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Lack of an association between clinical INSTI-related body weight gain and direct interference with MC4 receptor (MC4R), a key central regulator of body weight

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  • Carrie McMahon
  • James L Trevaskis
  • Christoph Carter
  • Kevin Holsapple
  • Kirsten White
  • Moupali Das
  • Sean Collins
  • Hal Martin
  • Leigh Ann Burns-Naas

Abstract

An increasing prevalence of overweight and obesity in people living with HIV has been associated with initiation of antiretroviral therapy with integrase strand transfer inhibitors (INSTIs). An off-target inhibition of the endogenous ligand binding to the human melanocortin 4 receptor (MC4R) has been suggested as a potential mechanism for clinical body weight gain following initiation of dolutegravir, an INSTI. In this study, we interrogated several INSTIs for their capacity for antagonism or agonism of MC4R in an in vitro cell-based assays including at concentrations far exceeding plasma concentrations reached at the recommended dosages. Our results indicate that while INSTIs do exhibit the capacity to antagonize MC4R, this occurs at concentrations well above predicted clinical exposure and is thus an implausible explanation for INSTI-associated weight gain.

Suggested Citation

  • Carrie McMahon & James L Trevaskis & Christoph Carter & Kevin Holsapple & Kirsten White & Moupali Das & Sean Collins & Hal Martin & Leigh Ann Burns-Naas, 2020. "Lack of an association between clinical INSTI-related body weight gain and direct interference with MC4 receptor (MC4R), a key central regulator of body weight," PLOS ONE, Public Library of Science, vol. 15(2), pages 1-7, February.
    • Handle: RePEc:plo:pone00:0229617
    DOI: 10.1371/journal.pone.0229617
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    References listed on IDEAS

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    1. Wei Fan & Bruce A. Boston & Robert A. Kesterson & Victor J. Hruby & Roger D. Cone, 1997. "Role of melanocortinergic neurons in feeding and the agouti obesity syndrome," Nature, Nature, vol. 385(6612), pages 165-168, January.
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