TY - JOUR
T1 - Inhibition of Sam68 triggers adipose tissue browning
AU - Zhou, Junlan
AU - Cheng, Min
AU - Boriboun, Chan
AU - Ardehali, Mariam M.
AU - Jiang, Changfei
AU - Liu, Qinghua
AU - Han, Shuling
AU - Goukassian, David A.
AU - Tang, Yao Liang
AU - Zhao, Ting C.
AU - Zhao, Ming
AU - Cai, Lu
AU - Richard, Stéphane
AU - Kishore, Raj
AU - Qin, Gangjian
N1 - Publisher Copyright:
© 2015 Society for Endocrinology Printed in Great Britain.
PY - 2015
Y1 - 2015
N2 - Obesity is associated with insulin resistance and type 2 diabetes; molecular mechanisms that promote energy expenditure can be utilized for effective therapy. Src-associated in mitosis of 68 kDa (Sam68) is potentially significant, because knockout (KO) of Sam68 leads to markedly reduced adiposity. In the present study, we sought to determine the mechanism by which Sam68 regulates adiposity and energy homeostasis.We first found that Sam68 KO mice have a significantly reduced body weight as compared to controls, and the difference is explained entirely by decreased adiposity. Interestingly, these effects were not mediated by a difference in food intake; rather, they were associated with enhanced physical activity. When they were fed a high-fat diet, Sam68 KO mice gained much less body weight and fat mass than their WT littermates did, and they displayed an improved glucose and insulin tolerance. In Sam68 KO mice, the brown adipose tissue (BAT), inguinal, and epididymal depots were smaller, and their adipocytes were less hypertrophied as compared to their WT littermates. The BAT of Sam68 KO mice exhibited reduced lipid stores and expressed higher levels of Ucp1 and key thermogenic and fatty acid oxidation genes. Similarly, depots of inguinal and epididymal white adipose tissue (WAT) in Sam68 KO mice appeared browner, their multilocular Ucp1-positive cells were much more abundant, and the expression of Ucp1, Cidea, Prdm16, and Ppargc1a genes was greater as compared to WT controls, which suggests that the loss of Sam68 also promotes WAT browning. Furthermore, in all of the fat depots of the Sam68 KO mice, the expression of M2 macrophage markers was up-regulated, and that of M1 markers was down-regulated. Thus, Sam68 plays a crucial role in controlling thermogenesis and may be targeted to combat obesity and associated disorders.
AB - Obesity is associated with insulin resistance and type 2 diabetes; molecular mechanisms that promote energy expenditure can be utilized for effective therapy. Src-associated in mitosis of 68 kDa (Sam68) is potentially significant, because knockout (KO) of Sam68 leads to markedly reduced adiposity. In the present study, we sought to determine the mechanism by which Sam68 regulates adiposity and energy homeostasis.We first found that Sam68 KO mice have a significantly reduced body weight as compared to controls, and the difference is explained entirely by decreased adiposity. Interestingly, these effects were not mediated by a difference in food intake; rather, they were associated with enhanced physical activity. When they were fed a high-fat diet, Sam68 KO mice gained much less body weight and fat mass than their WT littermates did, and they displayed an improved glucose and insulin tolerance. In Sam68 KO mice, the brown adipose tissue (BAT), inguinal, and epididymal depots were smaller, and their adipocytes were less hypertrophied as compared to their WT littermates. The BAT of Sam68 KO mice exhibited reduced lipid stores and expressed higher levels of Ucp1 and key thermogenic and fatty acid oxidation genes. Similarly, depots of inguinal and epididymal white adipose tissue (WAT) in Sam68 KO mice appeared browner, their multilocular Ucp1-positive cells were much more abundant, and the expression of Ucp1, Cidea, Prdm16, and Ppargc1a genes was greater as compared to WT controls, which suggests that the loss of Sam68 also promotes WAT browning. Furthermore, in all of the fat depots of the Sam68 KO mice, the expression of M2 macrophage markers was up-regulated, and that of M1 markers was down-regulated. Thus, Sam68 plays a crucial role in controlling thermogenesis and may be targeted to combat obesity and associated disorders.
KW - Adipocyte
KW - Insulin
KW - Metabolism
KW - Obesity
UR - http://www.scopus.com/inward/record.url?scp=84932132893&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84932132893&partnerID=8YFLogxK
U2 - 10.1530/JOE-14-0727
DO - 10.1530/JOE-14-0727
M3 - Article
C2 - 25934704
AN - SCOPUS:84932132893
SN - 0022-0795
VL - 225
SP - 181
EP - 189
JO - Journal of Endocrinology
JF - Journal of Endocrinology
IS - 3
ER -