Person: Flier, Jeffrey
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Flier
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Flier, Jeffrey
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Publication Fibroblast Growth Factor 21 (FGF21) Protects against High Fat Diet Induced Inflammation and Islet Hyperplasia in Pancreas(Public Library of Science, 2016) Singhal, Garima; Fisher, FFolliott; Chee, Melissa; Tan, Tze Guan; El Ouaamari, Abdelfattah; Adams, Andrew C.; Najarian, Robert M.; Kulkarni, Rohit N.; Benoist, Christophe; Flier, Jeffrey; Maratos-Flier, EleftheriaFibroblast growth factor 21 (FGF21) is an important endocrine metabolic regulator expressed in multiple tissues including liver and adipose tissue. Although highest levels of expression are in pancreas, little is known about the function of FGF21 in this tissue. In order to understand the physiology of FGF21 in the pancreas, we analyzed its expression and regulation in both acinar and islet tissues. We found that acinar tissue express 20-fold higher levels than that observed in islets. We also observed that pancreatic FGF21 is nutritionally regulated; a marked reduction in FGF21 expression was noted with fasting while obesity is associated with 3–4 fold higher expression. Acinar and islet cells are targets of FGF21, which when systemically administered, leads to phosphorylation of the downstream target ERK 1/2 in about half of acinar cells and a small subset of islet cells. Chronic, systemic FGF21 infusion down-regulates its own expression in the pancreas. Mice lacking FGF21 develop significant islet hyperplasia and periductal lymphocytic inflammation when fed with a high fat obesogenic diet. Inflammatory infiltrates consist of TCRb+ Thy1+ T lymphocytes with increased levels of Foxp3+ regulatory T cells. Increased levels of inflammatory cells were coupled with elevated expression of cytokines such as TNFα, IFNγ and IL1β. We conclude that FGF21 acts to limit islet hyperplasia and may also prevent pancreatic inflammation.Publication Irreproducibility of published bioscience research: Diagnosis, pathogenesis and therapy(Elsevier, 2016) Flier, JeffreyPublication Transplanted Hypothalamic Neurons Restore Leptin Signaling and Ameliorate Obesity in db/db Mice(American Association for the Advancement of Science (AAAS), 2011) Czupryn, A.; Zhou, Y.-D.; Chen, Xi; McNay, D.; Anderson, Matthew; Flier, Jeffrey; Macklis, JeffreyEvolutionarily old and conserved homeostatic systems in the brain, including hypothalamus, are organized into nuclear structures of heterogeneous and diverse neuron populations. To investigate whether such circuits can be functionally reconstituted by synaptic integration of similarly diverse populations of neurons, we generated physically chimeric hypothalami by micro-transplanting small numbers of embryonic enhanced green fluorescent protein-expressing, leptin-responsive hypothalamic cells into hypothalami of postnatal leptin receptor-deficient (db/db) mice that develop morbid obesity. Donor neurons differentiated and integrated as four distinct hypothalamic neuron subtypes, formed functional excitatory and inhibitory synapses, partially restored leptin responsiveness, and ameliorated hyperglycemia and obesity in db/db mice. These experiments serve as proof of concept that transplanted neurons can functionally reconstitute complex neuronal circuitry in the mammalian brain.Publication Polymerase I and Transcript Release Factor Regulates Lipolysis via a Phosphorylation-Dependent Mechanism(American Diabetes Association, 2011) Aboulaich, Nabila; Chui, Patricia C.; Asara, John; Flier, Jeffrey; Maratos-Flier, EleftheriaOBJECTIVE: Polymerase I and transcript release factor (PTRF) is a protein highly expressed in adipose tissue and is an integral structural component of caveolae. Here, we report on a novel role of PTRF in lipid mobilization. RESEARCH DESIGN AND METHODS: PTRF expression was examined in different adipose depots of mice during fasting, refeeding, and after administration of catecholamines and insulin. Involvement of PTRF during lipolysis was studied upon PTRF knockdown and overexpression and mutation of PTRF phosphorylation sites in 3T3-L1 adipocytes. RESULTS: PTRF expression in mouse white adipose tissue (WAT) is regulated by nutritional status, increasing during fasting and decreasing to baseline after refeeding. Expression of PTRF also is hormonally regulated because treatment of mice with insulin leads to a decrease in expression, whereas isoproterenol increases expression in WAT. Manipulation of PTRF levels revealed a role of PTRF in lipolysis. Lentiviral-mediated knockdown of PTRF resulted in a marked attenuation of glycerol release in response to isoproterenol. Conversely, overexpressing PTRF enhanced isoproterenol-stimulated glycerol release. Mass-spectrometric analysis revealed that PTRF is phosphorylated at multiple sites in WAT. Mutation of serine 42, threonine 304, or serine 368 to alanine reduced isoproterenol-stimulated glycerol release in 3T3-L1 adipocytes. CONCLUSIONS: Our study is the first direct demonstration for a novel adipose tissue–specific function of PTRF as a mediator of lipolysis and also shows that phosphorylation of PTRF is required for efficient fat mobilization.Publication Hormone Resistance in