Papers by Marianna Sadagurski
Supplementary Figure 1: <br>(A) Immunofluorescence staining for insulin (green) and DAPI (b... more Supplementary Figure 1: <br>(A) Immunofluorescence staining for insulin (green) and DAPI (blue) in representative pancreatic sections from 9-month-old female offspring; (<b>B</b>) quantitation of β-cell mass in female offspring <br><br>Supplementary Figure 2: <br><br>qPCR of hepatic genes of males (<b>A</b>) and (<b>B</b>). qPCR of hepatic genes of females (<b>C</b>) and (<b>D</b>).<br><br>Supplementary Table 1:<br>Primers sequence
Scientific Reports, 2020
Understanding the neural components modulating feeding-related behavior and energy expenditure is... more Understanding the neural components modulating feeding-related behavior and energy expenditure is crucial to combating obesity and its comorbidities. Neurons within the paraventricular nucleus of the hypothalamus (PVH) are a key component of the satiety response; activation of the PVH decreases feeding and increases energy expenditure, thereby promoting negative energy balance. In contrast, PVH ablation or silencing in both rodents and humans leads to substantial obesity. Recent studies have identified genetically-defined PVH subpopulations that control discrete aspects of energy balance (e.g. oxytocin (OXT), neuronal nitric oxide synthase 1 (NOS1), melanocortin 4-receptor (MC4R), prodynorphin (PDYN)). We previously demonstrated that non-OXT NOS1PVH neurons contribute to PVH-mediated feeding suppression. Here, we identify and characterize a non-OXT, non-NOS1 subpopulation of PVH and peri-PVH neurons expressing insulin-receptor substrate 4 (IRS4PVH) involved in energy balance control...
Molecular metabolism, 2017
The GH/IGF-1 axis has important roles in growth and metabolism. GH and GH receptor (GHR) are acti... more The GH/IGF-1 axis has important roles in growth and metabolism. GH and GH receptor (GHR) are active in the central nervous system (CNS) and are crucial in regulating several aspects of metabolism. In the hypothalamus, there is a high abundance of GH-responsive cells, but the role of GH signaling in hypothalamic neurons is unknown. Previous work has demonstrated that the Ghr gene is highly expressed in LepRb neurons. Given that leptin is a key regulator of energy balance by acting on leptin receptor (LepRb)-expressing neurons, we tested the hypothesis that LepRb neurons represent an important site for GHR signaling to control body homeostasis. To determine the importance of GHR signaling in LepRb neurons, we utilized Cre/loxP technology to ablate GHR expression in LepRb neurons (Lepr(EYFPΔGHR)). The mice were generated by crossing the Lepr(cre) on the cre-inducible ROSA26-EYFP mice to GHR(L/L) mice. Parameters of body composition and glucose homeostasis were evaluated. Our results de...
Molecular Metabolism, 2014
Insulin receptor substrates (Irs1, 2, 3 and Irs4) mediate the actions of insulin/IGF1 signaling. ... more Insulin receptor substrates (Irs1, 2, 3 and Irs4) mediate the actions of insulin/IGF1 signaling. They have similar structure, but distinctly regulate development, growth, and metabolic homeostasis. Irs2 contributes to central metabolic sensing, partially by acting in leptin receptor (LepRb)expressing neurons. Although Irs4 is largely restricted to the hypothalamus, its contribution to metabolic regulation is unclear because Irs4-null mice barely distinguishable from controls. We postulated that Irs2 and Irs4 synergize and complement each other in the brain. To examine this possibility, we investigated the metabolism of whole body Irs4 À /y mice that lacked Irs2 in the CNS (bIrs2 À / À Á Irs4 À /y) or only in LepRb-neurons (Lepr ΔIrs2 Á Irs4 À /y). bIrs2 À / À Á Irs4 À /y mice developed severe obesity and decreased energy expenditure, along with hyperglycemia and insulin resistance. Unexpectedly, the body weight and fed blood glucose levels of Lepr ΔIrs2 Á Irs4 À /y mice were not different from Lepr ΔIrs2 mice, suggesting that the functions of Irs2 and Irs4 converge upon neurons that are distinct from those expressing LepRb.
