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Browsing by Author "Yan, Shijun"
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Item Altered Central Nutrient Sensing in Male Mice Lacking Insulin Receptors in Glut4-Expressing Neurons(Oxford, 2019-09) Ren, Hongxia; Vieira-de-Abreu, Adriana; Yan, Shijun; Reilly, Austin M.; Chan, Owen; Accili, Domenico; Pediatrics, School of MedicineInsulin signaling in the central nervous system influences satiety, counterregulation, and peripheral insulin sensitivity. Neurons expressing the Glut4 glucose transporter influence peripheral insulin sensitivity. Here, we analyzed the effects of insulin receptor (IR) signaling in hypothalamic Glut4 neurons on glucose sensing as well as leptin and amino acid signaling. By measuring electrophysiological responses to low glucose conditions, we found that the majority of Glut4 neurons in the ventromedial hypothalamus (VMH) were glucose excitatory neurons. GLUT4-Cre-driven insulin receptor knockout mice with a combined ablation of IR in Glut4-expressing tissues showed increased counterregulatory response to either 2-deoxyglucose-induced neuroglycopenia or systemic insulin-induced hypoglycemia. The latter response was recapitulated in mice with decreased VMH IR expression, suggesting that the effects on the counterregulatory response are likely mediated through the deletion of IRs on Glut4 neurons in the VMH. Using immunohistochemistry in fluorescently labeled hypothalamic Glut4 neurons, we showed that IR signaling promoted hypothalamic cellular signaling responses to the rise of insulin, leptin, and amino acids associated with feeding. We concluded that hypothalamic Glut4 neurons modulated the glucagon counterregulatory response and that IR signaling in Glut4 neurons was required to integrate hormonal and nutritional cues for the regulation of glucose metabolism.Item Gpr17 deficiency in POMC neurons ameliorates the metabolic derangements caused by long-term high-fat diet feeding(Springer Nature, 2019-10-14) Reilly, Austin M.; Zhou, Shudi; Panigrahi, Sunil K.; Yan, Shijun; Conley, Jason M.; Sheets, Patrick L.; Wardlaw, Sharon L.; Ren, Hongxia; Medicine, School of MedicineBACKGROUND: Proopiomelanocortin (POMC) neurons in the arcuate nucleus of the hypothalamus (ARH) control energy homeostasis by sensing hormonal and nutrient cues and activating secondary melanocortin sensing neurons. We identified the expression of a G protein-coupled receptor, Gpr17, in the ARH and hypothesized that it contributes to the regulatory function of POMC neurons on metabolism. METHODS: In order to test this hypothesis, we generated POMC neuron-specific Gpr17 knockout (PGKO) mice and determined their energy and glucose metabolic phenotypes on normal chow diet (NCD) and high-fat diet (HFD). RESULTS: Adult PGKO mice on NCD displayed comparable body composition and metabolic features measured by indirect calorimetry. By contrast, PGKO mice on HFD demonstrated a sexually dimorphic phenotype with female PGKO mice displaying better metabolic homeostasis. Notably, female PGKO mice gained significantly less body weight and adiposity (p < 0.01), which was associated with increased energy expenditure, locomotor activity, and respiratory quotient, while males did not have an overt change in energy homeostasis. Though PGKO mice of both sexes had comparable glucose and insulin tolerance, detailed analyses of liver gene expression and serum metabolites indicate that PGKO mice could have reduced gluconeogenesis and increased lipid utilization on HFD. To elucidate the central-based mechanism(s) underlying the better-preserved energy and glucose homeostasis in PGKO mice on HFD, we examined the electrophysiological properties of POMC neurons and found Gpr17 deficiency led to increased spontaneous action potentials. Moreover, PGKO mice, especially female knockouts, had increased POMC-derived alpha-melanocyte stimulating hormone and beta-endorphin despite a comparable level of prohormone POMC in their hypothalamic extracts. CONCLUSIONS: Gpr17 deficiency in POMC neurons protects metabolic homeostasis in a sex-dependent manner during dietary and