Intergenerational effects of preconception opioids on glucose homeostasis and hepatic transcription in adult male rats

Abstract

Adolescence represents a period of significant neurodevelopment during which adverse experiences can lead to prolonged effects on disease vulnerability, including effects that can impact future offspring. Adolescence is a common period for the initiation of drug use, including the use of opioids. Beyond effects on central reward, opioids also impact glucose metabolism, which can impact the risk of diabetes. Moreover, recent animal models suggest that the effects of adolescent opioids can effect glucose metabolism in future offspring. Indeed, we demonstrated that the adult male offspring of females exposed to morphine for 10 days during adolescence (referred to as MORF1 males) are predisposed to the adverse effects of an obesogenic diet. As adults, MORF1 males fed a high fat moderate sucrose diet (FSD) for just 6 weeks had increased fasting glucose and insulin levels when compared to age-matched offspring of females exposed to saline during adolescence (SALF1 males). Clinically, a similar profile of impaired fasting glucose has been associated with hepatic insulin resistance and an increased risk of non-alcoholic fatty liver disease. Thus, in the current study, we used RNA sequencing to determine whether adult MORF1 males demonstrate significant alterations in the hepatic transcriptome suggestive of alterations in metabolism. Age-matched SALF1 and MORF1 males were fed either FSD or control diet (CD) for 8 weeks. Similar to our previous observations, FSD-maintained MORF1 males gained more weight and displayed both fasting hyperglycemia and hyperinsulinemia when compared to FSD-maintained SALF1 males, with no significant effect on glucagon. No differences in bodyweight or fasting-induce glucose were observed in control diet (CD)-maintained F1 males, although there was a trend for CD MORF1 males to display elevated levels of fasting insulin. Unexpectedly, transcriptional analyses revealed profound differences in the hepatic transcriptome of CD-maintained MORF1 and SALF1 (1686 differentially expressed genes) with no significant differences between FSD-maintained MORF1 and SALF1 males. As changes in the hepatic transcriptome were not revealed under 8 weeks FSD conditions, we extended the feeding paradigm and conducted a glucose tolerance test to determine whether impaired fasting glucose observed in FSD MORF1 males was due to peripheral insulin resistance. Impaired glucose tolerance was observed in both CD and FSD MORF1 males, and to a more limited extent in FSD SALF1 males. These findings implicate intergenerational effects of adolescent morphine exposure on the risk of developing insulin resistance and associated comorbidities, even in the absence of an obesogenic diet.

Profiling Neuronal Methylome and Hydroxymethylome of Opioid Use Disorder in the Human Orbitofrontal Cortex

“…Further, we identified the IGF1R signaling cascade and insulin receptor signaling cascade. It is known that opioids affect glucose homeostasis 30 , being suggested a role of opioids in the inhibition of insulin receptor during morphine use 31 . We also performed a PPI analysis to identify functional gene networks based on the 5mC and 5hmC modules identified.…”

Profiling neuronal methylome and hydroxymethylome of opioid use disorder in the human orbitofrontal cortex

“…Class B/2 (secretin family receptor) was also identified in a co-expression analysis of maternal exposure to oxycodone 32 . Chronic exposure to opioid drugs, such as morphine, is known to inhibit the insulin signaling pathway, leading to alterations in glucose homeostasis, and an increased risk of developing insulin resistance and associated comorbidities 33 , 34 . The PPI analysis for the modules showed evidence of co-expression in genes involved in neurogenesis pathways, which corroborates previous studies showing that opioids decrease neurogenesis by inhibiting cell division, mainly through blocking the S phase 35 .…”

Molecular and long-term behavioral consequences of neonatal opioid exposure and withdrawal in mice

“…We compared our pathway gene ontology, and differential expression (DE) analyses to curated datasets from the literature. These data were mostly derived from adult animals, either analyzing gene expression following chronic opioid exposure and/or withdrawal ( Zhang et al, 2017 ; Yuferov et al, 2018 ; Zhang Y. et al, 2018 ; Odegaard et al, 2020 ; Borrelli et al, 2021 ; Jiang et al, 2021 ; Liu et al, 2021 ; Mendez et al, 2021 ; Radhakrishna et al, 2021 ; Seney et al, 2021 ; Townsend et al, 2021 ; Coffey et al, 2022 ; Corradin et al, 2022 ; Fox et al, 2022 ; Toorie et al, 2022 ). The following cutoffs were used to filter datasets in the literature: IPA pathways [−log( p -value) > 1.3], GO terms ( p -value < 0.05), and DEGs (nominal and/or adjusted p -value < 0.05).…”