"Calpain Inhibition Attenuates Adipose Tissue Inflammation and Fibrosis in Diet-induced Obese Mice"

Latha Muniappan1, Aida Javidan1, Weihua Jiang1, Shayan Mohammadmoradi 1, Jessica J.
Moorleghen1, Wendy S. Katz1, Anju Balakrishnan1, Deborah A. Howatt1 & Venkateswaran
Subramanian1,2
Adipose tissue macrophages have been proposed as a link between obesity and insulin resistance.
However, the mechanisms underlying these processes are not completely defined. Calpains are calciumdependent
neutral cysteine proteases that modulate cellular function and have been implicated in
various inflammatory diseases. To define whether activated calpains influence diet-induced obesity
and adipose tissue macrophage accumulation, mice that were either wild type (WT) or overexpressing
calpastatin (CAST Tg), the endogenous inhibitor of calpains were fed with high (60% kcal) fat diet for
16 weeks. CAST overexpression did not influence high fat diet-induced body weight and fat mass gain
throughout the study. Calpain inhibition showed a transient improvement in glucose tolerance at 5
weeks of HFD whereas it lost this effect on glucose and insulin tolerance at 16 weeks HFD in obese mice.
However, CAST overexpression significantly reduced adipocyte apoptosis, adipose tissue collagen and
macrophage accumulation as detected by TUNEL, Picro Sirius and F4/80 immunostaining, respectively.
CAST overexpression significantly attenuated obesity-induced inflammatory responses in adipose
tissue. Furthermore, calpain inhibition suppressed macrophage migration to adipose tissue in vitro.
The present study demonstrates a pivotal role for calpains in mediating HFD-induced adipose tissue
remodeling by influencing multiple functions including apoptosis, fibrosis and inflammation.

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