Integrin Linked Kinase (ILK) Downregulation as an Early Event During the Development of Metabolic Alterations in a Short-Term High Fat Diet Mice Model

Hatem-Vaquero, Marco; Griera, Mercedes; García‐Ayuso, Diego; Campillo, Sofía; Bohórquez, Lourdes; Calleros, Laura; Rodríguez‐Puyol, Diego; Rodrı́guez-Puyol, Manuel; Garcı́a, Soledad

doi:10.33594/000000206

Cited by 7 publications

(20 citation statements)

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“…and rapidly dropped to undetectable values after 2 h (mean values of TF in ng/ml of serum: time 0 control 0.39; 15 min 19.87, 30 min 15.73, 45 min 6.03, 60 min 6, 90 min 5.36, 120 min 0.51). To further elucidate the prolonged use of TF during the early establishment of obesity in vivo and the involvement of ILK, we designed a transgenic mice model [ 36 , 37 ] with a global ILK downregulation during adulthood (cKDILK). These animals and their control counterparts (WT) without ILK depletion were divided to be challenged with either HFD or STD, the latter serving as control.…”

Section: Resultsmentioning

confidence: 99%

“…HFD-challenged WT allowed us to follow TF consequences on the establishment of obesity, while HFD-challenged cKDILK are a transgenic tool to understand the relevance of ILK. We previously demonstrated that short-term HFD administration in mice for 2 weeks allows for the early establishment of obesity and insulin-resistance and for observation of ILK involvement [ 36 ]. Considering this and TF pharmacokinetics, we administered a single daily bolus i.p.…”

Section: Resultsmentioning

confidence: 99%

“…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 ].…”

Section: Introductionmentioning

confidence: 99%

“…Here, we performed experimental approaches in cultured differentiated adipocytes, originating from C3H10T1/2 stem cells [ 51 ], with or without a pharmacological INTB1 blockade or the transgenic depletion of ILK. TF was administered systemically in wildtype (WT) and ILK knockdown (cKDILK) mice during the establishment of obesity based on a high-fat diet (HFD) [ 36 ]. We determined body and WAT weight gains, ILK expression and activity, and adipogenesis and lipid metabolism markers, as discerned from the cultured cell model.…”

Section: Introductionmentioning

confidence: 99%

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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

et al. 2022

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Background Obesity is caused by the enlargement of the white adipose tissue (WAT) depots, characterized by the hypertrophic enlargement of malfunctioning adipocytes within WAT which increases the storage of triglycerides (TG) in the lipid droplets (LD). Adipogenesis pathways as well as the expression and activity of some extracellular matrix receptors integrins are upregulated. Integrinβ1 (INTB1) is the main isoform involved in WAT remodeling during obesity and insulin resistance-related diseases. We recently described Integrin Linked Kinase (ILK), a scaffold protein recruited by INTB1, as an important mediator of WAT remodeling and insulin resistance. As the few approved drugs to fight obesity have brought long-term cardiovascular side effects and given that the consideration of INTB1 and/or ILK modulation as anti-obesogenic strategies remains unexplored, we aimed to evaluate the anti-obesogenic capacity of the clinically approved anticoagulant Tirofiban (TF), stated in preclinical studies as a cardiovascular protector. Methods Fully differentiated adipocytes originating from C3H10T1/2 were exposed to TF and were co-treated with specific INTB1 blockers or with siRNA-based knockdown ILK expression. Lipid-specific dyes were used to determine the TG content in LD. The genetic expression pattern of ILK, pro-inflammatory cytokines (MCP1, IL6), adipogenesis (PPARγ, Leptin), thermogenesis (UCP1), proliferation (PCNA), lipid metabolism (FASN, HSL, ATGL), and metabolite transporters (FABP4, FAT, AQP7) were detected using quantitative PCR. Cytoskeletal actin polymerization was detected by confocal microscopy. Immunoblotting was performed to detect INTB1 phosphorylation at Thr788/9 and ILK activity as phosphorylation levels of protein kinase B (AKT) in Ser473 and glycogen synthase kinase 3β (GSK3β) at Ser9. TF was intraperitoneally administered once per day to wildtype and ILK knockdown mice (cKDILK) challenged with a high-fat diet (HFD) or control diet (STD) for 2 weeks. Body and WAT weight gains were compared. The expression of ILK and other markers was determined in the visceral epididymal (epi) and inguinal subcutaneous (sc) WAT. Results TF reduced TG content and the expression of adipogenesis markers and transporters in adipocytes, while UCP-1 expression was increased and the expression of lipases, cytokines or PCNA was not affected. Mechanistically, TF rapidly increased and faded the intracellular phosphorylation of INTB1 but not AKT or GSK3β. F-actin levels were rapidly decreased, and INTB1 blockade avoided the TF effect. After 24 h, ILK expression and phosphorylation rates of AKT and GSK3β were upregulated, while ILK silencing increased TG content. INTB1 blockade and ILK silencing avoided TF effects on the TG content and the transcriptional expression of PPARγ and UCP1. In HFD-challenged mice, the systemic administration of TF for several days reduced the weight gain on WAT depots. TF reduced adipogenesis and pro-inflammatory biomarkers and increased lipolysis markers HSL and FAT in epiWAT from HFD, while increased UCP1 in scWAT. In both WATs, TF upregulated ILK expression and activity, while no changes were observed in other tissues. In HFD-fed cKDILK, the blunted ILK in epiWAT worsened weight gain and avoided the anti-obesogenic effect of in vivo TF administration. Conclusions ILK downregulation in WAT can be considered a biomarker of obesity establishment. Via an INTB1-ILK axis, TF restores malfunctioning hypertrophied WAT by changing the expression of adipocyte-related genes, increasing ILK expression and activity, and reducing TG storage. TF prevents obesity, a property to be added to its anticoagulant and cardiovascular protective advantages.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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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