aging challenges, suggesting that Gpr17 could be an effective anti-obesity target in specific populations with poor metabolic control.Item A high-fat diet catalyzes progression to hyperglycemia in mice with selective impairment of insulin action in Glut4-expressing tissues(Elsevier, 2022-01) Reilly, Austin M.; Yan, Shijun; Huang, Menghao; Abhyankar, Surabhi D.; Conley, Jason M.; Bone, Robert N.; Stull, Natalie D.; Horan, Daniel J.; Roh, Hyun C.; Robling, Alexander G.; Ericsson, Aaron C.; Dong, Xiaocheng C.; Evans-Molina, Carmella; Ren, Hongxia; Pediatrics, School of MedicineInsulin resistance impairs postprandial glucose uptake through glucose transporter type 4 (GLUT4) and is the primary defect preceding type 2 diabetes. We previously generated an insulin-resistant mouse model with human GLUT4 promoter-driven insulin receptor knockout (GIRKO) in the muscle, adipose, and neuronal subpopulations. However, the rate of diabetes in GIRKO mice remained low prior to 6 months of age on normal chow diet (NCD), suggesting that additional factors/mechanisms are responsible for adverse metabolic effects driving the ultimate progression of overt diabetes. In this study, we characterized the metabolic phenotypes of the adult GIRKO mice acutely switched to high-fat diet (HFD) feeding in order to identify additional metabolic challenges required for disease progression. Distinct from other diet-induced obesity (DIO) and genetic models (e.g., db/db mice), GIRKO mice remained leaner on HFD feeding, but developed other cardinal features of insulin resistance syndrome. GIRKO mice rapidly developed hyperglycemia despite compensatory increases in β-cell mass and hyperinsulinemia. Furthermore, GIRKO mice also had impaired oral glucose tolerance and a limited glucose-lowering benefit from exendin-4, suggesting that the blunted incretin effect contributed to hyperglycemia. Secondly, GIRKO mice manifested severe dyslipidemia while on HFD due to elevated hepatic lipid secretion, serum triglyceride concentration, and lipid droplet accumulation in hepatocytes. Thirdly, GIRKO mice on HFD had increased inflammatory cues in the gut, which were associated with the HFD-induced microbiome alterations and increased serum lipopolysaccharide (LPS). In conclusion, our studies identified important gene/diet interactions contributing to diabetes progression, which might be leveraged to develop more efficacious therapies.Item Intestinal Gpr17 deficiency improves glucose metabolism by promoting GLP-1 secretion(Elsevier, 2022-01) Yan, Shijun; Conley, Jason M.; Reilly, Austin M.; Stull, Natalie D.; Abhyankar, Surabhi D.; Ericsson, Aaron C.; Kono, Tatsuyoshi; Molosh, Andrei I.; Kubal, Chandrashekhar A.; Evans-Molina, Carmella; Ren, Hongxia; Medicine, School of MedicineG protein-coupled receptors (GPCRs) in intestinal enteroendocrine cells (EECs) respond to nutritional, neural, and microbial cues and modulate the release of gut hormones. Here we show that Gpr17, an orphan GPCR, is co-expressed in glucagon-like peptide-1 (GLP-1)-expressing EECs in human and rodent intestinal epithelium. Acute genetic ablation of Gpr17 in intestinal epithelium improves glucose tolerance and glucose-stimulated insulin secretion (GSIS). Importantly, inducible knockout (iKO) mice and Gpr17 null intestinal organoids respond to glucose or lipid ingestion with increased secretion of GLP-1, but not the other incretin glucose-dependent insulinotropic polypeptide (GIP). In an in vitro EEC model, overexpression or agonism of Gpr17 reduces voltage-gated calcium currents and decreases cyclic AMP (cAMP) production, and these are two critical factors regulating GLP-1 secretion. Together, our work shows that intestinal Gpr17 signaling functions as an inhibitory pathway for GLP-1 secretion in EECs, suggesting intestinal GPR17 is a potential target for diabetes and obesity intervention.Item Validating the experimental approaches for electrophysiological recording of hypothalamic POMC neurons and in vivo insulin receptor knockdown(2019-04-26) Yan, Shijun; Vieira-de-Abreu, Adriana; Reilly, Austin M.; Paranjape, Sachin A.; Accili, Domenico; Chan, Owen; Ren, Hongxia