Zoi Michailidou - Academia.edu (original) (raw)
Papers by Zoi Michailidou
Journal of Innate Immunity
Metabolic disorders, such as obesity, type 2 diabetes mellitus, and nonalcoholic fatty liver dise... more Metabolic disorders, such as obesity, type 2 diabetes mellitus, and nonalcoholic fatty liver disease, are characterized by chronic low-grade tissue and systemic inflammation. During obesity, the adipose tissue undergoes immunometabolic and functional transformation. Adipose tissue inflammation is driven by innate and adaptive immune cells and instigates insulin resistance. Here, we discuss the role of innate immune cells, that is, macrophages, neutrophils, eosinophils, natural killer cells, innate lymphoid type 2 cells, dendritic cells, and mast cells, in the adipose tissue in the healthy (lean) and diseased (obese) state and describe how their function is shaped by the obesogenic microenvironment, and humoral, paracrine, and cellular interactions. Moreover, we particularly outline the role of hypoxia as a central regulator in adipose tissue inflammation. Finally, we discuss the long-lasting effects of adipose tissue inflammation and its potential reversibility through drugs, calori...
Enhancing brown adipose tissue (BAT) function to combat metabolic disease is a promising therapeu... more Enhancing brown adipose tissue (BAT) function to combat metabolic disease is a promising therapeutic strategy. A major obstacle to this strategy is that a thermoneutral environment, relevant to most modern human living conditions, deactivates functional BAT. We showed that we can overcome the dormancy of BAT at thermoneutrality by inhibiting the main oxygen sensor HIF-prolyl hydroxylase, PHD2, specifically in adipocytes. Mice lacking adipocyte PHD2 (P2KOad) and housed at thermoneutrality maintained greater BAT mass, had detectable UCP1 protein expression in BAT and higher energy expenditure. Mouse brown adipocytes treated with the pan-PHD inhibitor, FG2216, exhibited higher Ucp1 mRNA and protein levels, effects that were abolished by antagonising the canonical PHD2 substrate, HIF-2a. Induction of UCP1 mRNA expression by FG2216, was also confirmed in human adipocytes isolated from obese individuals. Human serum proteomics analysis of 5457 participants in the deeply phenotyped Age, Ge...
Frontiers in Cell and Developmental Biology
Current Opinion in Physiology
Hepatology (Baltimore, Md.), Jan 18, 2017
A hallmark of chronic liver injury is fibrosis, with accumulation of extracellular matrix orchest... more A hallmark of chronic liver injury is fibrosis, with accumulation of extracellular matrix orchestrated by activated hepatic stellate cells (HSCs). Glucocorticoids limit HSC activation in vitro, and tissue glucocorticoid levels are amplified by 11beta-hydroxysteroid dehydrogenase-1 (11βHSD1). Although 11βHSD1 inhibitors have been developed for type 2 diabetes mellitus and improve diet-induced fatty liver in various mouse models, effects on the progression and/or resolution of liver injury and consequent fibrosis have not been characterized. We have used the reversible carbon tetrachloride-induced model of hepatocyte injury and liver fibrosis to show that in two models of genetic 11βHSD1 deficiency (global, Hsd11b1 , and hepatic myofibroblast-specific, Hsd11b1 /Pdgfrb-cre) 11βHSD1 pharmacological inhibition in vivo exacerbates hepatic myofibroblast activation and liver fibrosis. In contrast, liver injury and fibrosis in hepatocyte-specific Hsd11b1 /albumin-cre mice did not differ from...
Nature medicine, Jan 10, 2018
In the version of this article initially published, the numbers on the y-axis of Figure 2b were i... more In the version of this article initially published, the numbers on the y-axis of Figure 2b were incorrect by a power of 10, and the numbers in the text describing the frequency of MSI-H tumors were also incorrect. The original text read: "Still lower, but detectable, frequencies of MSI-H were observed in 12 other cancer types; collectively, one or more individual MSI-H tumors were identified in 16 of the 18 cancer types examined". This has been corrected to: "Still lower, but detectable, frequencies of MSI-H were observed in 10 other cancer types; collectively, one or more individual MSI-H tumors were identified in 14 of the 18 cancer types examined". These errors do not impact the findings or conclusions of this work; however, they have been corrected for accuracy. The error has been corrected in the HTML and PDF versions of the article.
