Tissue inhibitor of metalloproteases-4 (TIMP-4) modulates adipocyte differentiation in vitro

Mejia-Cristobal, Luz María; Reus, Erika; Lizárraga, Floria; Espinosa, Magali; Ceballos‐Cancino, Gisela; López, Tania; Garay, Sergio; Maldonado, Vilma; Meléndez-Zajgla, Jorge

doi:10.1016/j.yexcr.2015.05.006

Cited by 10 publications

(7 citation statements)

References 36 publications

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“…To the authors' knowledge, this is the first time that the expression of these factors has been described in canine VAT. Among other functions, TIMP4 modulates the differentiation of adipocytes, being upregulated during the terminal phase of maturation of preadipocytes [44]. Furthermore, TIMP4-deficient mice present a lower accumulation of visceral fat, in a mechanism that involves CD36 signaling through PI3 [45], the latter being upregulated by treatment in the present study.…”

Section: Discussionsupporting

confidence: 56%

Effects of ACTH-Induced Long-Term Hypercortisolism on the Transcriptome of Canine Visceral Adipose Tissue

Pereira

Martin

Rehrauer

et al. 2022

Veterinary Sciences

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Cushing’s syndrome, or hypercortisolism (HC), a common endocrinopathy in adult dogs, is caused by chronic hypercortisolemia. Among different metabolic disorders, this syndrome is associated with enhanced subcutaneous lipolysis and visceral adiposity. However, effects of HC in adipose tissue, especially regarding visceral adipose tissue (VAT), are still poorly understood. Herein, the transcriptomic effects of chronic HC on VAT of dogs were evaluated. For this, subcutaneously implanted ACTH-releasing pumps were used, followed by deep RNA sequencing of the canine VAT. Prolonged HC seems to affect a plethora of regulatory mechanisms in VAT of treated dogs, with 1190 differentially expressed genes (DEGs, p and FDR < 0.01) being found. The 691 downregulated DEGs were mostly associated with functional terms like cell adhesion and migration, intracellular signaling, immune response, extracellular matrix and angiogenesis. Treatment also appeared to modulate local glucocorticoid and insulin signaling and hormonal sensitivity, and several factors, e.g., TIMP4, FGF1, CCR2, CXCR4 and HSD11B1/2, were identified as possible important players in the glucocorticoid-related expansion of VAT. Modulation of their function during chronic HC might present interesting targets for further clinical studies. Similarities in the effects of chronic HC on VAT of dogs and humans are highlighted.

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Section: Discussionsupporting

confidence: 56%

Effects of ACTH-Induced Long-Term Hypercortisolism on the Transcriptome of Canine Visceral Adipose Tissue

Pereira

Martin

Rehrauer

et al. 2022

Veterinary Sciences

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“…TIMP4 is highly expressed in the adipose tissue 24 , however the role of TIMP4 in adipose tissue biology and obesity has not been explored so far. In this study, we investigated the role of TIMP4 in obesity using Timp4 -deficient mice and found that TIMP4 promotes high fat-induced obesity, fatty liver and dyslipidemia possibly by promoting intestinal lipid absorption by preventing proteolytic processing of CD36, the cell surface fatty acid transporters in enterocytes.…”

Section: Introductionmentioning

confidence: 99%

Absence of Tissue Inhibitor of Metalloproteinase-4 (TIMP4) ameliorates high fat diet-induced obesity in mice due to defective lipid absorption

Sakamuri

Watts

Takawale

et al. 2017

Sci Rep

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Tissue inhibitor of metalloproteases (TIMPs) are inhibitors of matrix metalloproteinases (MMPs) that regulate tissue extracellular matrix (ECM) turnover. TIMP4 is highly expressed in adipose tissue, its levels are further elevated following high-fat diet, but its role in obesity is unknown. Eight-week old wild-type (WT) and Timp4-knockout (Timp4 −/−) mice received chow or high fat diet (HFD) for twelve weeks. Timp4 −/− mice exhibited a higher food intake but lower body fat gain. Adipose tissue of Timp4 −/–-HFD mice showed reduced hypertrophy and fibrosis compared to WT-HFD mice. Timp4 −/–-HFD mice were also protected from HFD-induced liver and skeletal muscle triglyceride accumulation and dyslipidemia. Timp4 −/−-HFD mice exhibited reduced basic metabolic rate and energy expenditure, but increased respiratory exchange ratio. Increased free fatty acid excretion was detected in Timp4 −/−-HFD compared to WT-HFD mice. CD36 protein, the major fatty acid transporter in the small intestine, increased with HFD in WT but not in Timp4 −/− mice, despite a similar rise in Cd36 mRNA in both genotypes. Consistently, HFD increased enterocyte lipid content only in WT but not in Timp4 −/− mice. Our study reveals that absence of TIMP4 can impair lipid absorption and the high fat diet-induced obesity in mice possibly by regulating the proteolytic processing of CD36 protein in the intestinal enterocytes.

