Micrornas and metabolism crosstalk in energy homeostasis. In contrast, gain of mir103107 function in either liver or fat is sufficient to induce impaired glucose homeostasis. Additionally, antimirs targeting mir103107 function as unique insulin sensitizers as determined by hyperinsulinemiceuglycemic clamp, which is a robust method for assessing insulin sensitivity. Furthermore, long noncoding rna h19 repressed mir103107 by acting as a sponge rna. Trajkovski m, hausser j, soutschek j, bhat b, akin a, zavolan m, et al. We have shown that micrornas103 and 107 mirs103107 positively regulate endstage autophagy by ensuring dynamin activity in cultured keratinocytes. To identify micrornas mirnas that are deregulated in obesity and insulin resistance, we performed mirna microarray analysis on the livers of. The role of mir103107 has been also explored in adipocytes of obob. Micrornas mirnas, mirs are short, noncoding molecules engaged in normal functioning of eukaryotic cells, as negative regulators of gene expression. The actions of mirnas on insulin resistance in healthy and. Trajkovski m, hausser j, soutschek j, bhat b, akin a, zavolan m, heim mh and stoffel m. Jun 08, 2011 micrornas have been identified as a new class of regulatory molecules that influence many biological functions, including metabolism. In record time, micrornas mirnas have acquired the respected stature of important natural regulators of global gene expression.
Microrna103107 inhibition in caveolin1deficient mice has no effect on insulin sensitivity and signalling. To address the possible mechanism by which mir103 and mir107 regulate insulin sensitivity, we performed genomewide expression analysis using affymetrix microarrays, comparing livers from c57bl. Most work in endstage autophagy has been conducted using in vitro model systems. Microrna 103 107 inhibition in caveolin1deficient mice has no effect on insulin sensitivity and signalling. Micrornas in metabolism vienberg 2017 acta physiologica.
The ones marked may be different from the article in the profile. Micrornas 103 and 107 regulate insulin sensitivity core. Pdf micrornas 103 and 107 regulate insulin sensitivity. To determine the roles of porcine mir27a and mir143 in adipocyte lipid metabolism, porcine. The role of mir103107 in insulin sensitivity and resistance was first recognized by the laboratory of dr. Microrna103107 regulate systemic glucose metabolism and insulin sensitivity. Given the high metabolic demands of the heart and the abundant cardiac expression of mir103107, we questioned whether antagomirmediated inhibition of mir103107 in c57bl6j mice impacts. It has been shown that caveolin1deficient mice show insulin resistance. Our results reveal a novel myocardial necrosis regulation model, which is composed of h19, mir 103 107, and fadd. And, most recently, both mir 103 107 and mir802 were shown to regulate insulin sensitivity and glucose tolerance in mice 20,21.
Micrornas in insulin resistance and obesity hindawi. Vainio s, heino s, mansson je, fredman p, kuismanen e, vaarala o, ikonen e. Microrna 103 107 inhibition in mice leads to increased insulin sensitivity and signalling. Micrornas mirnas, a class of endogenous small noncoding rnas in eukaryotes, have been recognized as significant regulators of gene expression through posttranscriptional mechanisms. The role of mir 103 107 in insulin sensitivity and resistance was. Overexpression of mir143 can reduce insulin sensitivity by inhibiting orp8.
Similar to mir103 and mir107, mir143 is upregulated in dbdb mice and diet induced obese mice. Whether and how the gut microbiome affects adipose tissue homeostasis is an area of current investigation. A cardiac microrna governs systemic energy homeostasis by regulation of med. Crosstalk between micrornas, the putative target genes and. Here we show that the let7 family of micrornas regulates glucose metabolism in multiple organs. Microrna103107 inhibition in mice leads to increased insulin sensitivity and signalling. Diabetes mellitus is the most common metabolic disorder worldwide and a major risk factor for cardiovascular disease.
Control of glucose homeostasis and insulin sensitivity by. Polyphenols induced changes in mir103107 and mir122 expression. Micrornas in metabolic disease arteriosclerosis, thrombosis. Micrornas enhance keratinocyte proliferative capacity in a. Polyphenols induced changes in mir 103 107 and mir122 expression. Plantderived polyphenols regulate expression of mirna.
The micrornas mir3 and mir223, which are upregulated in the failing and insulin resistant heart, have been shown to regulate the insulin sensitive glucose transporter, glut4, in the heart. Rg125 azd4076, a microrna therapeutic targeting microrna. Apr 07, 2015 additionally, antimirs targeting mir 103 107 function as unique insulin sensitizers as determined by hyperinsulinemiceuglycemic clamp, which is a robust method for assessing insulin sensitivity. Notably, glucose levels, insulin levels, and homair in hprtmir26a tg mice fed a hfd were comparable to those of agematched wt controls fed a cd figure 2, eg, indicating that mir26a restoration is sufficient to increase insulin sensitivity and rescue features of obesityassociated metabolic syndrome. These findings demonstrate the central importance of mir 103 107 to insulin sensitivity.
