Abstract
Insulin resistance, the major metabolic abnormality underlying type 2 diabetes, is associated with chronic inflammation and heavy macrophage infiltration in white adipose tissue (WAT). The therapeutic properties of the synthetic adrenal steroid Δ5-androstene-17α-ethynyl-3β,7β,17β-triol (HE3286) were characterized in metabolic disease models. Treatment of diabetic db/db mice with HE3286 suppressed progression to hyperglycemia and markedly improved glucose clearance. Similar effects were also observed in insulin-resistant, diet-induced obese C57BL/6J mice and genetically obese ob/ob mice. This effect appeared to be a consequence of reduced insulin resistance because HE3286 lowered blood insulin levels in db/db and ob/ob mice. Treatment with HE3286 was accompanied by suppressed expression of the prototype macrophage-attracting chemokine monocyte chemoattractant protein-1 in WAT, along with its cognate receptor C-C motif chemokine receptor-2. Exposure of mouse macrophages to HE3286 in vitro caused partial suppression of endotoxin (lipopolysaccharide)-induced nuclear factor κ-B (NF-κB)-sensitive reporter gene expression, NF-κB nuclear translocation, and NF-κB/p65 serine phosphorylation. Proinflammatory kinases, including IκB kinase, c-Jun NH2-terminal kinase, and p38, were also inhibited by HE3286. In ligand competition experiments HE3286 did not bind to classical sex steroid or corticosteroid receptors, including androgen receptor (AR), progesterone receptor, estrogen receptor (ER) α or ERβ, and glucocorticoid receptor (GR). Likewise, in cells expressing nuclear receptor-sensitive reporter genes HE3286 did not substantially stimulate transactivation of AR, ER, GR, or peroxisome proliferator-activated receptor (PPAR) α, PPARδ, and PPARγ. These findings indicate that HE3286 improves glucose homeostasis in diabetic and insulin-resistant mice and suggest that the observed therapeutic effects result from attenuation of proinflammatory pathways, independent of classic sex steroid receptors, corticosteroid receptors, or PPARs.
Footnotes
- Received September 1, 2009.
- Accepted January 8, 2010.
J.M.O. is a consultant for Hollis-Eden Pharmaceuticals, Inc., and J.M.O. and M.L. received a 1-year research grant (2007–2008) from Hollis-Eden Pharmaceuticals.
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
doi:10.1124/jpet.109.161182.
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ABBREVIATIONS:
- HE3286
- Δ5-androstene-17α-ethynyl-3β,7β,17β-triol
- DHEA
- dehydroepiandrosterone
- MCP-1
- monocyte chemoattractant protein-1
- LPS
- lipopolysaccharide
- NF-κB
- nuclear factor κ-B
- IκB
- inhibitor of κ-B protein
- IKK
- IκB kinase
- JNK
- c-Jun NH2-terminal kinase
- AR
- androgen receptor
- GR
- glucocorticoid receptor
- ER
- estrogen receptor
- PR
- progesterone receptor
- PPAR
- peroxisome proliferator-activated receptor
- WAT
- white adipose tissue
- TZD
- thiazolidinedione
- OGTT
- oral glucose tolerance test
- DIO
- diet-induced obese
- MAPK
- mitogen-activated protein kinase
- TLR4
- Toll-like receptor-4
- CCR2
- C-C motif chemokine receptor-2
- KO
- knockout
- DMEM
- Dulbecco's modified Eagle medium
- FBS
- fetal bovine serum
- RT
- reverse transcription
- PCR
- polymerase chain reaction
- DMSO
- dimethyl sulfoxide
- ERE
- estrogen response element
- GRE
- glucocorticoid receptor element.
- Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics
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