The Endocrine Society's 93rd Annual Meeting & Expo, June 4–7, 2011 - Boston, 2011
The Endocrine Society's 93rd Annual Meeting & Expo, June 4–7, 2011 - Boston, 2011
Nature Medicine, 2016
Users may view, print, copy, and download text and data-mine the content in such documents, for t... more Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:
Endocrine Abstracts, 2015
Angiogenesis in Adipose Tissue, 2013
Human Molecular Genetics, 2013
Glucocorticoids are vital for the structural and functional maturation of foetal organs, yet exce... more Glucocorticoids are vital for the structural and functional maturation of foetal organs, yet excessive foetal exposure is detrimental to adult cardiovascular health. To elucidate the role of glucocorticoid signalling in late-gestation cardiovascular maturation, we have generated mice with conditional disruption of glucocorticoid receptor (GR) in cardiomyocytes and vascular smooth muscle cells using smooth muscle protein 22-driven Cre recombinase (SMGRKO mice) and compared them with mice with global deficiency in GR (GR 2/ 2). Echocardiography shows impaired heart function in both SMGRKO and GR 2/ 2 mice at embryonic day (E)17.5, associated with generalized oedema. Cardiac ultrastructure is markedly disrupted in both SMGRKO and GR 2/2 mice at E17.5, with short, disorganized myofibrils and cardiomyocytes that fail to align in the compact myocardium. Failure to induce critical genes involved in contractile function, calcium handling and energy metabolism underpins this common phenotype. However, although hearts of GR 2/2 mice are smaller, with 22% reduced ventricular volume at E17.5, SMGRKO hearts are normally sized. Moreover, while levels of mRNA encoding atrial natriuretic peptide are reduced in E17.5 GR 2/2 hearts, they are normal in foetal SMGRKO hearts. These data demonstrate that structural, functional and biochemical maturation of the foetal heart is dependent on glucocorticoid signalling within cardiomyocytes and vascular smooth muscle, though some aspects of heart maturation (size, ANP expression) are independent of GR at these key sites.
Glucocorticoid levels rise dramatically in late gestation in mammals and are essential for organ ... more Glucocorticoid levels rise dramatically in late gestation in mammals and are essential for organ maturation in preparation for birth. They are widely used clinically to mature the lungs of premature infants and hypomorphic GR mice die neonatally due to severe lung atelectasis. Here, we ...
AJP: Endocrinology and Metabolism, 2011
Increased dietary fat intake is associated with obesity, insulin resistance, and metabolic diseas... more Increased dietary fat intake is associated with obesity, insulin resistance, and metabolic disease. In transgenic mice, adipose tissue-specific overexpression of the glucocorticoid-amplifying enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) exacerbates high-fat (HF) diet-induced visceral obesity and diabetes, whereas 11β-HSD1 gene knockout ameliorates this, favoring accumulation of fat in nonvisceral depots. Paradoxically, in normal mice HF diet-induced obesity (DIO) is associated with marked downregulation of adipose tissue 11β-HSD1 levels. To identify the specific dietary fats that regulate adipose 11β-HSD1 and thereby impact upon metabolic disease, we either fed mice diets enriched (45% calories as fat) in saturated (stearate), monounsaturated (oleate), or polyunsaturated (safflower oil) fats ad libitum or we pair fed them a low-fat (11%) control diet for 4 wk. Adipose and liver mass and glucocorticoid receptor and 11β-HSD1 mRNA and activity levels were determined. Stear...
Pro-opiomelanocortin (POMC)-deficiency causes severe obesity through hyperphagia of hypothalamic ... more Pro-opiomelanocortin (POMC)-deficiency causes severe obesity through hyperphagia of hypothalamic origin. However, low glucocorticoid levels caused by adrenal insufficiency mitigates against insulin resistance, hyperphagia and fat accretion in Pomc -/mice. Upon exogenous glucocorticoid replacement, (CORT) Pomc -/mice show exaggerated responses including excessive fat accumulation, hyperleptinaemia and insulin resistance. To investigate the peripheral mechanisms underlying this glucocorticoid hypersensitivity we examined the expression levels of key determinants and targets of glucocorticoid action in adipose tissue and liver. Despite lower basal expression of 11 -hydroxysteroid dehydrogenase type 1 (11 -HSD1), which generates active glucocorticoids within cells, CORT-mediated induction of 11 -HSD1 mRNA levels was more pronounced in adipose tissues of Pomc -/mice. Similarly, CORT treatment increased lipoprotein lipase mRNA levels in all fat depots in Pomc -/mice, consistent with exaggerated fat accumulation. Glucocorticoid receptor (GR) mRNA levels were selectively elevated in liver and retroperitoneal fat of Pomc -/mice but were corrected by CORT in the latter depot. In liver, CORT increased PEPCK mRNA levels specifically in Pomc -/mice, consistent with their insulin resistant phenotype. Furthermore, CORT induced hypertension in Pomc -/mice, independently of adipose or liver renin-angiotensin system (RAS) activation. These data suggest CORT-inducible 11 -HSD1 expression in fat contributes to the adverse cardiometabolic effects of CORT in POMC deficiency, whereas higher GR levels may be more important in liver.