Possibly, mir 103 107 may also be involved in regulation of some of these pathways. In addition to mirnas regulating key proteins in insulin signaling, they may represent another crucial regulatory layer in regulating insulin sensitivity. Decreased levels of mir 103 107 in adipocytes increased caveolin1 expression, which led to stabilization of the insulin receptor, enhanced insulin signalling, decreased adipocyte size, and enhanced insulin stimulated glucose uptake. Micrornas are negative regulators of gene expression that have been implicated in many biological processes, including metabolism. To address the possible mechanism by which mir 103 and mir 107 regulate insulin sensitivity, we performed genomewide expression analysis using affymetrix microarrays, comparing livers from c57bl. Mice lacking the insr gene suffer from hyperglycemia and hyperinsulinemia, and a large number of studies reveal a decrease in insr in t2dm patients. For example, mir103, mir107, mir29, mir320, and mmumir18396182 cluster have been shown to regulate insulin sensitivity 4, and mir122 and mir370 are involved in the regulation of liver steatosis 5,6. Zhonghua shi, chun zhao, xirong guo, hongjuan ding, yugui cui, rong shen, jiayin liu, differential expression of micrornas in omental adipose tissue from gestational diabetes mellitus subjects reveals mir222 as a regulator of er. Grueter ce, van rooij e, johnson ba, deleon sm, sutherland lb, qi x, gautron l, elmquist jk, basselduby r, olson en.
For example, mir 103, mir 107, mir29, mir320, and mmumir18396182 cluster have been shown to regulate insulin sensitivity 4, and mir122 and mir370 are involved in the regulation of liver steatosis 5,6. Microrna 103 107 regulate systemic glucose metabolism and insulin sensitivity. Caveolin1, a critical regulator of insulin receptor has been identified as a direct target of mir103107 trajkovski et al. Insulin receptor insr the ligandreceptor interaction is the first step of insulin signaling. These findings strongly support the notion that mirnas are critical players in pathways that underlie metabolic disease etiology, thus raising the possibility that mirnabased therapy could be relevant for type 2. Micrornas103107 regulate autophagy in the epidermis. Oct 17, 2016 glut4 can be directly inhibited by mir199a and mir93223 in skeletal muscle and adipose tissue, respectively, which consequently has a negative impact on insulin sensitivity 52,53,54. They are known to be involved in many essential biological processes including development, insulin secretion, and adipocyte differentiation. Trajkovski m1, hausser j, soutschek j, bhat b, akin a, zavolan m, heim mh, stoffel m. Dec 27, 2011 diabetes mellitus is the most common metabolic disorder worldwide and a major risk factor for cardiovascular disease. This cited by count includes citations to the following articles in scholar.
Sep 19, 2015 trajkovski m, hausser j, soutschek j, bhat b, akin a, zavolan m, et al. Some mirnas have been classed as epigenetic regulators of metabolism and energy homeostasis. Expression in estrogeninduced insulin resistance, endocrinology, volume 155, issue 5, 1 may 2014, pages 1982. Similar to mir 103 and mir 107, mir143 is upregulated in dbdb mice and diet induced obese mice. The authors tied the increased expression of this microrna to a reduction in. Microrna26a regulates insulin sensitivity and metabolism of. For this reason, inhibitory strategies for these micrornas are currently being tested in clinical trials. Antagomir103 and 107 treatment affects cardiac function. Previous reports indicated that the mirnas mir27a and mir143 were involved in lipid metabolism in human and rodents.
Possibly, mir103107 may also be involved in regulation of some of these pathways. Microrna103107 regulate programmed necrosis and myocardial. If mir103 and mir107 are studied in nonhuman primates and humans, it can provide the therapeutic target for obesity induced insulin resistance 19. Knockdown of mir103107 diminished h 2 o 2 induced necrosis and ischemiareperfusion injury. We investigated the function of mir26a in vivo by using our recently established mir26a tg mouse line. Silencing of mir 103 107 leads to improved glucose homeostasis and insulin sensitivity.
Micrornas have been identified as a new class of regulatory molecules that influence many biological functions, including metabolism. These mirnas also regulate the insulin signaling pathway. Micrornas 103 and 107 regulate insulin sensitivity. Control of glucose homeostasis and insulin sensitivity by the. Micrornas 103 and 107 regulate insulin sensitivity nature. Micrornas mir27a and mir143 regulate porcine adipocyte. The actions of mirnas on insulin resistance in healthy and gotokakizaki rats a model of type 2 diabetes were investigated by he et al. Here we show that the expression of micrornas 103 and 107 mir 103 107 is upregulated in obese mice. Thus, micro103 107 may affect insulin sensitivity by.
