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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.

SUBMITTER: Toorie A

PROVIDER: S-EPMC8803846 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundThe authors tested the hypothesis that the effects of traumatic brain injury, surgery, and sevoflurane interact to induce neurobehavioral abnormalities in adult male rats and in their offspring (an animal model of intergenerational perioperative neurocognitive disorder).MethodsSprague-Dawley male rats (assigned generation F0) underwent a traumatic brain injury on postnatal day 60 that involved craniectomy (surgery) under 3% sevoflurane for 40 min followed by 2.1% sevoflurane for 3 h on postnatal days 62, 64, and 66 (injury group). The surgery group had craniectomy without traumatic brain injury, whereas the sevoflurane group had sevoflurane only. On postnatal day 90, F0 males and control females were mated to generate offspring (assigned generation F1).ResultsAcutely, F0 injury rats exhibited the greatest increases in serum corticosterone and interleukin-1β and -6, and activation of the hippocampal microglia. Long-term, compared to controls, F0 injury rats had the most exacerbated corticosterone levels at rest (mean ± SD, 2.21 ± 0.64 vs. 7.28 ± 1.95 ng/ml, n = 7 - 8; P < 0.001) and 10 min after restraint (133.12 ± 33.98 vs. 232.83 ± 40.71 ng/ml, n = 7 - 8; P < 0.001), increased interleukin-1β and -6, and reduced expression of hippocampal glucocorticoid receptor (Nr3c1; 0.53 ± 0.08 fold change relative to control, P < 0.001, n = 6) and brain-derived neurotrophic factor genes. They also exhibited greater behavioral deficiencies. Similar abnormalities were evident in their male offspring, whereas F1 females were not affected. The reduced Nr3c1 expression in F1 male, but not female, hippocampus was accompanied by corresponding Nr3c1 promoter hypermethylated CpG sites in F0 spermatozoa and F1 male, but not female, hippocampus.ConclusionsThese findings in rats suggest that young adult males with traumatic brain injury are at an increased risk of developing perioperative neurocognitive disorder, as are their unexposed male but not female offspring.Editor’s perspective

Project description:Aims/hypothesisRecovering functional beta cell mass is a promising approach for future diabetes therapies. The aim of the present study is to investigate the effects of adjudin, a small molecule identified in a beta cell screen using zebrafish, on pancreatic beta cells and diabetes conditions in mice and human spheroids.MethodsIn zebrafish, insulin expression was examined by bioluminescence and quantitative real-time PCR (qPCR), glucose levels were examined by direct measurements and distribution using a fluorescent glucose analogue, and calcium activity in beta cells was analysed by in vivo live imaging. Pancreatic islets of wild-type postnatal day 0 (P0) and 3-month-old (adult) mice, as well as adult db/db mice (i.e. BKS(D)-Leprdb/JOrlRj), were cultured in vitro and analysed by qPCR, glucose stimulated insulin secretion and whole mount staining. RNA-seq was performed for islets of P0 and db/db mice. For in vivo assessment, db/db mice were treated with adjudin and subjected to analysis of metabolic variables and islet cells. Glucose consumption was examined in primary human hepatocyte spheroids.ResultsAdjudin treatment increased insulin expression and calcium response to glucose in beta cells and decreased glucose levels after beta cell ablation in zebrafish. Adjudin led to improved beta cell function, decreased beta cell proliferation and glucose responsive insulin secretion by decreasing basal insulin secretion in in vitro cultured newborn mouse islets. RNA-seq of P0 islets indicated that adjudin treatment resulted in increased glucose metabolism and mitochondrial function, as well as downstream signalling pathways involved in insulin secretion. In islets from db/db mice cultured in vitro, adjudin treatment strengthened beta cell identity and insulin secretion. RNA-seq of db/db islets indicated adjudin-upregulated genes associated with insulin secretion, membrane ion channel activity and exocytosis. Moreover, adjudin promoted glucose uptake in the liver of zebrafish in an insulin-independent manner, and similarly promoted glucose consumption in primary human hepatocyte spheroids with insulin resistance. In vivo studies using db/db mice revealed reduced nonfasting blood glucose, improved glucose tolerance and strengthened beta cell identity after adjudin treatment.Conclusions/interpretationAdjudin promoted functional maturation of immature islets, improved function of dysfunctional islets, stimulated glucose uptake in liver and improved glucose homeostasis in db/db mice. Thus, the multifunctional drug adjudin, previously studied in various contexts and conditions, also shows promise in the management of diabetic states.Data availabilityRaw and processed RNA-seq data for this study have been deposited in the Gene Expression Omnibus under accession number GSE235398 ( https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE235398 ).

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

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