Specific down regulation of 3T3-L1 adipocyte differentiation by cell-permeable antisense HIF1alpha-oligonucleotide.
Hypoxia is a strong modulator of angiogenesis, accelerating adipose tissue expansion, suggesting that hypoxia inducible factor 1alpha (HIF1alpha) can be a novel target for anti-obesity. We conjugated antisense-HIF1alpha-oligonucleotide (ASO) with low molecular weight protamine (LMWP), a cell-penetrating peptide, to enhance its ability to block hypoxic-angiogenesis, thereby eliciting an anti-obesity effect. Nano-sized ASO-LMWP (AS-L) conjugates enhanced cellular uptake of ASO without yielding a cytotoxic effect and protected the ASO against enzymatic attack and chemical reduction. AS-L showed enhanced intra-cellular localization compared to naked ASO and the complex of ASO with lipofectamine during hypoxic-differentiation. Consequently AS-L induced significant down-regulation of leptin and VEGF gene expressions, thereby reducing fat accumulation in the cell. This proof-of-concept study shows that AS-L produces an inhibitory effect on adipogenesis and angiogenesis during differentiation, indicating LMWP mediated ASO delivery can potentially be a safe and promising treatment for obesity.
Park
Yoon Shin
YS
Department of Pharmaceutical Sciences, College of Pharmacy, The University of Michigan, 428, Church Street, Ann Arbor, Michigan 48109-1065, USA.
Huang
Yongzhuo
Y
Park
Yoon Jeong
YJ
David
Allan E
AE
White
Lindsay
L
He
Huining
H
Chung
Hee Sun
HS
Yang
Victor C
VC
D017667:Adipocytes / Q000187:drug effects* / Q000378:metabolism*; D050156:Adipogenesis / Q000187:drug effects* / Q000235:genetics / Q000502:physiology*; D000818:Animals; D002454:Cell Differentiation / Q000235:genetics; D015687:Cell Hypoxia / Q000235:genetics; D015536:Down-Regulation; D015870:Gene Expression; D000860:Hypoxia / Q000235:genetics / Q000378:metabolism; D020738:Leptin / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008970:Molecular Weight; D009765:Obesity / Q000235:genetics / Q000378:metabolism; D009841:Oligonucleotides / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D016376:Oligonucleotides, Antisense / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D010455:Peptides / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D011479:Protamines / Q000737:chemistry / Q000235:genetics / Q000378:metabolism
D020738:Leptin; D009841:Oligonucleotides; D016376:Oligonucleotides, Antisense; D010455:Peptides; D011479:Protamines