Loss of apoptosis repressor with caspase recruitment domain (ARC) worsens high fat diet-induced hyperglycemia in mice

Andrew T. Templin, Christine Schmidt, Meghan F. Hogan, Nathalie Esser, Richard N. Kitsis, Rebecca L. Hull, Sakeneh Zraika, Steven E. Kahn

Research output: Contribution to journalArticlepeer-review


Apoptosis repressor with caspase recruitment domain (ARC) is an endogenous inhibitor of cell death signaling that is expressed in insulin-producing β cells. ARC has been shown to reduce β-cell death in response to diabetogenic stimuli in vitro, but its role in maintaining glucose homeostasis in vivo has not been fully established. Here we examined whether loss of ARC in FVB background mice exacerbates high fat diet (HFD)-induced hyperglycemia in vivo over 24 weeks. Prior to commencing 24-week HFD, ARC−/− mice had lower body weight than wild type (WT) mice. This body weight difference was maintained until the end of the study and was associated with decreased epididymal and inguinal adipose tissue mass in ARC−/− mice. Non-fasting plasma glucose was not different between ARC−/− and WT mice prior to HFD feeding, and ARC−/− mice displayed a greater increase in plasma glucose over the first 4 weeks of HFD. Plasma glucose remained elevated in ARC−/− mice after 16 weeks of HFD feeding, at which time it had returned to baseline in WT mice. Following 24 weeks of HFD, non-fasting plasma glucose in ARC−/− mice returned to baseline and was not different from WT mice. At this final time point, no differences were observed between genotypes in plasma glucose or insulin under fasted conditions or following intravenous glucose administration. However, HFD-fed ARC−/− mice exhibited significantly decreased β-cell area compared to WT mice. Thus, ARC deficiency delays, but does not prevent, metabolic adaptation to HFD feeding in mice, worsening transient HFD-induced hyperglycemia.

Original languageEnglish
Pages (from-to)125-135
Number of pages11
JournalJournal of Endocrinology
Issue number2
StatePublished - Sep 2021
Externally publishedYes


  • ARC
  • Cell death
  • Diabetes
  • Islet
  • β cell


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