PPAR-alpha-null mice are protected from high-fat diet-induced insulin resistance.
Peroxisome proliferator-activated receptor (PPAR)-alpha controls the expression of genes involved in lipid metabolism. PPAR-alpha furthermore participates to maintain blood glucose during acute metabolic stress, as shown in PPAR-alpha-null mice, which develop severe hypoglycemia when fasted. Here, we assessed a potential role for PPAR-alpha in glucose homeostasis in response to long-term high-fat feeding. When subjected to this nutritional challenge, PPAR-alpha-null mice remained normoglycemic and normoinsulinemic, whereas wild-type mice became hyperinsulinemic (190%; P < 0.05) and slightly hyperglycemic (120%; NS). Insulin tolerance tests (ITTs) and glucose tolerance tests (GTTs) were performed to evaluate insulin resistance (IR). Under standard diet, the response to both tests was similar in wild-type and PPAR-alpha-null mice. Under high-fat diet, however, the efficiency of insulin in ITT was reduced and the amount of hyperglycemia in GTT was increased only in wild-type and not in PPAR-alpha-null mice. The IR index, calculated as the product of the areas under glucose and insulin curves in GTT, increased fourfold in high-fat-fed wild-type mice, whereas it remained unchanged in PPAR-alpha-null mice. In contrast, PPAR-alpha deficiency allowed the twofold rise in adiposity and blood leptin levels elicited by the diet. Thus, the absence of PPAR-alpha dissociates IR from high-fat diet-induced increase in adiposity. The effects of PPAR-alpha deficiency on glucose homeostasis seem not to occur via the pancreas, because glucose-stimulated insulin secretion of islets was not influenced by the PPAR-alpha genotype. These data suggest that PPAR-alpha plays a role for the development of IR in response to a Western-type high-fat diet.
Guerre-Millo
M
M
Unit 465, Institut National de la Santé et de la Recherche Médicale (INSERM), Paris, France.
Rouault
C
C
Poulain
P
P
André
J
J
Poitout
V
V
Peters
J M
JM
Gonzalez
F J
FJ
Fruchart
J C
JC
Reach
G
G
Staels
B
B
D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D002217:Carbachol / Q000494:pharmacology; D004041:Dietary Fats / Q000008:administration & dosage*; D004357:Drug Synergism; D005215:Fasting; D005947:Glucose / Q000494:pharmacology; D005951:Glucose Tolerance Test; D006706:Homeostasis; D006946:Hyperinsulinism / Q000209:etiology / Q000517:prevention & control; D007003:Hypoglycemia / Q000235:genetics; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019308:Palmitic Acid / Q000494:pharmacology; D018160:Receptors, Cytoplasmic and Nuclear / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D014157:Transcription Factors / Q000172:deficiency* / Q000235:genetics / Q000502:physiology
D001786:Blood Glucose; D004041:Dietary Fats; D007328:Insulin; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D019308:Palmitic Acid; D002217:Carbachol; D005947:Glucose; D015056:1-Methyl-3-isobutylxanthine