Fat-specific DsbA-L overexpression promotes adiponectin multimerization and protects mice from diet-induced obesity and insulin resistance.
The antidiabetic and antiatherosclerotic effects of adiponectin make it a desirable drug target for the treatment of metabolic and cardiovascular diseases. However, the adiponectin-based drug development approach turns out to be difficult due to extremely high serum levels of this adipokine. On the other hand, a significant correlation between adiponectin multimerization and its insulin-sensitizing effects has been demonstrated, suggesting a promising alternative therapeutic strategy. Here we show that transgenic mice overexpressing disulfide bond A oxidoreductase-like protein in fat (fDsbA-L) exhibited increased levels of total and the high-molecular-weight form of adiponectin compared with wild-type (WT) littermates. The fDsbA-L mice also displayed resistance to diet-induced obesity, insulin resistance, and hepatic steatosis compared with WT control mice. The protective effects of DsbA-L overexpression on diet-induced insulin resistance, but not increased body weight and fat cell size, were significantly decreased in adiponectin-deficient fDsbA-L mice (fDsbA-L/Ad(-/-)). In addition, the fDsbA-L/Ad(-/-) mice displayed greater activity and energy expenditure compared with adiponectin knockout mice under a high-fat diet. Taken together, our results demonstrate that DsbA-L protects mice from diet-induced obesity and insulin resistance through adiponectin-dependent and independent mechanisms. In addition, upregulation of DsbA-L could be an effective therapeutic approach for the treatment of obesity and its associated metabolic disorders.
Department of Pharmacology, University of Texas Health Science Center at San Antonio (UTHSCSA), San Antonio, TX, USA.
Meilian
M
Liu
Ruihua
R
Xiang
Sarah Ann
SA
Wilk
Ning
N
Zhang
Lauren B
LB
Sloane
Kian
K
Azarnoush
Lijun
L
Zhou
Hongzhi
H
Chen
Guangda
G
Xiang
Christi A
CA
Walter
Steven N
SN
Austad
Nicolas
N
Musi
Ralph A
RA
DeFronzo
Reto
R
Asmis
Philipp E
PE
Scherer
Lily Q
LQ
Dong
Feng
F
Liu
D052242:Adiponectin / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D000273:Adipose Tissue / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D059305:Diet, High-Fat / Q000009:adverse effects*; D060467:Disease Resistance; D004734:Energy Metabolism; D005234:Fatty Liver / Q000209:etiology / Q000517:prevention & control; D005982:Glutathione Transferase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D007333:Insulin Resistance; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D058990:Molecular Targeted Therapy; D008970:Molecular Weight; D065626:Non-alcoholic Fatty Liver Disease; D009765:Obesity / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D009928:Organ Specificity; D010101:Oxygen Consumption; D055550:Protein Stability; D015854:Up-Regulation
D052242:Adiponectin; C499919:Adipoq protein, mouse; D005982:Glutathione Transferase; C568627:glutathione transferase kappa, mouse