Diabetes and Obesity: Insulin, Leptin, and FGF21(YJBM, 2012) Flier, JeffreyThis an edited transcript of the Lee E. Farr Lecture given by Dr. Jeffrey Flier on May 8, 2012, at the culmination of the annual Student Research Day at the Yale School of Medicine. In this presentation, Dr. Flier discusses his and his wife’s research on insulin, leptin, and FGF21 in the context of his reflections upon his life’s work and his advice for young investigators.Publication Making Evolutionary Biology a Basic Science for Medicine(2009) Nesse, Randolph M.; Bergstrom, Carl T.; Ellison, Peter; Flier, Jeffrey; Gluckman, Peter; Govindaraju, Diddahally R.; Niethammer, Dietrich; Omenn, Gil S.; Perlman, Robert L.; Schwartz, Mark; Thomas, Mark G.; Stearns, Stephen C.; Valle, DavidNew applications of evolutionary biology in medicine are being discovered at an accelerating rate, but few physicians have sufficient educational background to utilize them fully. This article summarizes suggestions from several groups who have considered how evolutionary biology can be useful in medicine, what physicians should learn about it, and when and how they should learn it. Our general conclusion is that evolutionary biology is a crucial basic science for medicine. In addition to established evolutionary methods and topics, such as population genetics and pathogen evolution, the article also highlights questions about why natural selection leaves bodies vulnerable to disease. Knowledge about volution provides physicians with an integrative framework that links otherwise disparate bits of knowledge. It replaces the revalent view of bodies as machines with a biological view of bodies shaped by evolutionary processes. Like other basic sciences, evolutionary biology needs to be taught both before and during medical school. Most introductory biology courses are insufficient to establish competency in evolutionary biology. Premedical students need evolution courses, possibly ones that emphasize medically relevant aspects. In medical school, evolutionary biology should be taught as one of the basic medical sciences. This will require a course that reviews basic principles and specific medical applications, followed by an integrated presentation of evolutionary aspects that apply to each disease and organ system. Evolutionary biology is not just another topic vying for inclusion in the curriculum; it is an essential foundation for a biological understanding of health and disease.Publication Fibroblast growth factor 21 (FGF21) is robustly induced by ethanol and has a protective role in ethanol associated liver injury(Elsevier, 2017) Desai, Bhavna; Singhal, Garima; Watanabe, Mikiko; Stevanovic, Darko; Lundasen, Thomas; Fisher, ffolliott M.; Mather, Marie L.; Vardeh, Hilde; Douris, Nicholas; Adams, Andrew C.; Nasser, Imad; FitzGerald, Garret A.; Flier, Jeffrey; Skarke, Carsten; Maratos-Flier, EleftheriaObjective: Excess ethanol consumption has serious pathologic consequences. In humans, repeated episodes of binge drinking can lead to liver damage and have adverse effects on other organs such as pancreas and brain. Long term chronic consumption of ethanol can also result in progressive alcoholic liver disease and cirrhosis. Fibroblast growth factor 21 (FGF21) is a metabolic regulator with multiple physiologic functions. FGF21 is a novel biomarker for non-alcoholic fatty liver disease (NAFLD) in humans and limits hepatotoxicity in mice. Therefore, we explored the possibility that FGF21 plays a role in response to ethanol consumption in both humans and mice. Methods: We used a binge drinking paradigm in humans to examine the effect of acute ethanol consumption on circulating FGF21. We adapted this paradigm to evaluate the acute response to ethanol in mice. We then examined the role of FGF21 on liver pathology in two models of chronic ethanol consumption in both wild type (WT) mice and mice lacking FGF21 (FGF21-KO). Results: Acute ethanol consumption resulted in a robust induction of serum FGF21 after 6 h in both humans and mice. Serum ethanol peaked at 1 h in both species and was cleared by 6 h. Ethanol clearance was the same in WT and FGF21-KO mice, indicating that FGF21 does not play a major role in ethanol metabolism in a binge paradigm. When FGF21-KO mice were fed the Lieber–DeCarli diet, a high fat diet supplemented with ethanol, a higher mortality was observed compared to WT mice after 16 days on the diet. When FGF21-KO mice consumed 30% ethanol in drinking water, along with a normal chow diet, there was no mortality observed even after 16 weeks, but the FGF21-KO mice had significant liver pathology compared to WT mice. Conclusions: Acute or binge ethanol consumption significantly increases circulating FGF21 levels in both humans and mice. However, FGF21 does not play a role in acute ethanol clearance. In contrast, chronic ethanol consumption in the absence of FGF21 is associated with significant liver pathology alone or in combination with excess mortality, depending on the type of diet consumed with ethanol. This suggests that FGF21 protects against long term ethanol induced hepatic damage and may attenuate progression of alcoholic liver disease. Further study is required to assess the therapeutic potential of FGF21 in the treatment of alcoholic liver disease.