Adipocyte-Derived Exosomal MiR-27a Induces Insulin Resistance in Skeletal Muscle Through Repression of PPARγ

Yu, Yang; Du, Hongwu; Wei, Shengnan; Feng, Linjing; Li, Junnan; Fan, Yao; Zhang, Ming; Hatch, Grant M.; Chen, Li

doi:10.7150/thno.22565

Cited by 243 publications

(193 citation statements)

References 43 publications

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“…Exosomes are extracellular microvesicles (30 to 150 nm in diameter) derived from various cells, transferring different proteins, non-coding RNA and coding RNA, which have been looked as diseases biomarkers or cellcell communication factors [31,32]. Increasing studies have unveiled that exosomes derived from the insulinresistant adipocyte were implicated in the skeletal muscle insulin resistance, obesity-related liver disease, atherosclerosis, and lung cancer [33][34][35][36]. Given the broad spectrum of the discoveries of the function of these exosomes, it is not surprising that exosomes derived from insulin-resistant adipocytes, functioned as independent metabolic units, which might provide a promising therapeutic target on the insulin resistance, diabetes, and related metabolic disorders [37].…”

Section: Discussionmentioning

confidence: 99%

Identification of biomarkers, pathways and potential therapeutic agents for white adipocyte insulin resistance using bioinformatics analysis

Zhang

Zheng

et al. 2019

Adipocyte

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For the better understanding of insulin resistance (IR), the molecular biomarkers in IR white adipocytes and its potential mechanism, we downloaded two mRNA expression profiles from Gene Expression Omnibus (GEO). The white adipocyte samples in two databases were collected from the human omental adipose tissue of IR obese (IRO) subjects and insulin-sensitive obese (ISO) subjects, respectively. We identified 86 differentially expressed genes (DEGs) between the IRO and ISO subjects using limma package in R software. Gene Set Enrichment Analysis (GSEA) provided evidence that the most gene sets enriched in kidney mesenchyme development in the ISO subjects, as compared with the IRO subjects. The Gene Ontology (GO) analysis indicated that the most significantly enriched in cellular response to interferon-gamma. The Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis revealed that the DEGs were most significantly enriched in cytokine-cytokine receptor interaction. Protein-Protein Interaction (PPI) network was performed with the STRING, and the top 10 hub genes were identified with the Cytohubba. CMap analysis found several small molecular compounds to reverse the altered DEGs, including dropropizine, aceclofenac, melatonin, and so on. Our outputs could empower the novel potential targets to treat omental white adipocyte insulin resistance, diabetes, and diabetes-related diseases.

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Section: Discussionmentioning

confidence: 99%

Identification of biomarkers, pathways and potential therapeutic agents for white adipocyte insulin resistance using bioinformatics analysis

Zhang

Zheng

et al. 2019

Adipocyte

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“…We previously demonstrated that addition of PA promotes hypertrophy in adipocytes and that miR27a may be derived from hypertrophic adipocytes in the obese state 12 . To determine the direct effect of adipocyte derived miR27a on the development of macrophage characteristics in 3T3-L1 preadipocyte cells, 3T3-L1 preadipocytes were incubated for 48 h with conditional medium prepared from differentiated 3T3-L1 adipocytes incubated under various conditions (con, CM1, CM2 and CM3) and phagocytosis and cell migration were subsequently examined.…”

Section: Resultsmentioning

confidence: 99%

“…Our previous study showed that miR27a is mainly secreted by adipocytes under obese conditions and is capable of regulating insulin resistance in skeletal muscle 12 . Whether local adipose tissue secreted miR27a promotes macrophage-like development of adipose precursor cells was unknown.…”

Section: Discussionmentioning

confidence: 99%

“…In addition, preadipocytes have the capacity to develop phagocytic and antimicrobial abilities subsequent to cell-to-cell contact with peritoneal macrophages or with a broad spectrum of functional Toll-like receptors 5 - 11 . Previously we demonstrated that adipose tissue from obese individuals secreted miR27a and that adipocyte cell derived miR27a induced insulin resistance in skeletal muscle 12 . In addition, adipose cell derived miR27a induced activation of macrophages in insulin resistant high fat diet fed obese mice through inhibition of PPARγ 13 .…”

Section: Introductionmentioning

confidence: 94%

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MiR27a Promotes the Development of Macrophage-like Characteristics in 3T3-L1 Preadipocytes

Zhang¹,

Sheng²,

Zhang³

et al. 2018

Int. J. Biol. Sci.

