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1.
PLoS One ; 13(8): e0202182, 2018.
Article in English | MEDLINE | ID: mdl-30106981

ABSTRACT

Fibroblast growth factor 21 (FGF21) is a hormone secreted by the liver in response to metabolic stress. In addition to its well-characterized effects on energy homeostasis, FGF21 has been shown to increase water intake in animals. In this study, we sought to further explore the effects of FGF21 on fluid homeostasis in rats. A single dose of a long-acting FGF21 analog, PF-05231023, significantly increased water consumption, which was accompanied by an elevation in urine output that appeared prior to a significant change in water intake. We observed that FGF21 rapidly and significantly increased heart rate and blood pressure in telemeter-implanted rats, before changes in urine output and water intake were observed. Our data suggest that sympathetic activation may contribute to the pathogenesis by which FGF21 increases blood pressure as the baroreceptor unloading induced reflex tachycardia was significantly elevated in FGF21-treated animals. However, FGF21 was still capable of causing hypertension in animals in which approximately 40% of the sympathetic post-ganglionic neurons were ablated. Our data suggest that FGF21-induced water intake is in fact secondary to diuresis, which we propose to be a compensatory mechanism engaged to alleviate the acute hypertension caused by FGF21.


Subject(s)
Antibodies, Monoclonal, Humanized/pharmacology , Blood Pressure/drug effects , Cardiovascular Agents/pharmacology , Diuresis/drug effects , Diuretics/pharmacology , Drinking/drug effects , Fibroblast Growth Factors/pharmacology , Animals , Baroreflex/drug effects , Baroreflex/physiology , Blood Pressure/physiology , Delayed-Action Preparations , Diuresis/physiology , Drinking/physiology , Drinking Water , Electrolytes/blood , Electrolytes/urine , Fibroblast Growth Factors/metabolism , Guanethidine/pharmacology , Heart Rate/drug effects , Heart Rate/physiology , Hypertension/chemically induced , Hypertension/metabolism , Kidney/drug effects , Kidney/metabolism , Male , Rats, Wistar
2.
Cell Metab ; 23(2): 344-9, 2016 Feb 09.
Article in English | MEDLINE | ID: mdl-26724861

ABSTRACT

Fibroblast growth factor 21 (FGF21) is a hormone induced by various metabolic stresses, including ketogenic and high-carbohydrate diets, that regulates energy homeostasis. In humans, SNPs in and around the FGF21 gene have been associated with macronutrient preference, including carbohydrate, fat, and protein intake. Here we show that FGF21 administration markedly reduces sweet and alcohol preference in mice and sweet preference in cynomolgus monkeys. In mice, these effects require the FGF21 co-receptor ß-Klotho in the central nervous system and correlate with reductions in dopamine concentrations in the nucleus accumbens. Since analogs of FGF21 are currently undergoing clinical evaluation for the treatment of obesity and type 2 diabetes, our findings raise the possibility that FGF21 administration could affect nutrient preference and other reward behaviors in humans.


Subject(s)
Alcohols/pharmacology , Fibroblast Growth Factors/metabolism , Food Preferences/drug effects , Taste/drug effects , Animals , Central Nervous System/drug effects , Central Nervous System/metabolism , Dopamine/metabolism , Haplorhini , Humans , Male , Mice, Inbred C57BL , Saccharin/pharmacology , Signal Transduction/drug effects
3.
Mol Cell Neurosci ; 20(1): 21-9, 2002 May.
Article in English | MEDLINE | ID: mdl-12056837

ABSTRACT

PTEN is a lipid phosphatase, and PTEN mutations are associated with gliomas, macrocephaly, and mental deficiencies. We have used PTEN +/- mice to assess PTEN's role in subventricular zone (SVZ) precursor cells. For cultured SVZ neurosphere cells, haploinsufficiency for PTEN increases phosphorylation of Akt and forkhead transcription factor and slightly enhances proliferation. Based on a filter penetration assay, PTEN +/- cells are substantially more migratory and invasive than +/+ cells. The +/- cells also are more resistant to H(2)O(2)-induced apoptosis. Analysis of PTEN +/- and +/+ mice by BrdU labeling reveals no difference in the rate of cell proliferation in the SVZ. Exit of BrdU-labeled cells from the SVZ and radial migration to the outer layers of the olfactory bulb are more rapid for +/- cells. These observations indicate that PTEN regulates SVZ precursor cell function and is particularly important for migration and apoptosis in response to oxidative stress.


Subject(s)
Apoptosis/physiology , Brain/growth & development , Brain/metabolism , Cell Division/physiology , Cell Movement/physiology , Neurons/metabolism , Phosphoric Monoester Hydrolases/deficiency , Protein Serine-Threonine Kinases , Stem Cells/metabolism , Tumor Suppressor Proteins/deficiency , Animals , Brain/cytology , Bromodeoxyuridine , Cell Count , Cerebral Ventricles/cytology , Cerebral Ventricles/growth & development , Cerebral Ventricles/metabolism , Female , Forkhead Transcription Factors , Male , Mice , Mice, Knockout , Neurons/cytology , Olfactory Bulb/cytology , Olfactory Bulb/growth & development , Olfactory Bulb/metabolism , Oxidative Stress/physiology , PTEN Phosphohydrolase , Phosphatidylinositol Phosphates/metabolism , Phosphoric Monoester Hydrolases/genetics , Proto-Oncogene Proteins/metabolism , Proto-Oncogene Proteins c-akt , Stem Cells/cytology , Transcription Factors/metabolism , Tumor Suppressor Proteins/genetics
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