Abstract
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 calcium-dependent 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.
Highlights
Using a pharmacological inhibitor and calpain-1 deficient mice, we demonstrated that calpain inhibition significantly attenuated inflammatory processes present in aortic vascular diseases such as angiotensin II (AngII)-induced abdominal aortic aneurysms (AAA) and atherosclerosis in mice[18,19]
Western blot analyses using antibodies against calpains showed that protein abundance of calpain-1 was slightly increased whereas the protein abundance of calpain-2 and calpain-4 were highly increased in epididymal white adipose tissue (EpiWAT) from high fat diet (HFD) fed obese mice compared to low fat diet (LFD) fed lean mice (Fig. 1A)
Using bone marrow-derived macrophages (BMDMs) harvested from wild type (WT) and CAST Tg mice, we examined the effect of CAST overexpression on macrophage migration towards monocyte chemoattractant, monocyte chemoattractant protein-1 (MCP-1), using an in vitro transwell migration assay[29]
Summary
Using a pharmacological inhibitor and calpain-1 deficient mice, we demonstrated that calpain inhibition significantly attenuated inflammatory processes present in aortic vascular diseases such as angiotensin II (AngII)-induced abdominal aortic aneurysms (AAA) and atherosclerosis in mice[18,19]. The beneficial effect of calpain inhibition was associated with reduction of macrophage accumulation, NF-kB mediated inflammation, and cytoskeletal protein, filamin A, fragmentation in the aorta[19]. The functional contributions of calpain activation in chronic adipose tissue inflammation, and macrophage infiltration under the condition of obesity remains to be elucidated. Using CAST transgenic mice, we demonstrate that calpain inhibition transiently improved glucose tolerance and resulted in decreased adipose tissue macrophage accumulation in obese mice. Calpain inhibition significantly modulated adipose tissue remodeling by influencing multiple functions including adipocyte apoptosis, fibrosis, inflammation and migratory properties of macrophages
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