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“…The role of TIMP4 is complex, controversial, and not fully understood as it is tightly linked to MMP3. TIMP4 was shown to be highly expressed in the adipose tissue and its expression level is almost undetectable in 3T3-L1 pre-adipocytes, weak in committed pre-adipocytes and rises further upon induction of differentiation in parallel with expression of the master differentiation factor PPARγ [ 59 , 178 ]. Notably, Wu et al reported that in vitro MMP3 overexpression in 3T3-L1 cells or cells treated with human recombinant MMP3 significantly reduced adipogenesis, whereas concomitant treatment of these cells with recombinant TIMP4 was shown to improve adipogenesis and decrease the inhibitory effect of MMP3 [ 58 ].…”

Section: Adipose Tissue Functions and Pathologiesmentioning

confidence: 99%

“…Unexpectedly, Mejia-Cristobal et al showed also that TIMP4 silencing using short hairpin RNA (shRNA- TIMP4 ) accelerates late phase adipocyte differentiation through decreased NFκB activity contributing to the terminal differentiation burst [ 178 ]. Moreover, microarray analyses of shRNA- TIMP4 3T3-L1 adipocytes showed that the NFκB pathway is among the top regulated pathways [ 178 ]. This study revealed that upon TIMP4 inactivation, the expression levels of Pparγ and Cepbα are significantly enhanced [ 178 ].…”

Section: Adipose Tissue Functions and Pathologiesmentioning

confidence: 99%

“…Moreover, microarray analyses of shRNA- TIMP4 3T3-L1 adipocytes showed that the NFκB pathway is among the top regulated pathways [ 178 ]. This study revealed that upon TIMP4 inactivation, the expression levels of Pparγ and Cepbα are significantly enhanced [ 178 ]. Activation of the NFκB pathway has previously been shown to inhibit adipogenesis through decreased expression of Pparγ [ 179 ].…”

Section: Adipose Tissue Functions and Pathologiesmentioning

confidence: 99%

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Roles of Matrix Metalloproteinases and Their Natural Inhibitors in Metabolism: Insights into Health and Disease

Molière

Jaulin

Tomasetto

et al. 2023

IJMS

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Matrix metalloproteinases (MMPs) are a family of zinc-activated peptidases that can be classified into six major classes, including gelatinases, collagenases, stromelysins, matrilysins, membrane type metalloproteinases, and other unclassified MMPs. The activity of MMPs is regulated by natural inhibitors called tissue inhibitors of metalloproteinases (TIMPs). MMPs are involved in a wide range of biological processes, both in normal physiological conditions and pathological states. While some of these functions occur during development, others occur in postnatal life. Although the roles of several MMPs have been extensively studied in cancer and inflammation, their function in metabolism and metabolic diseases have only recently begun to be uncovered, particularly over the last two decades. This review aims to summarize the current knowledge regarding the metabolic roles of metalloproteinases in physiology, with a strong emphasis on adipose tissue homeostasis, and to highlight the consequences of impaired or exacerbated MMP actions in the development of metabolic disorders such as obesity, fatty liver disease, and type 2 diabetes.

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Tissue inhibitor of metalloproteases-4 (TIMP-4) modulates adipocyte differentiation in vitro

Cited by 10 publications

References 36 publications

Effects of ACTH-Induced Long-Term Hypercortisolism on the Transcriptome of Canine Visceral Adipose Tissue

Effects of ACTH-Induced Long-Term Hypercortisolism on the Transcriptome of Canine Visceral Adipose Tissue

Absence of Tissue Inhibitor of Metalloproteinase-4 (TIMP4) ameliorates high fat diet-induced obesity in mice due to defective lipid absorption

Roles of Matrix Metalloproteinases and Their Natural Inhibitors in Metabolism: Insights into Health and Disease

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