Biology subjects

Coate, K. C.

Publications and source records attributed to Coate, K. C..

6 recordsLinked to original sources

bioRxiv2026

Glutamine Metabolism Supports α cell Mass and Glucagon Secretion

The liver- cell axis is a finely tuned biological rheostat that regulates whole body amino acid availability. Pancreatic cells secrete glucagon that regulates amino acid catabolism through gluconeogenesis and ureagenesis, yet the mechanisms linking amino acid levels to cell growth and function are not fully understood. Here, we identify glutaminase, the enzyme that catalyzes glutamine catabolism, as a critical cell regulator. Glutaminase is highly enriched in cells across species. cell expression of glutaminase is required for nutrient-dependent mTORC1 activation, suppression of AMPK signaling, and sustained expression of the glutamine transporter SLC38A5. This establishes a feed-forward loop linking glutamine metabolism to amino acid sensing and growth. Reduced glutaminase activity impairs dynamic glucagon secretion in response to low glucose and amino acids. Together, these findings highlight the importance of glutamine metabolism in cell growth and hormone secretion and suggest it may play a role in cell adaptation to hyperaminoacidemia.

physiology↗

bioRxiv2024

Systemic inhibition of de novo purine biosynthesis prevents weight gain and improves metabolic health by increasing thermogenesis and decreasing food intake

ObjectiveObesity is a major health concern, largely because it contributes to type 2 diabetes mellitus (T2DM), cardiovascular disease, and various malignancies. Increase in circulating amino acids and lipids, in part due to adipose dysfunction, have been shown to drive obesity-mediated diseases. Similarly, elevated purines and uric acid, a degradation product of purine metabolism, are found in the bloodstream and in adipose tissue. These metabolic changes are correlated with metabolic syndrome, but little is known about the physiological effects of targeting purine biosynthesis. MethodsTo determine the effects of purine biosynthesis on organismal health we treated mice with mizoribine, an inhibitor of inosine monophosphate dehydrogenase 1 and 2 (IMPDH1/2), key enzymes in this pathway. Mice were fed either a low-fat (LFD; 13.5% kcal from fat) or a high-fat (HFD; 60% kcal from fat) diet for 30 days during drug or vehicle treatment. We ascertained the effects of mizoribine on weight gain, body composition, food intake and absorption, energy expenditure, and overall metabolic health. ResultsMizoribine treatment prevented mice on a HFD from gaining weight, but had no effect on mice on a LFD. Body composition analysis demonstrated that mizoribine significantly reduced fat mass but did not affect lean mass. Although mizoribine had no effect on lipid absorption, food intake was reduced. Furthermore, mizoribine treatment induced adaptive thermogenesis in skeletal muscle by upregulating sarcolipin, a regulator of muscle thermogenesis. While mizoribine-treated mice exhibited less adipose tissue than controls, we did not observe lipotoxicity. Rather, mizoribine-treated mice displayed improved glucose tolerance and reduced ectopic lipid accumulation. ConclusionsInhibiting purine biosynthesis prevents mice on a HFD from gaining weight, and improves their metabolic health, to a significant degree. We also demonstrated that the purine biosynthesis pathway plays a previously unknown role in skeletal muscle thermogenesis. A deeper mechanistic understanding of how purine biosynthesis promotes thermogenesis and decreases food intake may pave the way to new anti-obesity therapies. Crucially, given that many purine inhibitors have been FDA-approved for use in treating various conditions, our results indicate that they may benefit overweight or obese patients. HighlightsO_LIA purine biosynthesis inhibitor, mizoribine, protects against diet-induced weight gain C_LIO_LIMizoribine prevents fat mass gain in high-fat diet-fed male mice C_LIO_LIMizoribine reduces food intake and increases thermogenesis C_LIO_LIMizoribine induces expression of sarcolipin, a regulator of thermogenesis C_LIO_LIMizoribine treatment reduces ectopic lipids and increases glucose tolerance C_LI

physiology↗

bioRxiv2024

Interruption of glucagon signaling augments islet non-alpha cell proliferation in SLC7A2- and mTOR-dependent manners

ObjectiveDysregulated glucagon secretion and inadequate functional beta cell mass are hallmark features of diabetes. While glucagon receptor (GCGR) antagonism ameliorates hyperglycemia and elicits beta cell regeneration in pre-clinical models of diabetes, it also promotes alpha and delta cell hyperplasia. We sought to investigate the mechanism by which loss of glucagon action impacts pancreatic islet non-alpha cells, and the relevance of these observations in a human islet context. MethodsWe used zebrafish, rodents, and transplanted human islets comprising six different models of interrupted glucagon signaling to examine their impact on delta and beta cell proliferation and mass. We also used models with global deficiency of the cationic amino acid transporter, SLC7A2, and mTORC1 inhibition via rapamycin, to determine whether amino acid-dependent nutrient sensing was required for islet non-alpha cell growth. ResultsInhibition of glucagon signaling stimulated delta cell proliferation in mouse and transplanted human islets, and in mouse islets. This was rapamycin-sensitive and required SLC7A2. Likewise, gcgr deficiency augmented beta cell proliferation via SLC7A2- and mTORC1-dependent mechanisms in zebrafish and promoted cell cycle engagement in rodent beta cells but was insufficient to drive a significant increase in beta cell mass in mice. ConclusionOur findings demonstrate that interruption of glucagon signaling augments islet non-alpha cell proliferation in zebrafish, rodents, and transplanted human islets in a manner requiring SLC7A2 and mTORC1 activation. An increase in delta cell mass may be leveraged for future beta cell regeneration therapies relying upon delta cell reprogramming.

