Tissue-specific postprandial clearance is the major determinant of PPARgamma-induced triglyceride lowering in the rat.
Peroxisome proliferator-activated receptor-gamma (PPARgamma) agonism potently reduces circulating triglycerides (TG) in rodents and more modestly so in humans. This study aimed to quantify in vivo the relative contribution of hepatic VLDL-TG secretion and tissue-specific TG clearance to such action. Rats were fed an obesogenic diet, treated with the PPARgamma full agonist COOH (30 mg.kg(-1).day(-1)) for 3 wk, and studied in both the fasted and refed (fat-free) states. Hepatic VLDL-TG secretion rate was not affected by chronic COOH in the fasted state and was only modestly decreased (-30%) in refed rats. In contrast, postprandial VLDL-TG clearance was increased 2.6-fold by COOH, which concomitantly stimulated adipose tissue TG-derived lipid uptake and one of its major determinants, lipoprotein lipase (LPL) activity, in a highly depot-specific manner. TG-derived lipid uptake and LPL were indeed strongly increased in subcutaneous inguinal white adipose tissue and in brown adipose tissue, independently of the nutritional state, whereas of the three visceral fat depots examined (epididymal, retroperitoneal, mesenteric) only the latter responded consistently to COOH. Robust correlations (0.5 < r < 0.9) were observed between TG-derived lipid uptake and LPL in adipose tissues. The agonist did not increase LPL in muscle, and its enhancing action on postprandial muscle lipid uptake appeared to be mediated by post-LPL processes involving increased expression of fatty acid binding/transport proteins (aP2, likely in infiltrated adipocytes, FAT/CD36, and FATP-1). The study establishes in a diet-induced obesity model the major contribution of lipid uptake by specific, metabolically safe adipose depots to the postprandial hypotriglyceridemic action of PPARgamma agonism, and suggests a key role for LPL therein.
Laplante
Mathieu
M
Laval Hospital Research Center, Faculty of Medicine, Laval Univ., 2725 Ch Sainte-Foy, Québec, QC, Canada G1V 4G5.
Festuccia
William T
WT
Soucy
Geneviève
G
Blanchard
Pierre-Gilles
PG
Renaud
Alexandra
A
Berger
Joel P
JP
Olivecrona
Gunilla
G
Deshaies
Yves
Y
D000085:Acetates / Q000494:pharmacology*; D052436:Adipose Tissue, White / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D000818:Animals; D001786:Blood Glucose / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D004195:Disease Models, Animal; D015536:Down-Regulation; D004435:Eating / Q000187:drug effects; D050556:Fatty Acid-Binding Proteins / Q000378:metabolism; D005230:Fatty Acids, Nonesterified / Q000097:blood; D005990:Glycerol / Q000097:blood; D000960:Hypolipidemic Agents / Q000494:pharmacology*; D007211:Indoles / Q000494:pharmacology*; D007328:Insulin / Q000097:blood; D008071:Lipoprotein Lipase / Q000378:metabolism; D008079:Lipoproteins, VLDL / Q000097:blood / Q000378:metabolism*; D008099:Liver / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D008297:Male; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism; D009752:Nutritional Status; D009765:Obesity / Q000188:drug therapy* / Q000378:metabolism; D047495:PPAR gamma / Q000819:agonists* / Q000378:metabolism; D019518:Postprandial Period; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors; D014280:Triglycerides / Q000097:blood / Q000378:metabolism*
C483845:2-(2-(4-phenoxy-2-propylphenoxy)ethyl)indole-5-acetic acid; D000085:Acetates; D001786:Blood Glucose; D050556:Fatty Acid-Binding Proteins; D005230:Fatty Acids, Nonesterified; D000960:Hypolipidemic Agents; D007211:Indoles; D007328:Insulin; D008079:Lipoproteins, VLDL; D047495:PPAR gamma; D014280:Triglycerides; C030106:very low density lipoprotein triglyceride; D008071:Lipoprotein Lipase; D005990:Glycerol