Endocrine Abstracts, 2013
The FASEB Journal, 2008
Glucocorticoid hormones are critical to respond and adapt to stress. Genetic variations in the gl... more Glucocorticoid hormones are critical to respond and adapt to stress. Genetic variations in the glucocorticoid receptor (GR) gene alter hypothalamicpituitary-adrenal (HPA) axis activity and associate with hypertension and susceptibility to metabolic disease. Here we test the hypothesis that reduced GR density alters blood pressure and glucose and lipid homeostasis and limits adaption to obesogenic diet. Heterozygous GR geo/؉ mice were generated from embryonic stem (ES) cells with a gene trap integration of a -galactosidase-neomycin phosphotransferase (geo) cassette into the GR gene creating a transcriptionally inactive GR fusion protein.
PLoS ONE, 2011
Background: Obesity and metabolic syndrome results from a complex interaction between genetic and... more Background: Obesity and metabolic syndrome results from a complex interaction between genetic and environmental factors. In addition to brain-regulated processes, recent genome wide association studies have indicated that genes highly expressed in adipose tissue affect the distribution and function of fat and thus contribute to obesity. Using a stratified transcriptome gene enrichment approach we attempted to identify adipose tissue-specific obesity genes in the unique polygenic Fat (F) mouse strain generated by selective breeding over 60 generations for divergent adiposity from a comparator Lean (L) strain.
Journal of Innate Immunity
Metabolic disorders, such as obesity, type 2 diabetes mellitus, and nonalcoholic fatty liver dise... more Metabolic disorders, such as obesity, type 2 diabetes mellitus, and nonalcoholic fatty liver disease, are characterized by chronic low-grade tissue and systemic inflammation. During obesity, the adipose tissue undergoes immunometabolic and functional transformation. Adipose tissue inflammation is driven by innate and adaptive immune cells and instigates insulin resistance. Here, we discuss the role of innate immune cells, that is, macrophages, neutrophils, eosinophils, natural killer cells, innate lymphoid type 2 cells, dendritic cells, and mast cells, in the adipose tissue in the healthy (lean) and diseased (obese) state and describe how their function is shaped by the obesogenic microenvironment, and humoral, paracrine, and cellular interactions. Moreover, we particularly outline the role of hypoxia as a central regulator in adipose tissue inflammation. Finally, we discuss the long-lasting effects of adipose tissue inflammation and its potential reversibility through drugs, calori...
Enhancing brown adipose tissue (BAT) function to combat metabolic disease is a promising therapeu... more Enhancing brown adipose tissue (BAT) function to combat metabolic disease is a promising therapeutic strategy. A major obstacle to this strategy is that a thermoneutral environment, relevant to most modern human living conditions, deactivates functional BAT. We showed that we can overcome the dormancy of BAT at thermoneutrality by inhibiting the main oxygen sensor HIF-prolyl hydroxylase, PHD2, specifically in adipocytes. Mice lacking adipocyte PHD2 (P2KOad) and housed at thermoneutrality maintained greater BAT mass, had detectable UCP1 protein expression in BAT and higher energy expenditure. Mouse brown adipocytes treated with the pan-PHD inhibitor, FG2216, exhibited higher Ucp1 mRNA and protein levels, effects that were abolished by antagonising the canonical PHD2 substrate, HIF-2a. Induction of UCP1 mRNA expression by FG2216, was also confirmed in human adipocytes isolated from obese individuals. Human serum proteomics analysis of 5457 participants in the deeply phenotyped Age, Ge...
