Mandala, A. | Search bioRxiv

bioRxiv2025

Beta hydroxybutyrate alters beta cell identity and function in human islets

Fasting alters insulin secretion in humans and islet cell composition in mice. Fasting triggers ketogenesis, which increases beta hydroxybutyrate (BHB) levels. BHB is a signaling molecule that alters insulin secretion in primary islets. We hypothesized that BHB alters human islet cell composition and identity. Primary human islets were cultured with R-BHB or its non-metabolizable enantiomer, S-BHB. Human islets cultured with R-BHB, but not S-BHB, resulted in an increased C-peptide-glucagon+ to C-peptide+glucagon- cell ratio, and an increased frequency of C-peptide+glucagon+ bihormonal cells and NKX6.1+glucagon+ cells. Single-cell transcriptomics revealed upregulation of alpha cell identity genes in R-BHB treated islet beta cells. Alterations in beta cell identity were accompanied by increased basal insulin secretion in response to low glucose, and a reduced insulin stimulation index in response to high glucose. The differential effects of the two BHB enantiomers on islet cell composition indicated that ketone metabolism is involved in islet cell identity change. Supporting this hypothesis, a subpopulation of beta cells in islets treated with R-BHB characterized by low ketolysis genes, OXCT1 and ACAT1, did not show altered alpha and beta cell identity genes. Additionally, primary islets from type 2 diabetes donors, which exhibited reduced OXCT1 and ACAT1 expression relative to donors without diabetes, did not display altered islet cell composition and beta cell function from R-BHB treatment. Our findings uncover a novel role of BHB in modulating beta cell identity, with potential implications for islet function in states with chronically elevated ketone concentrations.

cell biology↗

bioRxiv2022

Western diet-induced shifts in the maternal microbiome are associated with altered microRNA expression in baboon placenta and fetal liver

Maternal consumption of a high-fat, Western-style diet (WD) disrupts the maternal/infant microbiome and contributes to developmental programming of the immune system and nonalcoholic fatty liver disease (NAFLD) in the offspring. Epigenetic changes, including non-coding miRNAs in the fetus and/or placenta may also underlie this risk. We previously showed that obese nonhuman primates (NHP) fed a WD during pregnancy results in the loss of beneficial maternal gut microbes and dysregulation of cellular metabolism and mitochondrial dysfunction in the fetal liver, leading to a perturbed postnatal immune response with accelerated NAFLD in juvenile offspring. Here, we investigated associations between WD-induced maternal metabolic and microbiome changes, in the absence of obesity, and miRNA and gene expression changes in the placenta and fetal liver. After [~]8-11 months of maternal WD feeding (mWD), dams were similar in body weight but exhibited mild, systemic inflammation (elevated CRP and neutrophil count) and dyslipidemia (increased triglycerides and cholesterol) compared with dams fed a control diet. The maternal gut microbiome was mainly comprised of Lactobacillales and Clostridiales, with significantly decreased alpha diversity (P = 0.0163) in WD-fed dams but no community-wide differences (P = 0.26). At 0.9 gestation, mRNA expression of IL6 and TNF in mWD-exposed placentas trended higher, while increased triglycerides, expression of pro-inflammatory CCR2, and histological evidence for fibrosis were found in mWD-exposed fetal livers. In the mWD-exposed fetus, hepatic expression levels of miR-204-5p and miR-145-3p were significantly downregulated, whereas in mWD-exposed placentas, miR-182-5p and miR-183-5p were significantly decreased. Notably, miR-1285-3p expression in the liver and miR-183-5p in the placenta were significantly associated with inflammation and lipid synthesis pathway genes, respectively. Blautia and Ruminococcus were significantly associated with miR-122-5p in liver, while Coriobacteriacea and Prevotellacea were strongly associated with miR-1285-3p in the placenta; both miRNAs are implicated in pathways mediating postnatal growth and obesity. Our findings demonstrate that mWD shifts the maternal microbiome, lipid metabolism, and inflammation prior to obesity and are associated with epigenetic changes in the placenta and fetal liver. These changes may underlie inflammation, oxidative stress, and fibrosis patterns that drive NAFLD and metabolic disease risk in the next generation.

developmental biology↗