Biology subjects

Harris, T. E.

Publications and source records attributed to Harris, T. E..

6 recordsLinked to original sources

bioRxiv2026

Adenosine A2A and A2B receptor signaling in neurons promotes glucose and fatty acid release in the postprandial state

Adenosine is a widely distributed signaling molecule whose levels rise during conditions of metabolic stress, hypoxia, or inflammation. Adenosine is a homeostatic regulator of neuronal, cardiovascular, immune, and metabolic functions through activation of adenosine receptors. Here, we show that administration of adenosine rapidly elicits an immediate and pronounced excursion of glucose and non-esterified fatty acids (NEFA) in mice refed for four hours but is greatly attenuated in fasted mice. This adenosine-mediated postprandial response suggests that adenosine is a potent regulator of postprandial nutrient handling. Selective agonists and antagonists of A2A and A2B adenosine receptors demonstrate that activation of either is sufficient to evoke adenosines metabolic response, but both receptors must be inhibited simultaneously to abolish it. Adenosine strongly stimulates hepatic glucose production and adipose lipolysis, and this catabolic activity depends on sympathetic nerve activity as it requires autonomic signal transmission and is inhibited by blocking adrenergic receptors. Genetic ablation studies identify A2A and A2B receptors expressed on neurons, likely central neurons, as the primary site of action for mediating adenosines effects on whole-body metabolism. Collectively, these data demonstrate that acute adenosine administration promotes centrally mediated metabolic effects, particularly during the postprandial period. Rigorous dissection of signaling pathways shows that A2A and A2B receptors are individually sufficient and collectively necessary for adenosine-mediated glucose and fatty acid excursion.

physiology↗

bioRxiv2024

Matrix Metalloproteinase-2 as a novel regulator of glucose utilization by adipocytes

Glucose transporter 4 (GLUT4) expression on white adipocytes is critical for absorbing excess blood glucose, failure of which promotes hyperglycemia. Matrix metalloproteinases (MMPs) play a crucial role in remodeling the white adipose tissue (WAT) during obesity. MMPs have multiple protein substrates, and surprisingly, it is unknown if they can directly target GLUT4 on the adipocyte surface and impair glucose absorption. We identified MMP2 as the highly active gelatinase, a class of MMP, in the gonadal WAT of high-fat diet-induced obese mice. In vitro, metabolic studies in 3T3-L1 adipocytes revealed MMP2 attenuated glucose absorption and glycolysis, which were recovered by an MMP2 inhibitor. In silico structural analysis using AlphaFold identified a putative MMP2 cleavage site on the extracellular domain of GLUT4. Further, in a substrate competition assay, a peptide mimicking the MMP2 cleavage motif on GLUT4 attenuated the cleavage of an MMP substrate by MMP2. Altogether, our results suggest a novel mechanism of impaired glucose absorption by adipocytes, which may contribute to hyperglycemia during obesity. ARTICLE HIGHLIGHTSO_LIIt is unknown if MMPs directly affect adipocyte metabolism via targeting adipocyte surface proteins. C_LIO_LIWe aimed to determine the highly active gelatinases, a class of MMP, in the white adipose tissue of obese mice, and examined its effect on adipocyte glucose metabolism. C_LIO_LIMMP2 was the highly active gelatinase in obese adipose tissue and, in vitro, MMP2 reduced adipocyte glucose metabolism, in part, by targeting the GLUT4 receptor. C_LIO_LIA harmful role of MMP2 is implicated in cardiometabolic diseases and our novel finding on the role of MMP2 on glucose metabolism may add to the pathogenesis of the diseases. C_LI

pathology↗

bioRxiv2024

Targeting Iron - Respiratory Reciprocity Promotes Bacterial Death

Discovering new bacterial signaling pathways offers unique antibiotic strategies. Here, through an unbiased resistance screen of 3,884 gene knockout strains, we uncovered a previously unknown non-lytic bactericidal mechanism that sequentially couples three transporters and downstream transcription to lethally suppress respiration of the highly virulent P. aeruginosa strain PA14 - one of three species on the WHOs Priority 1: Critical list. By targeting outer membrane YaiW, cationic lacritin peptide N-104 translocates into the periplasm where it ligates outer loops 4 and 2 of the inner membrane transporters FeoB and PotH, respectively, to suppress both ferrous iron and polyamine uptake. This broadly shuts down transcription of many biofilm-associated genes, including ferrous iron-dependent TauD and ExbB1. The mechanism is innate to the surface of the eye and is enhanced by synergistic coupling with thrombin peptide GKY20. This is the first example of an inhibitor of multiple bacterial transporters.

