Reduction of hepatic and adipose tissue glucocorticoid receptor expression with antisense oligonucleotides improves hyperglycemia and hyperlipidemia in diabetic rodents without causing systemic glucocorticoid antagonism.
Glucocorticoids (GCs) increase hepatic gluconeogenesis and play an important role in the regulation of hepatic glucose output. Whereas systemic GC inhibition can alleviate hyperglycemia in rodents and humans, it results in adrenal insufficiency and stimulation of the hypothalamic-pituitary-adrenal axis. In the present study, we used optimized antisense oligonucleotides (ASOs) to cause selective reduction of the glucocorticoid receptor (GCCR) in liver and white adipose tissue (WAT) and evaluated the resultant changes in glucose and lipid metabolism in several rodent models of diabetes. Treatment of ob/ob mice with GCCR ASOs for 4 weeks resulted in approximately 75 and approximately 40% reduction in GCCR mRNA expression in liver and WAT, respectively. This was accompanied by approximately 65% decrease in fed and approximately 30% decrease in fasted glucose levels, a 60% decrease in plasma insulin concentration, and approximately 20 and 35% decrease in plasma resistin and tumor necrosis factor-alpha levels, respectively. Furthermore, GCCR ASO reduced hepatic glucose production and inhibited hepatic gluconeogenesis in liver slices from basal and dexamethasone-treated animals. In db/db mice, a similar reduction in GCCR expression caused approximately 40% decrease in fed and fasted glucose levels and approximately 50% reduction in plasma triglycerides. In ZDF and high-fat diet-fed streptozotocin-treated (HFD-STZ) rats, GCCR ASO treatment caused approximately 60% reduction in GCCR expression in the liver and WAT, which was accompanied by a 40-70% decrease in fasted glucose levels and a robust reduction in plasma triglyceride, cholesterol, and free fatty acids. No change in circulating corticosterone levels was seen in any model after GCCR ASO treatment. To further demonstrate that GCCR ASO does not cause systemic GC antagonism, normal Sprague-Dawley rats were challenged with dexamethasone after treating with GCCR ASO. Dexamethasone increased the expression of GC-responsive genes such as PEPCK in the liver and decreased circulating lymphocytes. GCCR ASO treatment completely inhibited the increase in dexamethasone-induced PEPCK expression in the liver without causing any change in the dexamethasone-induced lymphopenia. These studies demonstrate that tissue-selective GCCR antagonism with ASOs may be a viable therapeutic strategy for the treatment of the metabolic syndrome.
Watts
Lynnetta M
LM
Executive Antisense Drug Discovery, Isis Pharmaceuticals, 2292, Faraday Ave., Carlsbad, CA 92008, USA.
Manchem
Vara Prasad
VP
Leedom
Thomas A
TA
Rivard
Amber L
AL
McKay
Robert A
RA
Bao
Dingjiu
D
Neroladakis
Teri
T
Monia
Brett P
BP
Bodenmiller
Diane M
DM
Cao
Julia Xiao-Chun
JX
Zhang
Hong Yan
HY
Cox
Amy L
AL
Jacobs
Steven J
SJ
Michael
M Dodson
MD
Sloop
Kyle W
KW
Bhanot
Sanjay
S
D000273:Adipose Tissue / Q000378:metabolism*; D000818:Animals; D003907:Dexamethasone / Q000494:pharmacology; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D005938:Glucocorticoids / Q000378:metabolism; D006943:Hyperglycemia / Q000188:drug therapy; D006949:Hyperlipidemias / Q000188:drug therapy; D008099:Liver / Q000378:metabolism*; D008231:Lymphopenia / Q000139:chemically induced / Q000503:physiopathology; D051379:Mice; D008820:Mice, Obese; D020320:Oligoribonucleotides, Antisense / Q000494:pharmacology*; D010902:Pituitary Gland / Q000187:drug effects / Q000378:metabolism; D011333:Pro-Opiomelanocortin / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011965:Receptors, Glucocorticoid / Q000378:metabolism*
D005938:Glucocorticoids; D020320:Oligoribonucleotides, Antisense; D012333:RNA, Messenger; D011965:Receptors, Glucocorticoid; D011333:Pro-Opiomelanocortin; D003907:Dexamethasone