Biology subjects

Feola, K.

Publications and source records attributed to Feola, K..

4 recordsLinked to original sources

bioRxiv2025

Nutritional hyperketonemia by dietary medium-chain fatty acids is driven by the liver without contribution from the intestine

Saturated medium-chain fatty acids (MCFAs) are ketogenic nutrients, and their dietary intake has been linked to health benefits such as improved energy balance and increased insulin sensitivity. Here, we tested the hypothesis that MCFA-mediated hyperketonemia is required for these benefits. Using tissue-specific 3-hydroxy-3-methylglutaryl-CoA synthase 2 (Hmgcs2) knockout mouse models, we show that the hyperketonemia induced by oral administration of triacylglycerols with the MCFA octanoic acid (C8:0-MCT) is mediated by hepatic, but not intestinal, ketogenesis. Remarkably, acute reductions in food intake and body weight induced by C8:0-MCT in obese mice were independent of hepatic ketogenesis; likewise, chronic protection against weight gain and marked improvements in insulin sensitivity elicited by MCFA-rich diets did not require hepatic ketogenesis. These data demonstrate that dietary MCFAs are potent bioactive lipids capable of inducing metabolic benefits independently of their ketogenic properties.

physiology↗

bioRxiv2024

Cell-specific oxidative metabolism of the renal cortex

The metabolic health of the kidney is a primary determinant of the risk of progressive kidney disease. Our understanding of the metabolic processes that fuel kidney functions is limited by the kidneys structural and functional heterogeneity. As the kidney contains many different cell types, we sought to determine the intra-renal mitochondrial heterogeneity that contributes to cell-specific metabolism. To interrogate this, we utilized a recently developed mitochondrial tagging technique to isolate kidney cell-type specific mitochondria. Here, we investigate mitochondrial functional capacities and the metabolomes of the early and late proximal tubule (PT) and the distal convoluted tubule (DCT). The conditional MITO-Tag transgene was combined with Slc34a1-CreERT2, Ggt1-Cre, or Pvalb-Cre transgenes to generate mouse models capable of cell-specific isolation of hemagglutinin (HA)-tagged mitochondria from the early PT, late PT, or the DCT, respectively. Functional assays measuring mitochondrial respiratory and fatty acid oxidation (FAO) capacities and metabolomics were performed on anti-HA immunoprecipitated mitochondria from kidneys of ad libitum fed and 24-hour fasted male mice. The renal MITO-Tag models targeting the early PT, late PT, and DCT revealed differential mitochondrial respiratory and FAO capacities which dynamically changed during fasting conditions. The renal MITO-Tag model captured differential mitochondrial metabolism and functional capacities across the early PT, late PT, and DCT at baseline and in response to fasting. New & NoteworthyThis study described the generation and utilization of mouse models capable of interrogating kidney tubular epithelial cell-specific mitochondrial metabolism. Applying the MITO-Tag system in the kidney, we have for the first time defined the mitochondrial metabolic heterogeneity of renal cortical tubular epithelium and discovered differential mitochondrial functional capacities in response to an acute metabolic stress such as fasting.

molecular biology↗

bioRxiv2022

An RNA binding module of SWI/SNF is required for activation of cell-type specific enhancers and super-enhancers in early development

The mammalian SWI/SNF complex is an ATP-dependent chromatin remodeler and master regulator in development that when mutated is the cause for several human diseases including cancer. Although SWI/SNF is highly enriched at enhancers and its basic chromatin remodeling activities have been studied for over 30 years, there is little known about how it regulates enhancer activity or enhancer-promoter interactions. We find a putative RNA binding module located near the C-terminus of the catalytic subunit of SWI/SNF required for SWI/SNF recruitment to cell-type specific enhancers and super-enhancers in naive and cell lineage primed pluripotent cells. The AT-hook is required for acquisition of the active histone marks H3K27ac and H3K4me1 and recruitment of the MLL3/4 co-activator to these enhancers and super-enhancers. Consistent with changes in enhancer architecture, loss of the AT-hook interferes with activation of genes involved in cell lineage priming as well as genes normally activated in naive pluripotent cells.

genomics↗

bioRxiv2020

Hepatic FGF21 mediates tissue tolerance during bacterial inflammation by preserving cardiac function

Sickness behaviors, including anorexia, are evolutionarily conserved responses to acute infections. Inflammation-induced anorexia causes dramatic metabolic changes, of which components critical to survival are unique depending on the type of inflammation. Glucose supplementation during the anorectic period induced by bacterial inflammation suppresses adaptive fasting metabolic pathways, including fibroblast growth factor-21 (FGF21), and decreases survival. Consistent with this observation, FGF21 deficient mice are more susceptible to mortality from endotoxemia and poly-bacterial peritonitis, but not viral infection. Here we report that increased circulating FGF21 during bacterial inflammation is hepatic-derived, promotes cardiac function, and is required for survival. FGF21 signaling downstream of its obligate co-receptor beta-Klotho (KLB) is required. However, mice with central nervous system or adipose-specific deletion of Klb do not demonstrate any difference in response to bacterial inflammation, suggesting that multiple tissues and/or a novel FGF21 target tissue are required for the full protective effect of FGF21. These data suggest that hepatic FGF21 is a novel cardioprotective factor in bacterial sepsis. eTOC SummaryIn response to bacterial inflammation, hepatic fibroblast growth factor 21 (FGF21), an endocrine hormone that mediates adaptive responses to metabolic stresses such as starvation, promotes survival by supporting heart function.

immunology↗