Journal of Cellular Physiology, 2007
Insulin receptor substrate (IRS) proteins play a central role in insulin signaling. Previously we... more Insulin receptor substrate (IRS) proteins play a central role in insulin signaling. Previously we have demonstrated that insulin is essential for normal skin development and function. In the present study we investigated the involvement of the IRS-1 and IRS-2 proteins in skin physiology and in mediating insulin action in skin. For this purpose we have investigated the effects of inactivation of each of the IRSs on skin, studying skin sections and primary skin cells derived from IRS-1 or IRS-2 null mice. We have demonstrated that while the skin of the IRS-2 null mice appeared normal, the skin of the IRS-1 null mice was thinner and translucent. Histological analysis revealed that the thinning of the IRS-1 null skin was a consequence of the thinning of the spinous compartment, consisting of fewer layers. Proliferation of the IRS-1 and IRS-2 null skin epidermal cells was normal. However, the differentiation process of the IRS-1 skin and skin cells was impaired. There was a marked decrease in the induction of the expression of K1, the marker of advanced stages of skin differentiation. In contrary, IRS-2 inactivation had no effects on skin differentiation. In conclusion, we have shown for the first time that IRS-1 but not IRS-2 has an effect on skin formation and development, being one of the main activators of the differentiation process in skin keratinocytes. Furthermore, we suggest that IRS-1 and IRS-2 have distinct roles in skin physiology.
Journal of Biological Chemistry, 2005
The insulin receptor substrate 2 (IRS-2) protein is one of the major insulin-signaling substrates... more The insulin receptor substrate 2 (IRS-2) protein is one of the major insulin-signaling substrates. In the present study, we investigated the role of IRS-2 in skin epidermal keratinocytes and dermal fibroblasts. Although skin is not a classical insulin target tissue, we have previously demonstrated that insulin, via the insulin receptor, is essential for normal skin cell physiology. To identify the role of IRS-2 in skin cells, we studied cells isolated from IRS-2 knockout (KO) mice. Whereas proliferation and differentiation were not affected in the IRS-2 KO cells, a striking effect was observed on glucose transport. In IRS-2 KO keratinocytes, the lack of IRS-2 resulted in a dramatic increase in basal and insulinstimulated glucose transport. The increase in glucose transport was associated with an increase in total phosphatidylinositol (PI) 3-kinase and Akt activation. In contrast, fibroblasts lacking IRS-2 exhibited a significant decrease in basal and insulin-induced glucose transport. We identified the point of divergence, leading to these differences between keratinocytes and fibroblasts, at the IRS-PI 3-kinase association step. In epidermal keratinocytes, PI 3-kinase is associated with and activated by only the IRS-1 protein. On the other hand, in dermal fibroblasts, PI 3-kinase is exclusively associated with and activated by the IRS-2 protein. These observations suggest that IRS-2 functions as a negative or positive regulator of glucose transport in a cell-specific manner. Our results also show that IRS-2 function depends on its cell-specific association with PI 3-kinase.
Endocrinology and Metabolism Clinics of North America, 2013
Understanding how metabolism integrates nutrient homeostasis with life span is a complicated unde... more Understanding how metabolism integrates nutrient homeostasis with life span is a complicated undertaking. The insulin pathway coordinates growth, development, metabolic homoeostasis, fertility and stress resistance, which ultimately influence lifespan. From a clinical perspective, compensatory hyperinsulinemia to overcome systemic insulin resistance is thought to be a healthy goal, because it circumvents to immediate catastrophic consequences of hyperglycemia; however, work in flies, nematodes and mice indicate that excess insulin signaling ultimately damages cellular function and accelerates aging. Maintenance of the central nervous system (CNS) has particular importance for lifespan. Depending upon the exact site, reduced insulin/IGF1 signaling in the CNS can dysregulate peripheral energy homeostasis and metabolism, promote obesity, and extend lifespan. In this review, we explore how genetic manipulations of insulin/IGF1 signaling components are beginning to reveal neuronal circuits which might resolve the central regulation of systemic metabolism from organism longevity. Keywords Aging; central nervous system; insulin/IGF signaling; lifespan; neurodegeneration; metabolism; leptin; energy balance; glucose homeostasis disease (2). By comparison, genetic strategies to reduce insulin/IGF1 signaling in Caenorhabditis elegans, Drosophila melanogaster, and rodents has emerged as a reliable means of extending lifespan (3-7). Understanding the relation between insulin 'resistance' and 'reduced' insulin/IGF signaling might provide important insight into the pathology of metabolic disease, its sequelae, and strategies for treatment.
