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Download filePinch Loss Ameliorates Obesity, Glucose Intolerance and Fatty Liver by Modulating Adipocyte Apoptosis in Mice
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posted on 2021-08-11, 14:07 authored by Huanqing Gao, Yiming Zhong, Zhen Ding, Sixiong Lin, Xiaoting Hou, Wanze Tang, Xiaoqian Zhou, Xuenong Zou, Jie Shao, Fan Yang, Xiaochun Bai, Chuanju Liu, Huiling Cao, Guozhi XiaoThe mammalian focal
adhesion proteins Pinch1/2 activate integrins and promote cell-ECM adhesion and
migration; however, their roles in adipose tissue and metabolism are unclear. Here
we find that high fat diet (HFD) feeding dramatically increases expression of
Pinch1/2 proteins in white adipose tissues (WAT)
in mice. Furthermore, expression of
Pinch1 is largely up-regulated in WAT in the Leptin-deficient ob/ob type 2
diabetic mice and obese humans. While mice with the loss of Pinch1 in
adipocytes or global Pinch2 do not display any notable phenotypes, deleting
Pinch1 in adipocytes and Pinch2 globally significantly decreases body weight
and WAT, but not brown adipose
tissue (BAT), mass in HFD-, but not normal chow diet (NCD)-, fed mice. Pinch
loss ameliorates HFD-induced glucose intolerance
and fatty liver. After HFD challenge, Pinch loss slightly, but
significantly, accelerates energy expenditure. While
Pinch loss decreases adipocyte size and alters adipocyte size distribution, it greatly accelerates cell apoptosis primarily in epididymal WAT and to a less extent
subcutaneous WAT. In vitro studies demonstrate that Pinch loss accelerates adipocyte apoptosis by activating the
Bim/Caspase-8 pathway. In
vivo, genetic ablation of Caspase-8 expression in adipocytes essentially abolishes
the ameliorating effects of Pinch deficiency on obesity, glucose intolerance
and fatty liver in mice. Thus, we demonstrate a
previously unknown function of Pinch in control of adipose mass, glucose and
fat metabolism via modulation of adipocyte apoptosis. We may define a novel
target for the prevention and treatment of metabolic diseases, such as obesity
and diabetics.