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Recruitment and polarization of classically activated (M1) macrophages within adipose tissue contribute to chronic low-grade inflammation in obesity. Adipose tissue precursor cells exhibit the capacity to develop macrophage-like characteristics and adipocyte-derived miR27a is known to promote reprogramming of somatic cells. It was unknown whether exogenous addition of miR27a promote the development of macrophage-like characteristics of adipose precursor cells. We examined macrophage surface antigen, phagocytosis and migration ability in 3T3-L1 preadipocytes transfected with miR27a mimics. Transfection of 3T3-L1 preadipocytes with miR27a mimics increased phagocytosis and migration and increased the number of cells expressing the macrophage makers F4/80 and MHC compared to controls. M2 and CD206 macrophage markers were unaltered. In addition, transfection of 3T3-L1 preadipocytes with miR27a mimics reduced PPARγ expression, activated NF-κB and promoted secretion of the inflammatory cytokines MCP-1, TNF-α and IL-1β compared to controls. The level of anti-inflammatory factors Arg-1, IL-10, Ym1 and Fizz1 were unaltered. Secretion of miR27a was increased in conditioned medium prepared from palmitic acid-treated differentiated 3T3-L1 adipocytes compared to controls. Incubation of 3T3-L1 preadipocytes with this conditioned medium increased phagocytosis and migration compared to controls. Finally, conditioned medium prepared from differentiated 3T3-L1 adipocytes transfection with miR27a inhibitors reduced phagocytosis and migration in 3T3-L1 preadipocytes compared to controls. The data indicate that PPARγ agonists may reverse the activation of NF-κB pathway mediated by miR27a overexpression and reduce phagocytosis and migration of adipose precursor cells. In addition, miR27a may promote the development of macrophage-like characteristics in 3T3-L1 preadipocytes.

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“…Skeletal muscle consumes nearly 80% of glucose [10], and liver regulates glycogen storage, glucose uptake and output [11], indicating skeletal muscle and liver play an important role in glucose homeostasis. Glucose homeostasis is disrupted when the insulin signal pathway is suppressed in liver and muscle [12,13]. In the present study, the insulin signaling pathway in the liver and muscle of the HE offspring was examined to explore the molecular mechanism underlying their impaired glucose tolerance.…”

Section: Discussionmentioning

confidence: 98%

Dietary Energy Levels from Middle to Late Gestation of Guangdong Small-Ear Spotted Pig: Effects on Body Weight, Muscle Development, and Glucose Metabolism of its Newborn Piglets

Yang

Chen

et al. 2020

Preprint

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Background: Guangdong Small-ear Spotted pigs are Chinese indigenous pig that have the characteristic of desired meat quality and resistance to coarse feeding. However, no study has elucidated the effects of dietary energy levels on body weight, muscle development and glucose metabolism of its newborn piglets. Therefore, a total of 66 pregnant gilts with an average body weight of 80.6±6.6 kg at day 60 of gestation were randomly divided into two groups: control group (CON group; 11.50 MJ/kg digestible energy), and high-energy diet group (HE group; 13.42 MJ/kg digestible energy). Results: The results showed that the maternal HE diet was shown to decrease the birth weight of piglets that from the gilts with total or alive litter size of 12 to 13. Additionally, the HE diet group were shown to impair the glucose tolerance of newborn piglets, as evidenced by the glucose tolerance test and the inhibition of insulin signaling pathway in liver and soleus muscle. Despite no significant change in the muscle weight in the two groups, the maternal HE diet was shown to downregulate the protein level of slow-twitch fiber myosin heavy chain I (MyHC I), and upregulate the protein levels of fast-twitch fiber myosin heavy chain IIb (MyHC IIb) and IIx (MyHC IIx) in soleus muscle of their progeny. Furthermore, the newborn piglets in HE group were showed a decrease in mitochondrial biogenesis in liver and soleus muscle when compared to that in CON group. Conclusions: Maternal high-energy diet from middle to late gestation decreases the birth weight of piglets that from the gilts with total or alive litter size of 12 to 13, induces the formation of glycolytic muscle fibers, and impairs glucose tolerance of their newborn piglets.

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Adipocyte-Derived Exosomal MiR-27a Induces Insulin Resistance in Skeletal Muscle Through Repression of PPARγ

Cited by 243 publications

References 43 publications

Identification of biomarkers, pathways and potential therapeutic agents for white adipocyte insulin resistance using bioinformatics analysis

Identification of biomarkers, pathways and potential therapeutic agents for white adipocyte insulin resistance using bioinformatics analysis

MiR27a Promotes the Development of Macrophage-like Characteristics in 3T3-L1 Preadipocytes

Dietary Energy Levels from Middle to Late Gestation of Guangdong Small-Ear Spotted Pig: Effects on Body Weight, Muscle Development, and Glucose Metabolism of its Newborn Piglets

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