Silencing of mir103107 leads to improved glucose homeostasis and insulin sensitivity. Conversely, it is now well recognized that mirnas control metabolism, thereby. Conversely, it is now well recognized that mirnas control metabolism, thereby generating a. Mir103107mediated downregulation of fadd contributed to h 2 o 2induced cardiomyocyte necrosis. However, the direct regulation of insulin sensitivity by micrornas in vivo has not been demonstrated. Insulin resistance is a crucial feature and risk factor for type 2 diabetes t2d. Jul 26, 2016 it is also known that mirnas are involved in hepatic glucose metabolism. It is also known that mirnas are involved in hepatic glucose metabolism. A microrna therapeutic targeting microrna103107 for the. These findings support the importance of insr for maintaining insulin sensitivity. Briefly, a genomic dna fragment encoding the mir26a1 locus, preceded by the synthetic cag promoter and a loxpflanked neostop cassette, was inserted into the rosa26 locus to.
Multiple studies have demonstrated that a large number of mirnas are under the control of various metabolic stimuli, including nutrients, hormones, and cytokines. Jul 18, 2012 these findings demonstrate the central importance of mir 103 107 to insulin sensitivity. Microrna26a regulates insulin sensitivity and metabolism. The role of mir103107 in insulin sensitivity and resistance was. Micrornas mirnas are noncoding small rnas that play roles in regulating gene expression. Here we show that the expression of micrornas 103 and. This led to a suggestion that these micrornas represent potential targets for the treatment of type 2 diabetes. Similarly, in adipose tissue, a defined number of mirnas. From the above studies, it is clear that mirnas play a central. To date, 2000 mirnas have been identified in the human genome, and they orchestrate a variety of biological and pathological processes.
Posttranscriptional regulation in metabolic diseases. Apr 07, 2015 the role of mir103107 in insulin sensitivity and resistance was first recognized by the laboratory of dr. A novel function of microrna a3p in hepatic insulin. Micrornas 103 and 107 regulate insulin sensitivity mirko trajkovski 1,2, jean hausser 2,3,ju. Polyphenols accumulated in the liver and attenuated deleterious effects. Micrornas 103107 regulate autophagy in the epidermis sijia wang1,2,5, aya kobeissi2,5, ying dong2,3, nihal kaplan2, wending yang2, congcong he4, kang zeng1 and han peng2 we have shown that micrornas103 and 107 mirs103107 positively regulate endstage autophagy by ensuring dynamin activity in cultured keratinocytes. Regulation of liver fatty acid utilization is a probable common mechanism of action. Human cyp2c8, a member of cyp2c subfamily of cytochrome p450 enzymes is also posttranscriptionally regulated by micrornas 103 and 107 in human liver zhang et al. In exploring the molecular mechanism by which mir 103 107 are regulated, we show that long noncoding rna h19 directly binds to mir 103 107 and regulates fadd expression and necrosis. Insulin resistance is a pathological condition in adipose tissue, liver, and skeletal. The mir103 microrna precursor homologous to mir107, is a short noncoding rna gene involved in gene regulation. Improved glucose homeostasis and insulin sensitivity in mir26a tg mice. Markus stoffel, professor of the institute of molecular health sciences at eth zurich and member of regulus scientific advisory board.
Given the high metabolic demands of the heart and the abundant cardiac expression of mir 103 107, we questioned whether antagomirmediated inhibition of mir 103 107 in c57bl6j mice impacts on cardiac function. Human cyp2c8 is posttranscriptionally regulated by. Dynamic association of human insulin receptor with lipid rafts in cells lacking caveolae. These findings demonstrate the central importance of mir103107 to insulin sensitivity. Mice with dietinduced fatty liver disease were used to test interactions. Thus, micro103107 may affect insulin sensitivity by. And, most recently, both mir103107 and mir802 were shown to regulate insulin sensitivity and glucose tolerance in mice 20,21. In vivo regulation of endstage autophagy in epidermis remains unknown. The other mirnas were also found to be increased in the obesity model. Differential expression of micrornas in omental adipose. Human cyp2c8 is posttranscriptionally regulated by micrornas. Integrative mrnamicrorna analyses reveal novel interactions. Since the first discovery of mirna in the early 1990s, hundreds of different mirnas and. Micrornas have been identified as a new class of regulatory molecules that influence many biological functions, including metabolism4, 5.
Control of glucose homeostasis and insulin sensitivity by the let7. Here we show that the expression of micrornas 103 and 107 mir103107 is upregulated in obese mice. Micrornas 103 and 107 link type 2 diabetes and post. Micrornas 103 and 107 regulate insulin sensitivity article pdf available in nature 4747353. Antagomir103 and 107 treatment affects cardiac function and. Micrornas mirnas are a class of short, singlestranded nonprotein coding gene products which can regulate the gene expression through posttranscriptional inhibition of messenger rna mrna translation. Micrornas and metabolic disorders where are we heading.
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