ApoA1: mimetic peptide reverses adipocyte dysfunction in vivo and in vitro via an increase in heme oxygenase (HO-1) and Wnt10b.
Insulin resistance is a risk factor in the development of type 2 diabetes and is a major cause of atherosclerosis. Reduction in heme oxygenase (HO-1) has been shown to exacerbate vascular dysfunction and insulin resistance in obese mice and involves a decrease in adiponectin levels. Adiponectin is released from mesenchymal stem cell (MSC)-derived adipocytes, its levels are decreased in type 2 diabetes. We hypothesized that the apoA1 mimetic peptide, L-4F, will target the expression of the HO-1-adiponectin axis and reverse adipocyte dysfunction both in vivo and in vitro. The administration of L-4F [2 mg/Kg/daily (i.p.) for 4-week to 8-week-old obese (ob) mice restored adipocyte function, increased adiponectin release (p < 0.05) and decreased the levels of IL-1 and IL-6 (p < 0.05)]. These perturbations were associated with an increase in insulin sensitivity (p < 0.01 vs. untreated ob mice) and decreased glucose levels (309 + 42 vs. 201 + 8 mg/d after L-4F treatment). Treatment of both mesenchymal stem cell (MSC)-derived adipocytes with L-4F (50 μg/ml) increased adiponectin (p < 0.05), decreased IL-1 and IL-6 (p < 0.05) levels and increased MSC-derived adipocyte cell numbers by 50% in S phase (p < 0.05). MSC-derived adipocytes treated with L-4F increased WNT10b and decreased Peg 1/Mest. Inhibition of HO activity reversed the decrease in the adipogenic response gene, Peg 1/Mest. An increase of HO-1 expression by L-4F increased insulin-receptor phosphorylation. These findings support the hypothesis that L-4F increases early adipocyte markers, HO-1-adiponectin, WNT10b and decreases Peg1/Mest, negative regulators of adipocyte differentiation.
Department of Physiology & Pharmacology, University of Toledo College of Medicine, Toledo, OH, USA.
Luca
L
Vanella
Ming
M
Li
DongHyun
D
Kim
Giuseppe
G
Malfa
Lars
L
Bellner
Tomoko
T
Kawakami
Nader G
NG
Abraham
D017667:Adipocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D000818:Animals; D016632:Apolipoprotein A-I / Q000494:pharmacology*; D015153:Blotting, Western; D055396:Bone Morphogenetic Protein 2 / Q000378:metabolism; D002478:Cells, Cultured; D005434:Flow Cytometry; D051547:Heme Oxygenase-1 / Q000378:metabolism*; D007375:Interleukin-1 / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D008297:Male; D059630:Mesenchymal Stem Cells / Q000166:cytology; D051379:Mice; D010006:Osteoblasts / Q000166:cytology / Q000378:metabolism; D010455:Peptides / Q000494:pharmacology; D051153:Wnt Proteins / Q000378:metabolism*
D016632:Apolipoprotein A-I; C525719:Bmp2 protein, mouse; D055396:Bone Morphogenetic Protein 2; D007375:Interleukin-1; D015850:Interleukin-6; C472885:L-4F peptide; D010455:Peptides; D051153:Wnt Proteins; C102068:Wnt10b protein, mouse; D051547:Heme Oxygenase-1