Premium
Inhibition of Adenylyl Cyclase Type 5 Protects Against Obesity and Diabetes
Author(s) -
Ho David,
Iwatsubo Kosaku,
Yan Lin,
De Lorenzo Mariana,
Vatner Dorothy E.,
Vatner Stephen F.
Publication year - 2011
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.25.1_supplement.1095.17
Subject(s) - adenylyl cyclase , endocrinology , medicine , type 2 diabetes , obesity , forskolin , diabetes mellitus , chemistry , stimulation
We reported adenylyl cyclase type 5 (AC5) disruption (knock out, KO) increases food intake, but reduces weight, implying a metabolic profile consistent with protection against obesity and diabetes. We compared AC5 KO and wild type littermates (WTL) on a normal diet and examined the effects of a pharmacological inhibitor, specific for AC5, on WT mice on a high fat diet (HFD). The AC5 KO mice, despite eating more, weighed 12% less compared against WTL (P<0.05). At sacrifice, fat pads were isolated and adiposity index calculated. In the KO mice adiposity index was 34% less than WTL. The pharmacolgical inhibitor of AC5 (Vidarabine), was administered to WT mice via a subcutaneous osmotic pump (30 mg/kg/day). The specificity of this inhibitor was demonstrated by the degree of inhibition of forskolin‐stimulated AC activity in cardiac myocytes as follows: AC5 overexpression (OE) > WT, AC6 OE > AC5 KO. Mice on HFD treated with the AC5 inhibitor ate similarly but gained 41% less weight (p<0.05), compared to vehicle treated mice and the adiposity index was reduced by 30% (p<0.05), with a 32% reduction in visceral fat cell size (p<0.05). The AC5 inhibitor also normalized the impaired glucose tolerance in mice on the HFD. Thus, inhibiting AC5 reduces obesity and improves glucose tolerance, suggesting a potentially novel therapeutic approach to obesity and diabetes.