Frontiers in Cell and Developmental Biology
Current Opinion in Physiology
Hepatology (Baltimore, Md.), Jan 18, 2017
A hallmark of chronic liver injury is fibrosis, with accumulation of extracellular matrix orchest... more A hallmark of chronic liver injury is fibrosis, with accumulation of extracellular matrix orchestrated by activated hepatic stellate cells (HSCs). Glucocorticoids limit HSC activation in vitro, and tissue glucocorticoid levels are amplified by 11beta-hydroxysteroid dehydrogenase-1 (11βHSD1). Although 11βHSD1 inhibitors have been developed for type 2 diabetes mellitus and improve diet-induced fatty liver in various mouse models, effects on the progression and/or resolution of liver injury and consequent fibrosis have not been characterized. We have used the reversible carbon tetrachloride-induced model of hepatocyte injury and liver fibrosis to show that in two models of genetic 11βHSD1 deficiency (global, Hsd11b1 , and hepatic myofibroblast-specific, Hsd11b1 /Pdgfrb-cre) 11βHSD1 pharmacological inhibition in vivo exacerbates hepatic myofibroblast activation and liver fibrosis. In contrast, liver injury and fibrosis in hepatocyte-specific Hsd11b1 /albumin-cre mice did not differ from...
Nature medicine, Jan 10, 2018
In the version of this article initially published, the numbers on the y-axis of Figure 2b were i... more In the version of this article initially published, the numbers on the y-axis of Figure 2b were incorrect by a power of 10, and the numbers in the text describing the frequency of MSI-H tumors were also incorrect. The original text read: "Still lower, but detectable, frequencies of MSI-H were observed in 12 other cancer types; collectively, one or more individual MSI-H tumors were identified in 16 of the 18 cancer types examined". This has been corrected to: "Still lower, but detectable, frequencies of MSI-H were observed in 10 other cancer types; collectively, one or more individual MSI-H tumors were identified in 14 of the 18 cancer types examined". These errors do not impact the findings or conclusions of this work; however, they have been corrected for accuracy. The error has been corrected in the HTML and PDF versions of the article.
The Endocrine Society's 93rd Annual Meeting & Expo, June 4–7, 2011 - Boston, 2011
The Endocrine Society's 93rd Annual Meeting & Expo, June 4–7, 2011 - Boston, 2011
Nature Medicine, 2016
Users may view, print, copy, and download text and data-mine the content in such documents, for t... more Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:
Endocrine Abstracts, 2015
Angiogenesis in Adipose Tissue, 2013
Human Molecular Genetics, 2013
Glucocorticoids are vital for the structural and functional maturation of foetal organs, yet exce... more Glucocorticoids are vital for the structural and functional maturation of foetal organs, yet excessive foetal exposure is detrimental to adult cardiovascular health. To elucidate the role of glucocorticoid signalling in late-gestation cardiovascular maturation, we have generated mice with conditional disruption of glucocorticoid receptor (GR) in cardiomyocytes and vascular smooth muscle cells using smooth muscle protein 22-driven Cre recombinase (SMGRKO mice) and compared them with mice with global deficiency in GR (GR 2/ 2). Echocardiography shows impaired heart function in both SMGRKO and GR 2/ 2 mice at embryonic day (E)17.5, associated with generalized oedema. Cardiac ultrastructure is markedly disrupted in both SMGRKO and GR 2/2 mice at E17.5, with short, disorganized myofibrils and cardiomyocytes that fail to align in the compact myocardium. Failure to induce critical genes involved in contractile function, calcium handling and energy metabolism underpins this common phenotype. However, although hearts of GR 2/2 mice are smaller, with 22% reduced ventricular volume at E17.5, SMGRKO hearts are normally sized. Moreover, while levels of mRNA encoding atrial natriuretic peptide are reduced in E17.5 GR 2/2 hearts, they are normal in foetal SMGRKO hearts. These data demonstrate that structural, functional and biochemical maturation of the foetal heart is dependent on glucocorticoid signalling within cardiomyocytes and vascular smooth muscle, though some aspects of heart maturation (size, ANP expression) are independent of GR at these key sites.
Glucocorticoid levels rise dramatically in late gestation in mammals and are essential for organ ... more Glucocorticoid levels rise dramatically in late gestation in mammals and are essential for organ maturation in preparation for birth. They are widely used clinically to mature the lungs of premature infants and hypomorphic GR mice die neonatally due to severe lung atelectasis. Here, we ...
