: E
authors.lastname: Surmacz
authors.forename: Sunita
authors.initials: S
authors.lastname: Gupta
authors.forename: Jeffrey N
authors.initials: JN
authors.lastname: Keller
authors.forename: Annadora J
authors.initials: AJ
authors.lastname: Bruce-Keller
mesh_terms: D052242:Adiponectin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000627:therapeutic use; D000818:Animals; D001930:Brain Injuries / Q000139:chemically induced* / Q000378:metabolism / Q000517:prevention & control*; D015195:Drug Design; D017320:HIV Protease Inhibitors / Q000633:toxicity*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D054419:Receptors, Adiponectin / Q000819:agonists* / Q000378:metabolism
chemical_list: D052242:Adiponectin; D017320:HIV Protease Inhibitors; D054419:Receptors, Adiponectin