title: Peroxisome proliferator-activated receptor-alpha-null mice have increased white adipose tissue glucose utilization, GLUT4, and fat mass: Role in liver and brain.
abstract: Activation of the peroxisome proliferator-activated receptor (PPAR)-alpha increases lipid catabolism and lowers the concentration of circulating lipid, but its role in the control of glucose metabolism is not as clearly established. Here we compared PPARalpha knockout mice with wild type and confirmed that the former developed hypoglycemia during fasting. This was associated with only a slight increase in insulin sensitivity but a dramatic increase in whole-body and adipose tissue glucose use rates in the fasting state. The white sc and visceral fat depots were larger due to an increase in the size and number of adipocytes, and their level of GLUT4 expression was higher and no longer regulated by the fed-to-fast transition. To evaluate whether these adipocyte deregulations were secondary to the absence of PPARalpha from liver, we reexpresssed this transcription factor in the liver of knockout mice using recombinant adenoviruses. Whereas more than 90% of the hepatocytes were infected and PPARalpha expression was restored to normal levels, the whole-body glucose use rate remained elevated. Next, to evaluate whether brain PPARalpha could affect glucose homeostasis, we activated brain PPARalpha in wild-type mice by infusing WY14643 into the lateral ventricle and showed that whole-body glucose use was reduced. Hence, our data show that PPARalpha is involved in the regulation of glucose homeostasis, insulin sensitivity, fat accumulation, and adipose tissue glucose use by a mechanism that does not require PPARalpha expression in the liver. By contrast, activation of PPARalpha in the brain stimulates peripheral glucose use. This suggests that the alteration in adipocyte glucose metabolism in the knockout mice may result from the absence of PPARalpha in the brain.
authors.affiliation: Unit Mixté de Recherche, 5018, Centre National de la Recherche Scientifique-University Paul Sabatier, IFR 31, Bt L1 Rue J. Poulhès, 31403 Toulouse, France.
authors.forename: Claude
authors.initials: C
authors.lastname: Knauf
authors.forename: Jennifer
authors.initials: J
authors.lastname: Rieusset
authors.forename: Marc
authors.initials: M
authors.lastname: Foretz
authors.forename: Patrice D
authors.initials: PD
authors.lastname: Cani
authors.forename: Marc
authors.initials: M
authors.lastname: Uldry
authors.forename: Masaya
authors.initials: M
authors.lastname: Hosokawa
authors.forename: Estelle
authors.initials: E
authors.lastname: Martinez
authors.forename: Matthieu
authors.initials: M
authors.lastname: Bringart
authors.forename: Aurélie
authors.initials: A
authors.lastname: Waget
authors.forename: Sander
authors.initials: S
authors.lastname: Kersten
authors.forename: Béatrice
authors.initials: B
authors.lastname: Desvergne
authors.forename: Sandrine
authors.initials: S
authors.lastname: Gremlich
authors.forename: Walter
authors.initials: W
authors.lastname: Wahli
authors.forename: Josiane
authors.initials: J
authors.lastname: Seydoux
authors.forename: Nathalie M
authors.initials: NM
authors.lastname: Delzenne
authors.forename: Bernard
authors.initials: B
authors.lastname: Thorens
authors.forename: Rémy
authors.initials: R
authors.lastname: Burcelin
mesh_terms: D017667:Adipocytes / Q000166:cytology / Q000378:metabolism; D000273:Adipose Tissue / Q000737:chemistry / Q000378:metabolism*; D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D001823:Body Composition; D001921:Brain / Q000187:drug effects / Q000502:physiology*; D048429:Cell Size; D005215:Fasting; D005260:Female; D005947:Glucose / Q000378:metabolism*; D051275:Glucose Transporter Type 4 / Q000032:analysis*; D022781:Hepatocytes / Q000378:metabolism; D007031:Hypothalamus / Q000737:chemistry; D008099:Liver / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009479:Neuropeptides / Q000235:genetics; D047493:PPAR alpha / Q000172:deficiency* / Q000502:physiology; D020025:Peroxisome Proliferators / Q000008:administration & dosage; D011743:Pyrimidines / Q000008:administration & dosage; D012333:RNA, Messenger / Q000032:analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D001786:Blood Glucose; D051275:Glucose Transporter Type 4; D009479:Neuropeptides; D047493:PPAR alpha; D020025:Peroxisome Proliferators; D011743:Pyrimidines; D012333:RNA, Messenger; C495693:Slc2a4 protein, mouse; C006253:pirinixic acid; D005947:Glucose