cell biology↗

bioRxiv2023

Integration of metabolic flux with hepatic glucagon signaling and gene expression profiles in the conscious dog

Glucagon rapidly and profoundly simulates hepatic glucose production (HGP), but for reasons which are unclear, this effect normally wanes after a few hours, despite sustained plasma glucagon levels. This study characterized the time course and relevance (to metabolic flux) of glucagon-mediated molecular events in the livers of conscious dogs. Glucagon was either infused into the hepato-portal vein at a 6-fold basal rate in the presence of somatostatin and basal insulin, or it was maintained at a basal level in control studies. In one control group glucose remained at basal while in the other glucose was infused to match the hyperglycemia that occurred in the hyperglucagonemic group. Elevated glucagon caused a rapid (30 min) but only partially sustained increase in hepatic cAMP over 4h, a continued elevation in G6P, and activation and deactivation of glycogen phosphorylase and synthase activities, respectively. Net hepatic glycogenolysis and HGP increased rapidly, peaking at 30 min, then returned to baseline over the next three hours (although glucagons stimulatory effect on HGP was sustained relative to the hyperglycemic control group). Hepatic gluconeogenic flux did not increase due to lack of glucagon effect on substrate supply to the liver. Global gene expression profiling highlighted glucagon-regulated activation of genes involved in cellular respiration, metabolic processes, and signaling, and downregulation of genes involved in extracellular matrix assembly and development.

physiology↗

bioRxiv2023

Pancreatic islet α cell function and proliferation requires the arginine transporter SLC7A2

Interrupting glucagon signaling decreases gluconeogenesis and the fractional extraction of amino acids by liver from blood resulting in lower glycemia. The resulting hyperaminoacidemia stimulates cell proliferation and glucagon secretion via a liver- cell axis. We hypothesized that cells detect and respond to circulating amino acids levels via a unique amino acid transporter repertoire. We found that Slc7a2ISLC7A2 is the most highly expressed cationic amino acid transporter in cells with its expression being three-fold greater in than {beta} cells in both mouse and human. Employing cell culture, zebrafish, and knockout mouse models, we found that the cationic amino acid arginine and SLC7A2 are required for cell proliferation in response to interrupted glucagon signaling. Ex vivo and in vivo assessment of islet function in Slc7a2-/- mice showed decreased arginine-stimulated glucagon and insulin secretion. We found that arginine activation of mTOR signaling and induction of the glutamine transporter SLC38A5 was dependent on SLC7A2, showing that boths role in cell proliferation is dependent on arginine transport and SLC7A2. Finally, we identified single nucleotide polymorphisms in SLC7A2 associated with HbA1c. Together, these data indicate a central role for SLC7A2 in amino acid-stimulated cell proliferation and islet hormone secretion.

physiology↗

bioRxiv2020

SARS-CoV-2 Cell Entry Factors ACE2 and TMPRSS2 are Expressed in the Pancreas but Not in Islet Endocrine Cells

Summary/AbstractReports of new-onset diabetes and diabetic ketoacidosis in individuals with COVID-19 have led to the hypothesis that SARS-CoV-2, the virus that causes COVID-19, is directly cytotoxic to pancreatic islet {beta} cells. This would require binding and entry of SARS-CoV-2 into host {beta} cells via cell surface co-expression of ACE2 and TMPRSS2, the putative receptor and effector protease, respectively. To define ACE2 and TMPRSS2 expression in the human pancreas, we examined six transcriptional datasets from primary human islet cells and assessed protein expression by immunofluorescence in pancreata from donors with and without diabetes. ACE2 and TMPRSS2 transcripts were low or undetectable in pancreatic islet endocrine cells as determined by bulk or single cell RNA sequencing, and neither protein was detected in or {beta} cells from these donors. Instead, ACE2 protein was expressed in the islet and exocrine tissue microvasculature and also found in a subset of pancreatic ducts, whereas TMPRSS2 protein was restricted to ductal cells. The absence of significant ACE2 and TMPRSS2 co-expression in islet endocrine cells reduces the likelihood that SARS-CoV-2 directly infects pancreatic islet {beta} cells through these cell entry proteins.

cell biology↗