1: Endocrinology. 2006 Sep;147(9):4067-78. Epub 2006 Jun 15.

Peroxisome proliferator-activated receptor-alpha-null mice have increased white
adipose tissue glucose utilization, GLUT4, and fat mass: Role in liver and
brain.

Knauf C, Rieusset J, Foretz M, Cani PD, Uldry M, Hosokawa M, Martinez E,
Bringart M, Waget A, Kersten S, Desvergne B, Gremlich S, Wahli W, Seydoux J,
Delzenne NM, Thorens B, Burcelin R.

Unit Mixte de Recherche, 5018, Centre National de la Recherche
Scientifique-University Paul Sabatier, IFR 31, Bt L1 Rue J. Poulhes, 31403
Toulouse, France.

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.

PMID: 16777972 [PubMed - in process]

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