et al. 2022

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“…Similarly, AQP9 overexpression in HFD treated CTRL and ILK-low mice is visible already after 2 weeks and increases even more after 6 weeks. In conclusion they state that ILK could be used to predict metabolic disorders establishment [ 131 ].…”

Section: Possible Role Of Aqps “Metabolic Network” In Obesity-induced Systemic Insulin Resistancementioning

confidence: 99%

Aquaporins in insulin resistance and diabetes: More than channels!

et al. 2021

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Aquaporins (AQPs) are part of the family of the integral membrane proteins. Their function is dedicated to the transport of water, glycerol, ammonia, urea, H 2 O 2 , and other small molecules across the biological membranes. Although for many years they were scarcely considered, AQPs have a relevant role in the development of many diseases. Recent discoveries suggest, that AQPs may play an important role in the process of fat accumulation and regulation of oxidative stress, two crucial aspects of insulin resistance and type-2 diabetes (T2D). Insulin resistance (IR) and T2D are multi-faceted systemic diseases with multiple connections to obesity and other comorbidities such as hypertension, dyslipidemia and metabolic syndrome. Both IR and T2D transcends different tissues and organs, creating the maze of mutual relationships between adipose fat depots, skeletal muscle, liver and other insulin-sensitive organs. AQPs with their heterogenous properties, distinctive tissue distribution and documented involvement in both the lipid metabolism and regulation of the oxidative stress appear to be feasible candidates in the search for the explanation to this third-millennium plague. A lot of research has been assigned to adipose tissue AQP7 and liver tissue AQP9, clarifying their relationship and coordinated work in the induction of hepatic insulin resistance. Novel research points also to other aquaporins, such as AQP11 which may be associated with the induction of insulin resistance and T2D through its involvement in hydrogen peroxide transport. In this review we collected recent discoveries in the field of AQP's involvement in the insulin resistance and T2D. Novel paths which connect AQPs with metabolic disorders can give new fuel to the research on obesity, insulin resistance and T2D - one of the most worrying problems of the modern society.

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A new graphene-based nanomaterial increases lipolysis and reduces body weight gain through integrin linked kinase (ILK)

de Frutos,

Griera,

Lavín-López

et al. 2023

Biomater. Sci.

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Integrin Linked Kinase (ILK) Downregulation as an Early Event During the Development of Metabolic Alterations in a Short-Term High Fat Diet Mice Model

Cited by 7 publications

References 0 publications

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

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

Aquaporins in insulin resistance and diabetes: More than channels!

A new graphene-based nanomaterial increases lipolysis and reduces body weight gain through integrin linked kinase (ILK)

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