ObjectiveObesity is associated with consumption of a Western diet low in dietary fiber, while prebiotics reduce body weight. Fiber induces short‐chain fatty acid (SCFA) production, and SCFA administration is beneficial to host metabolic homeostasis. However, the role of endogenous SCFA signaling in the development of obesity is contentious. Therefore, the primary objective of this study is to evaluate the postprandial time course of SCFA production and uptake in healthy (chow‐fed), Western diet‐fed (high‐fat diet [HFD]) obese, and oligofructose‐treated HFD‐fed (HFD + OFS) rats.MethodsMale Sprague–Dawley rats were maintained on chow or HFD for 5 weeks, with or without supplementation of 10% OFS for 3 weeks. SCFAs were measured in the ileum, cecum, colon, portal vein, and vena cava at 0, 2, 4, 6, and 8 hours postprandially.ResultsPostprandial cecal and portal vein SCFAs were decreased in obese rats compared with lean chow controls, whereas no differences were observed in fasting SCFA concentrations. OFS supplementation increased SCFA levels in the cecum and portal vein during obesity. Butyrate levels were positively associated with portal glucagon‐like peptide 1 and adiposity and with Roseburia relative abundance.ConclusionsThe current study demonstrates that obesity is associated with reduced SCFA production, and that OFS supplementation increases SCFA levels. Additionally, postprandial butyrate production appears to be beneficial to host energy homeostasis.
Key Points
Question
Has the amputation rate among African American, Hispanic, and other racial and ethnic minority adults with diabetic foot ulcerations (DFUs) changed during the early implementation of the Patient Protection and Affordable Care Act (ACA)?
Findings
In a cohort study of 115 071 hospitalizations for DFUs among racial and ethnic minority adults, early Medicaid expansion was associated with decreased major amputation and hospitalization rates in early-adoption states compared with nonadoption states.
Meaning
These findings suggest that early ACA implementation was associated with decreased lower extremity amputation among underserved racial and ethnic minority adults with DFUs.
Hypothesis
p21-Activated Kinase (PAK) regulates signaling pathways that promote cell survival and proliferation; therefore, pharmacological inhibition of PAK will induce cell death in vestibular schwannomas (VS) and meningiomas.
Background
All VS and many meningiomas result from loss of the neurofibromatosis type 2 (NF2) gene product merlin, with ensuing PAK hyperactivation and increased cell proliferation/survival.
Methods
The novel small molecule PAK inhibitors PI-8 and PI-15 – tested in schwannoma and meningioma cells – perturb molecular signaling and induce cell death. MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide), flow cytometry and TUNEL (Terminal deoxynucleotidyl transferase dUTP nick end labeling) assay analyzed PAK inhibitors’ effect on cell viability, cell cycle and cell death, respectively. Western blots evaluated activation and expression of cell proliferation, apoptotic, and mitotic catastrophe markers. Light microscopy evaluated cell morphology, and immunocytochemistry analyzed cellular localization of phospho-Merlin and ATG5 (autophagy-related protein).
Results
Treatment with PI-8 and PI-15 decreased cell viability at 0.65–3.7 μM IC50 in schwannoma and meningioma cells. TUNEL and immunocytochemistry studies show that PI-8 and PI-15 induce mitotic catastrophe but not apoptosis in HEI193 cells while in BenMen1 cells, PI-8 induces autophagy and mitotic catastrophe. PI-15 induces apoptosis in BenMen1 cells. PAK inhibitor treated cells show phospho-Merlin localized to over-duplicated centrosomes of dividing cells, multiple enlarged nuclei, and misaligned/missegregated chromosomes – markers for mitotic catastrophe. Increased ATG5 levels in the nucleus confirmed this cell death type. PI-8 and PI-15 inhibits PAK in both cell lines. However, only PI-15 inhibits AKT (v-Akt Murine Thymoma Viral Oncogene Homolog) in BenMen1 cells.
Conclusion
PAK inhibitors induce cell death in schwannoma and meningioma cells, at least in part, by mitotic catastrophe.
Hyperglycemia is a hallmark characteristic of type II diabetes, due in part to increased hepatic glucose production (HGP). The gut microbiota is now recognized as an important contributor to host energy and glucose homeostasis, and our lab has demonstrated that the gut microbiota can impact HGP. One mechanism that the gut microbiome may be impact HGP is through alterations in gut-derived metabolites from breakdown of ingested foodstuff. Specifically, short chain fatty acids (SCFAs) are bacterial metabolites produced primarily in the distal intestine from dietary fibers, and when administered exogenously, SCFAs improve glucose tolerance. However, the mechanisms underlying the effects of SCFAs on glucose tolerance are not fully understood. Given that SCFAs bind to free fatty acid receptors (FFARs) 2 and 3 localized on enteroendocrine cells to induce gut peptide release, and gut peptides regulate HGP via a gut-brain-liver neuronal axis, we propose colonic SCFAs activate a neuronal signaling mechanism to lower HGP mediated via gut peptide signaling. We infused SCFAs into the colon (50min at 0.01mL/min) during a basal insulin euglycemic clamp in rats. Compared with saline infusion, colonic administration of 10mM butyrate increased the glucose infusion rate needed to maintain glycemia due to a reduction in HGP. This was associated with increased portal concentrations of GLP-1 following butyrate infusion compared to saline. We investigated the role of colonic FFAR2 signaling, which is known to induce release of GLP-1, through either co-administration of a FFAR2 antagonist with butyrate or by colon-specific FFAR2 lentiviral knockdown; both abolished the HGP-lowering effect. Next, co-administering a GLP-1 receptor antagonist with 10mM butyrate during a clamp abolished the butyrate-induced reduction of HGP. Additionally, hepatic or celiac branch vagotomy abolished the HGP-lowering effect of colonic butyrate, suggesting a celiac afferent and hepatic efferent neuronal signaling pathway. Together, these studies uncover a FFAR2, GLP-1 receptor, vagal-dependent signaling mechanism by which colonic butyrate lowers HGP. Research presented was supported under NIH award R01DK121804. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
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