AJP: Endocrinology and Metabolism, 2011
Increased dietary fat intake is associated with obesity, insulin resistance, and metabolic diseas... more Increased dietary fat intake is associated with obesity, insulin resistance, and metabolic disease. In transgenic mice, adipose tissue-specific overexpression of the glucocorticoid-amplifying enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) exacerbates high-fat (HF) diet-induced visceral obesity and diabetes, whereas 11β-HSD1 gene knockout ameliorates this, favoring accumulation of fat in nonvisceral depots. Paradoxically, in normal mice HF diet-induced obesity (DIO) is associated with marked downregulation of adipose tissue 11β-HSD1 levels. To identify the specific dietary fats that regulate adipose 11β-HSD1 and thereby impact upon metabolic disease, we either fed mice diets enriched (45% calories as fat) in saturated (stearate), monounsaturated (oleate), or polyunsaturated (safflower oil) fats ad libitum or we pair fed them a low-fat (11%) control diet for 4 wk. Adipose and liver mass and glucocorticoid receptor and 11β-HSD1 mRNA and activity levels were determined. Stear...
Pro-opiomelanocortin (POMC)-deficiency causes severe obesity through hyperphagia of hypothalamic ... more Pro-opiomelanocortin (POMC)-deficiency causes severe obesity through hyperphagia of hypothalamic origin. However, low glucocorticoid levels caused by adrenal insufficiency mitigates against insulin resistance, hyperphagia and fat accretion in Pomc -/mice. Upon exogenous glucocorticoid replacement, (CORT) Pomc -/mice show exaggerated responses including excessive fat accumulation, hyperleptinaemia and insulin resistance. To investigate the peripheral mechanisms underlying this glucocorticoid hypersensitivity we examined the expression levels of key determinants and targets of glucocorticoid action in adipose tissue and liver. Despite lower basal expression of 11 -hydroxysteroid dehydrogenase type 1 (11 -HSD1), which generates active glucocorticoids within cells, CORT-mediated induction of 11 -HSD1 mRNA levels was more pronounced in adipose tissues of Pomc -/mice. Similarly, CORT treatment increased lipoprotein lipase mRNA levels in all fat depots in Pomc -/mice, consistent with exaggerated fat accumulation. Glucocorticoid receptor (GR) mRNA levels were selectively elevated in liver and retroperitoneal fat of Pomc -/mice but were corrected by CORT in the latter depot. In liver, CORT increased PEPCK mRNA levels specifically in Pomc -/mice, consistent with their insulin resistant phenotype. Furthermore, CORT induced hypertension in Pomc -/mice, independently of adipose or liver renin-angiotensin system (RAS) activation. These data suggest CORT-inducible 11 -HSD1 expression in fat contributes to the adverse cardiometabolic effects of CORT in POMC deficiency, whereas higher GR levels may be more important in liver.
Endocrine Abstracts, 2013
The FASEB Journal, 2008
Glucocorticoid hormones are critical to respond and adapt to stress. Genetic variations in the gl... more Glucocorticoid hormones are critical to respond and adapt to stress. Genetic variations in the glucocorticoid receptor (GR) gene alter hypothalamicpituitary-adrenal (HPA) axis activity and associate with hypertension and susceptibility to metabolic disease. Here we test the hypothesis that reduced GR density alters blood pressure and glucose and lipid homeostasis and limits adaption to obesogenic diet. Heterozygous GR geo/؉ mice were generated from embryonic stem (ES) cells with a gene trap integration of a -galactosidase-neomycin phosphotransferase (geo) cassette into the GR gene creating a transcriptionally inactive GR fusion protein.
PLoS ONE, 2011
Background: Obesity and metabolic syndrome results from a complex interaction between genetic and... more Background: Obesity and metabolic syndrome results from a complex interaction between genetic and environmental factors. In addition to brain-regulated processes, recent genome wide association studies have indicated that genes highly expressed in adipose tissue affect the distribution and function of fat and thus contribute to obesity. Using a stratified transcriptome gene enrichment approach we attempted to identify adipose tissue-specific obesity genes in the unique polygenic Fat (F) mouse strain generated by selective breeding over 60 generations for divergent adiposity from a comparator Lean (L) strain.