Diabetologia, 2009
Aims/hypothesis Interleukin-6 is an inflammatory cytokine with pleiotropic effects upon nutrient ... more Aims/hypothesis Interleukin-6 is an inflammatory cytokine with pleiotropic effects upon nutrient homeostasis. Many reports show that circulating IL6 correlates with obesity and contributes to insulin resistance; however, IL6 can promote energy expenditure that improves glucose homeostasis. Methods We investigated nutrient homeostasis in C57BL/ 6J mice with sustained circulating human IL6 (hIL6) secreted predominantly from brain and lung (hIL6 tg mice). Results The hIL6 tg mice displayed no features of systemic inflammation and were more insulin-sensitive than wild-type mice. On a high-fat diet, hIL6 tg mice were lean, had low leptin concentrations, consumed less food and expended more energy than wild-type mice. Like ob/ob mice, the ob/ob IL6 mice (generated by intercrossing ob/ob and hIL6 tg mice) were obese and glucose-intolerant. However, low-dose leptin injections increased physical activity and reduced both body weight and food intake in ob/ob IL6 mice, but was ineffective in ob/ob mice. Leptin increased hypothalamic signal transducer and activator of transcription-3 phosphorylation in ob/ob IL6 mice, whereas ob/ob mice barely responded. Conclusions/interpretation Human IL6 enhanced central leptin action in mice, promoting nutrient homeostasis and preventing diet-induced obesity.
Cell Metabolism, 2012
Irs2-mediated insulin/IGF1 signaling in the CNS modulates energy balance and glucose homeostasis;... more Irs2-mediated insulin/IGF1 signaling in the CNS modulates energy balance and glucose homeostasis; however, the site for Irs2 function is unknown. The hormone leptin mediates energy balance by acting on leptin receptor (LepR-b)-expressing neurons. To determine whether LepR-b neurons mediate the metabolic actions of Irs2 in the brain, we utilized Lepr cre together with Irs2 L/L to ablate Irs2 expression in LepR-b neurons (Lepr DIrs2). Lepr DIrs2 mice developed obesity, glucose intolerance, and insulin resistance. Leptin action was not altered in young Lepr DIrs2 mice, although insulin-stimulated FoxO1 nuclear exclusion was reduced in Lepr DIrs2 mice. Indeed, deletion of Foxo1 from LepR-b neurons in Lepr DIrs2 mice normalized energy balance, glucose homeostasis, and arcuate nucleus gene expression. Thus, Irs2 signaling in LepR-b neurons plays a crucial role in metabolic sensing and regulation. While not required for leptin action, Irs2 suppresses FoxO1 signaling in LepR-b neurons to promote energy balance and metabolism.
BMC Developmental Biology, 2010
Background Male Irs2 -/- mice develop fatal type 2 diabetes at 13-14 weeks. Defects in neuronal p... more Background Male Irs2 -/- mice develop fatal type 2 diabetes at 13-14 weeks. Defects in neuronal proliferation, pituitary development and photoreceptor cell survival manifest in Irs2 -/- mice. We identify retarded renal growth in male and female Irs2 -/- mice, independent of diabetes. Results Kidney size and kidney:body weight ratio were reduced by approximately 20% in Irs2 -/- mice at postnatal day 5 and was maintained in maturity. Reduced glomerular number but similar glomerular density was detected in Irs2 -/- kidney compared to wild-type, suggesting intact global kidney structure. Analysis of insulin signalling revealed renal-specific upregulation of PKBβ/Akt2, hyperphosphorylation of GSK3β and concomitant accumulation of β-catenin in Irs2 -/- kidney. Despite this, no significant upregulation of β-catenin targets was detected. Kidney-specific increases in Yes-associated protein (YAP), a key driver of organ size were also detected in the absence of Irs2. YAP phosphorylation on its...
Canagliflozin (Cana) is an inhibitor of the sodium glucose transporter 2 (SGLT2), and is thought ... more Canagliflozin (Cana) is an inhibitor of the sodium glucose transporter 2 (SGLT2), and is thought to act by blocking renal reuptake and intestinal absorption of glucose. Cana is FDA-approved for treatment of diabetes, and affords protection from cardiovascular and kidney diseases. In the context of the mouse Interventions Testing Program, genetically heterogeneous mice were given chow containing 180 ppm Cana at 7 months of age until their death. Cana extended median survival of male mice by 14%, with p < 0.001 by log-rank test. Cana also increased by 9% the age for 90th percentile survival (p < 0.001 by Wang/Allison test), with parallel effects seen at each of three test sites. Cana did not alter the distribution of inferred cause of death, nor of incidental pathology findings at end-of-life necropsies. No benefits were seen in female mice. The lifespan benefit of Cana is likely to reflect blunting of peak glucose levels, because similar longevity effects are seen in mice given...
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Papers by Marianna Sadagurski