Adipocyte integrin-linked kinase plays a key role in the development of diet-induced adipose insulin resistance in male mice

Abstract

Objective Increased deposition of the extracellular matrix (ECM) in adipose tissue (AT) during obesity contributes to insulin resistance. The integrin receptors transmit changes in the extracellular environment causing corresponding intracellular adaptations. Integrin-linked kinase (ILK), an adaptor protein, is a central hub for intracellular signaling of integrins. This study determined the role of ILK in adipose function and insulin resistance. Methods The pathogenic role of ILK in obesity and insulin resistance was studied in human adipose tissue and adipocyte-specific ILK-deficient mice (ILK lox/lox AdCre ). ILK lox/lox AdCre mice together with wild-type littermates (ILK lox/lox ) were fed a chow diet or 60% high-fat (HF) diet for 16 weeks. In vivo insulin sensitivity was determined by hyperinsulinemic-euglycemic clamps. Results AT ILK expression was increased by HF diet feeding in mice and increased in visceral fat of morbidly obese humans. The HF-fed ILK lox/lox AdCre mice displayed reduced fat mass and improved glucose tolerance relative to the HF-fed ILK lox/lox mice. During a hyperinsulinemic-euglycemic clamp, the HF-fed ILK lox/lox AdCre mice exhibited partially improved insulin resistance in AT. Lipolysis was suppressed to a greater extent by insulin and glucose uptake in brown AT (BAT) increased. Increased inhibition of lipolysis may have been attributed to increased vascularization in white AT, while increased glucose uptake in BAT was associated with increased Akt phosphorylation and P38/JNK dephosphorylation. Notably, AT insulin sensitivity in lean mice was not affected by ILK deletion. Moreover, reduced fat mass in the HF-fed ILK lox/lox AdCre mice may have been attributed to decreased free fatty acid uptake into adipocytes via the downregulation of CD36 gene expression. Consistent with the results in the mice, knockdown and knockout of ILK in 3T3-L1 cells decreased lipid accumulation and CD36 gene expression during adipogenesis. Conclusions These data show that adipocyte ILK is important for regulating HF diet-mediated insulin resistance in AT in a manner consistent with AT function.

Integrin-Linked Kinase Reduces H3K9 Trimethylation to Enhance Herpes Simplex Virus 1 Replication

“…To confirm if ILK enhances HSV-1 replication in other cell types, we attempted to establish ILK knockdown in ARPE-19 cells but failed, suggesting that ILK regulates cell survival in a manner specific to cell types. The results are consistent with previous studies showing that ILK is required for the proliferation of T cells and chondrocytes, but not adipocytes and muscles in mice ( Grashoff et al., 2003 ; Liu et al., 2005 ; Kang et al., 2016 ; Bugler-Lamb et al., 2021 ). Therefore, we transfected SK-N-SH and ARPE-19 cells with specific siRNA targeting ILK coding sequence (si ILK ).…”

The integrin beta1 modulator Tirofiban prevents adipogenesis and obesity by the overexpression of integrin-linked kinase: a pre-clinical approach in vitro and in vivo

“…Together with the present work, our results support the hypothesis that ILK expression is decreased during the development of obesity and WAT transgenic downregulation of ILK (in cKDILK) exacerbates the obesity-related symptoms. The opposite hypothesis has been stated in Bugler-Lamb´s work [ 38 ], where ILK expression was increased by a long-term HFD and the use of adipocyte-specific ILK-deficient mice displayed reduced fat mass and improvement of glucose tolerance, as the in vitro knockdown of ILK in 3T3-L1 cells decreased lipid accumulation in their work. The differences of both methodological and conceptual approaches between Bugler-Lamb´s models and ours are several and may explain the apparently contradictory results between studies.…”

“…Some publications have timidly highlighted changes in ILK during adipogenesis in stem cells [ 33 – 35 ]. Few recent publications, including ours, have described ILK as a mediator during insulin-resistance and WAT remodeling in cells and mice models [ 36 – 38 ]. Most INT-target drugs are based on the amino acid consensus motif Arg-Gly-Asp (RGD), featured in ECM proteins and disintegrins from snakes venom [ 39 ].…”

SERPINA3C ameliorates adipose tissue inflammation through the Cathepsin G/Integrin/AKT pathway

“…Because adipose SERPINA3C was found to play protective role against insulin resistance in our study, the involvement and mechanism of β1 Integrin in the regulation of adipose tissue metabolism by SERPINA3C was then investigated. β1 Integrin is known to form heterodimers with α5 Integrin to activate AKT signaling [ 44 , [46] , [47] , [48] , [49] , [50] , [51] ]. We examined α5 Integrin and β1 Integrin protein expressions in KO and AAV-SERPINA3C mice.…”