Dexamethasone induction of hypertension and diabetes is PPAR-alpha dependent in LDL receptor-null mice.
Hypertension and diabetes are common side effects of glucocorticoid treatment. To determine whether peroxisome proliferator-activated receptor-alpha (PPAR-alpha) mediates these sequelae, mice deficient in low-density lipoprotein receptor (Ldlr-/-), with (Ppara+/+) or without (Ppara-/-) PPAR-alpha, were treated chronically with dexamethasone. Ppara+/+, but not Ppara-/-, mice developed hyperglycemia, hyperinsulinemia and hypertension. Similar effects on glucose metabolism were seen in a different model using C57BL/6 mice. Hepatic gluconeogenic gene expression was increased and insulin-mediated suppression of endogenous glucose production was less effective in dexamethasone-treated Ppara+/+ mice. Adenoviral reconstitution of PPAR-alpha in the livers of nondiabetic, normotensive, dexamethasone-treated Ppara-/- mice induced hyperglycemia, hyperinsulinemia and increased gluconeogenic gene expression. It also increased blood pressure, renin activity, sympathetic nervous activity and renal sodium retention. Human hepatocytes treated with dexamethasone and the PPAR-alpha agonist Wy14,643 induced PPARA and gluconeogenic gene expression. These results identify hepatic activation of PPAR-alpha as a mechanism underlying glucocorticoid-induced insulin resistance.
Bernal-Mizrachi
Carlos
C
Department of Medicine, Washington University School of Medicine, St. Louis, Missouri 63110 USA.
Weng
Sherry
S
Feng
Chu
C
Finck
Brian N
BN
Knutsen
Russell H
RH
Leone
Teresa C
TC
Coleman
Trey
T
Mecham
Robert P
RP
Kelly
Daniel P
DP
Semenkovich
Clay F
CF
D000818:Animals; D002460:Cell Line; D008076:Cholesterol, HDL / Q000378:metabolism; D003907:Dexamethasone / Q000494:pharmacology*; D003920:Diabetes Mellitus / Q000378:metabolism*; D005938:Glucocorticoids / Q000494:pharmacology*; D005947:Glucose / Q000378:metabolism; D022781:Hepatocytes / Q000166:cytology / Q000502:physiology; D006801:Humans; D006973:Hypertension / Q000378:metabolism*; D007328:Insulin / Q000378:metabolism; D007668:Kidney / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D011973:Receptors, LDL / Q000235:genetics / Q000378:metabolism*; D012964:Sodium / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism*
D008076:Cholesterol, HDL; D005938:Glucocorticoids; D007328:Insulin; D018160:Receptors, Cytoplasmic and Nuclear; D011973:Receptors, LDL; D014157:Transcription Factors; D003907:Dexamethasone; D012964:Sodium; D005947:Glucose