Biology subjects

Akingbesote, N. D.

Publications and source records attributed to Akingbesote, N. D..

3 recordsLinked to original sources

bioRxiv2022

Gene Expression and Tracer-Based Metabolic Flux Analysis Reveals Tissue-Specific Metabolic Scaling in vitro, ex vivo, and in vivo

Metabolic scaling, the inverse correlation of metabolic rates to body mass, has been appreciated for more than 80 years. Studies of metabolic scaling have almost exclusively been restricted to mathematical modeling of oxygen consumption. The possibility that other metabolic processes scale with body size has not been studied. To address this gap in knowledge, we employed a systems approach spanning from transcriptomics to in vitro and in vivo tracer-based flux. Gene expression in livers of five species spanning a 30,000-fold range in mass revealed differential expression of genes related to cytosolic and mitochondrial metabolic processes, in addition to detoxication of oxidative damage. This suggests that transcriptional scaling of damage control mechanisms accommodates increased oxidative metabolism in smaller species. To determine whether flux through key implicated metabolic pathways scaled, we applied stable isotope tracer methodology to study multiple cellular compartments, tissues, and species. Comparing mice and rats, we demonstrate that while scaling of metabolic fluxes is not observed in the cell-autonomous setting, it is present in liver slices and in vivo. Together, these data reveal that metabolic scaling extends beyond oxygen consumption to numerous other metabolic pathways, and is likely regulated at the level of gene expression and substrate supply.

physiology↗

bioRxiv2021

A Precision Medicine Approach to Metabolic Therapy for Breast Cancer in Mice

Increasing evidence highlights the possibility for approaches targeting metabolism as potential adjuvants to cancer therapy. Sodium-glucose transport protein 2 (SGLT2) inhibitors are the newest class of antihyperglycemic therapies, and have recently been highlighted as a novel therapeutic approach to breast cancer. To our knowledge, however, SGLT2 inhibitors have not been applied in the neoadjuvant setting as a precision medicine approach to combining metabolic therapy with standard of care therapy for this devastating disease. In this study we combine the SGLT2 inhibitor dapagliflozin with paclitaxel chemotherapy in both lean and obese mice. We show that dapagliflozin enhances the efficacy of paclitaxel, reducing tumor glucose uptake and prolonging survival in an insulin-dependent manner in some but not all breast tumors. Our data find a genetic signature for breast tumors most likely to respond to dapagliflozin in combination with paclitaxel. Tumors driven by mutations upstream of canonical insulin signaling pathways are likely to respond to such treatment, whereas tumors driven by mutations downstream of canonical insulin signaling are not. These data demonstrate that dapagliflozin enhances the response to chemotherapy in mice with breast cancer and suggest that breast cancer patients with driver mutations upstream of canonical insulin signaling may be most likely to benefit from this neoadjuvant approach. A clinical trial is currently in preparation, with an application recently submitted for Yale Human Investigations Committee approval, to test this hypothesis in breast cancer patients. One Sentence SummaryWe identify a driver mutation signature by which glucose-wasting metabolic therapy (dapagliflozin) enhances the efficacy of chemotherapy in mice with breast cancer.

cancer biology↗

bioRxiv2021

Gut bacteria regulate the pathogenesis of Huntington's disease in Drosophila

Changes in the composition of gut microbiota are implicated in the pathogenesis of several neurodegenerative disorders. Here, we investigated whether gut bacteria affect the progression of Huntingtons disease (HD) in transgenic Drosophila melanogaster (fruit fly) models expressing human full-length or N-terminal fragments of mutant huntingtin (HTT) protein, here referred to as HD flies. We find that elimination of commensal gut bacteria by antibiotics reduces the aggregation of amyloidogenic N-terminal fragments of HTT and delays the development of motor defects. Conversely, colonization of HD flies with Escherichia coli (E. coli), a known pathobiont of human gut with links to neurodegeneration, accelerates HTT aggregation, aggravates immobility and shortens lifespan. Similar to antibiotics, treatment of HD flies with small compounds such as luteolin, a flavone, or crocin a beta-carotenoid, ameliorates disease phenotypes and promotes survival. Crocin prevents colonization of E. coli in the gut and alters the abundance of commensal bacteria, which may be linked to its protective effects. The opposing effects of E. coli and crocin on HTT aggregation, motor defects and survival in transgenic Drosophila models support the involvement of gut-brain networks in the pathogenesis of HD.

neuroscience↗