TY - JOUR
T1 - Direct Angiotensin II Type 2 Receptor Stimulation Ameliorates Insulin Resistance in Type 2 Diabetes Mice with PPAR gamma Activation
AU - Ohshima, Kousei
AU - Mogi, Masaki
AU - Jing, Fei
AU - Iwanami, Jun
AU - Tsukuda, Kana
AU - Min, Li-Juan
AU - Ogimoto, Akiyoshi
AU - Dahlof, Bjorn
AU - Steckelings, Ulrike Muscha
AU - Unger, Tomas
AU - Higaki, Jitsuo
AU - Horiuchi, Masatsugu
PY - 2012/11/14
Y1 - 2012/11/14
N2 - The role of angiotensin II type 2 (AT(2)) receptor stimulation in the pathogenesis of insulin resistance is still unclear. Therefore we examined the possibility that direct AT(2) receptor stimulation by compound 21 (C21) might contribute to possible insulin-sensitizing/anti-diabetic effects in type 2 diabetes (T2DM) with PPAR? activation, mainly focusing on adipose tissue.T2DM mice, KK-Ay, were subjected to intraperitoneal injection of C21 and/or a PPAR? antagonist, GW9662 in drinking water for 2 weeks. Insulin resistance was evaluated by oral glucose tolerance test, insulin tolerance test, and uptake of 2-[(3)H] deoxy-D-glucose in white adipose tissue. Morphological changes of adipose tissues as well as adipocyte differentiation and inflammatory response were examined.Treatment with C21 ameliorated insulin resistance in KK-Ay mice without influencing blood pressure, at least partially through effects on the PPAR? pathway. C21 treatment increased serum adiponectin concentration and decreased TNF-? concentration; however, these effects were attenuated by PPAR? blockade by co-treatment with GW9662. Moreover, we observed that administration of C21 enhanced adipocyte differentiation and PPAR? DNA-binding activity, with a decrease in inflammation in white adipose tissue, whereas these effects of C21 were attenuated by co-treatment with GW9662. We also observed that administration of C21 restored ? cell damage in diabetic pancreatic tissue.The present study demonstrated that direct AT(2) receptor stimulation by C21 accompanied with PPAR? activation ameliorated insulin resistance in T2DM mice, at least partially due to improvement of adipocyte dysfunction and protection of pancreatic ? cells.
AB - The role of angiotensin II type 2 (AT(2)) receptor stimulation in the pathogenesis of insulin resistance is still unclear. Therefore we examined the possibility that direct AT(2) receptor stimulation by compound 21 (C21) might contribute to possible insulin-sensitizing/anti-diabetic effects in type 2 diabetes (T2DM) with PPAR? activation, mainly focusing on adipose tissue.T2DM mice, KK-Ay, were subjected to intraperitoneal injection of C21 and/or a PPAR? antagonist, GW9662 in drinking water for 2 weeks. Insulin resistance was evaluated by oral glucose tolerance test, insulin tolerance test, and uptake of 2-[(3)H] deoxy-D-glucose in white adipose tissue. Morphological changes of adipose tissues as well as adipocyte differentiation and inflammatory response were examined.Treatment with C21 ameliorated insulin resistance in KK-Ay mice without influencing blood pressure, at least partially through effects on the PPAR? pathway. C21 treatment increased serum adiponectin concentration and decreased TNF-? concentration; however, these effects were attenuated by PPAR? blockade by co-treatment with GW9662. Moreover, we observed that administration of C21 enhanced adipocyte differentiation and PPAR? DNA-binding activity, with a decrease in inflammation in white adipose tissue, whereas these effects of C21 were attenuated by co-treatment with GW9662. We also observed that administration of C21 restored ? cell damage in diabetic pancreatic tissue.The present study demonstrated that direct AT(2) receptor stimulation by C21 accompanied with PPAR? activation ameliorated insulin resistance in T2DM mice, at least partially due to improvement of adipocyte dysfunction and protection of pancreatic ? cells.
U2 - 10.1371/journal.pone.0048387
DO - 10.1371/journal.pone.0048387
M3 - Article
SN - 1932-6203
VL - 7
JO - PLOS ONE
JF - PLOS ONE
IS - 11
M1 - e48387
ER -