PT  - JOURNAL ARTICLE
AU  - Tianlun Wang
AU  - Sonia Villegas
AU  - Yujin Huang
AU  - Steve K. White
AU  - Clarence Ahlem
AU  - Min Lu
AU  - Jerrold M. Olefsky
AU  - Chris Reading
AU  - James M. Frincke
AU  - David Alleva
AU  - Jaime Flores-Riveros
TI  - Amelioration of Glucose Intolerance by the Synthetic Androstene HE3286: Link to Inflammatory Pathways
AID  - 10.1124/jpet.109.161182
DP  - 2010 Apr 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 70--80
VI  - 333
IP  - 1
4099  - http://jpet.aspetjournals.org/content/333/1/70.short
4100  - http://jpet.aspetjournals.org/content/333/1/70.full
SO  - J Pharmacol Exp Ther2010 Apr 01; 333
AB  - 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.