microbiology↗

bioRxiv2022

Feeding desensitizes A1 adenosine receptors in adipose through FOXO1-mediated transcriptional regulation

Adipose tissue is a critical regulator of energy balance that must rapidly shift its metabolism between fasting and feeding to maintain homeostasis. Adenosine has been characterized as an important regulator of adipocyte metabolism primarily through its actions on A1 adenosine receptors (A1R). We sought to understand the role A1R plays in adipocytes during fasting and feeding to regulate glucose and lipid metabolism by using an inducible, adiponectin-Cre with Adora1 floxed mice (FAdora1-/-), where F designates a fat-specific deletion. Fadora1-/- mice had impairments in the suppression of lipolysis by insulin on normal chow and impaired glucose tolerance on high-fat diet. FAdora1-/- mice also exhibited a higher lipolytic response to isoproterenol than WT controls when fasted, but not after a 4-hour refeeding period. We found that FOXO1 binds to the A1R promoter in adipocytes. Upon feeding, signaling along the insulin-Akt-FOXO1 axis leads to a rapid downregulation of A1R transcript and desensitization of adipocytes to A1R agonism. Obesity also desensitizes adipocyte A1R, and this is accompanied by a disruption of cyclical changes in A1R transcription between fasting and refeeding. We propose that FOXO1 drives high A1R expression under fasted conditions to limit excess lipolysis during stress and augment insulin action upon feeding. Subsequent downregulation of A1R under fed conditions facilitates reentrance into the catabolic state upon fasting.

physiology↗

bioRxiv2021

Adipocyte-specific modulation of KLF14 expression in mice leads to sex-dependent impacts in adiposity and lipid metabolism

Genome-wide association studies identified single nucleotide polymorphisms on chromosome 7 upstream of KLF14 to be associated with metabolic syndrome traits and increased risk for Type 2 Diabetes (T2D). The associations were more significant in women than in men. The risk allele carriers expressed lower levels of the transcription factor KLF14 in adipose tissues than non-risk allele carriers. To investigate how adipocyte KLF14 regulates metabolic traits in a sex-dependent manner, we characterized high-fat diet fed male and female mice with adipocyte-specific Klf14 deletion or overexpression. Klf14 deletion resulted in increased fat mass in female mice and decreased fat mass in male mice. Female Klf14-deficient mice had overall smaller adipocytes in subcutaneous fat depots but larger adipocytes in parametrial depots, indicating a shift in lipid storage from subcutaneous to visceral fat depots. They had reduced metabolic rates and increased respiratory exchange ratios consistent with increased utilization of carbohydrates as an energy source. Fasting and isoproterenol-induced adipocyte lipolysis was defective in female Klf14-deficient mice and concomitantly adipocyte triglycerides lipase mRNA levels were downregulated. Female Klf14-deficient mice cleared blood triglyceride and NEFA less efficiently than wild type. Finally, adipocyte-specific overexpression of Klf14 resulted in lower total body fat in female but not male mice. Taken together, consistent with human studies, adipocyte KLF14 deficiency in female but not in male mice causes increased adiposity and redistribution of lipid storage from subcutaneous to visceral adipose tissues. Increasing KLF14 abundance in adipocytes of females with obesity and T2D may provide a novel treatment option to alleviate metabolic abnormalities.

physiology↗

bioRxiv2021

A CTDNEP1-lipin 1-mTOR regulatory network restricts ER membrane biogenesis to enable chromosome motions necessary for mitotic fidelity

The endoplasmic reticulum (ER) dramatically restructures in open mitosis to become excluded from the mitotic spindle; however, the significance of ER reorganization to mitotic progression is not known. Here, we demonstrate that limiting ER membrane biogenesis enables mitotic chromosome movements necessary for chromosome biorientation and prevention of micronuclei formation. Aberrantly expanded ER membranes increase the effective viscosity of the mitotic cytoplasm to physically restrict chromosome dynamics - slowed chromosome motions impede correction of mitotic errors induced by transient spindle disassembly, leading to severe micronucleation. We define the mechanistic link between regulation of ER membrane biogenesis and mitotic fidelity by demonstrating that a CTDNEP1-lipin 1-mTOR regulatory network limits ER lipid synthesis to prevent chromosome missegregation. Together, this work shows that ER membranes reorganize in mitosis to enable chromosome movements necessary for mitotic error correction and reveal dysregulated lipid metabolism as a potential source of aneuploidy in cancer cells.

cell biology↗