Antisense oligonucleotides against monoacylglycerol acyltransferase 1 (Mogat1) improve glucose metabolism independently of Mogat1

Abstract

ObjectiveMonoacylglycerol acyltransferase (MGAT) enzymes catalyze the synthesis of diacylglycerol from monoacylglycerol. Previous work has suggested the importance of MGAT activity in the development of obesity-related hepatic insulin resistance. Indeed, antisense oligonucleotide (ASO)-mediated knockdown of the gene encoding MGAT1, Mogat1, reduced hepatic MGAT activity and improved glucose tolerance and insulin resistance in high fat diet (HFD) fed mice. However, recent work has suggested that some ASOs may have off-target effects on body weight and metabolic parameters via activation of the interferon alpha/beta receptor 1 (IFNAR-1) pathway. MethodsMice with whole-body Mogat1 knockout or a floxed allele for Mogat1 to allow for liver-specific Mogat1-knockout (by either a liver-specific transgenic or adeno-associated virus-driven Cre recombinase) were generated. These mice were placed on a high fat diet and glucose metabolism and insulin sensitivity was assessed after 16 weeks on diet. In some experiments, mice were treated with control or Mogat1 or control ASOs in the presence or absence of IFNAR-1 neutralizing antibody. ResultsGenetic deletion of hepatic Mogat1, either acutely or chronically, did not improve hepatic steatosis, glucose tolerance, or insulin sensitivity in HFD-fed mice. Furthermore, constitutive Mogat1 knockout in all tissues actually exacerbated HFD-induced weight gain, insulin resistance, and glucose intolerance on a HFD. Despite markedly reduced Mogat1 expression, liver MGAT activity was unaffected in all knockout mouse models. Mogat1 overexpression hepatocytes increased liver MGAT activity and TAG content in low-fat fed mice, but did not cause insulin resistance. Interestingly, Mogat1 ASO treatment improved glucose tolerance in both wild-type and Mogat1 null mice, suggesting an off target effect. Inhibition of IFNAR-1 did not block the effect of Mogat1 ASO on glucose homeostasis. ConclusionThese results indicate that genetic loss of Mogat1 does not affect hepatic MGAT activity or metabolic homeostasis on HFD and show that Mogat1 ASOs improve glucose metabolism through effects independent of targeting Mogat1 or activation of IFNAR-1 signaling. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=65 SRC="FIGDIR/small/238535v1_ufig1.gif" ALT="Figure 1"> View larger version (18K): org.highwire.dtl.DTLVardef@18d43c4org.highwire.dtl.DTLVardef@15c1974org.highwire.dtl.DTLVardef@18b396dorg.highwire.dtl.DTLVardef@16745bf_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIMogat1 liver-specific KO or KD does not improve metabolism in HFD fed mice. C_LIO_LIWhole-body Mogat1-deletion impairs insulin tolerance in HFD fed mice. C_LIO_LIMogat1 ASOs improves whole body metabolism independently of gene knockdown. C_LIO_LIBlockade of the INFR response does not prevent off-target effects of Mogat1 ASOs. C_LI