The Role of MicroRNA in the Modulation of the Melanocortinergic System

Derghal, Adel; Djelloul, Mehdi; Trouslard, Jérôme; Mounien, Lourdes

doi:10.3389/fnins.2017.00181

Cited by 19 publications

(31 citation statements)

References 70 publications

(98 reference statements)

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“…More precisely, POMC-induced stimulation of BAT thermogenesis occurs following downstream melanocortin activation of sympathetic projections via MC4-R-expressing neurons located in the paraventricular nucleus of the hypothalamus and hindbrain [47][48][49]. In addtion, it has been clearly established that leptin increase thermogenesis and body temperature through activation of the POMC neurons and then the sympathetic nerves that control BAT activity [1,47,49]. In PDKO mice, we observed the induction of the expression of genes controlling fatty acid oxidation (Pparα, Pgc1α and Mcad) as well as thermogenesis (Dio2 and Ucp1).…”

Section: Discussionmentioning

confidence: 99%

“…The hypothalamus is involved in the monitoring of the modifications in metabolic parameters (blood glucose and lipids) and/or hormones (insulin or leptin) and elicits adaptive responses like food intake regulation or autonomic nervous system modulation [1]. Within the arcuate nucleus (ARC) of the hypothalamus, pro-opiomelanocortin (POMC) neurons are the first to respond to the circulating signals of hunger and satiety such as leptin, insulin, ghrelin or glucose [1][2][3][4][5][6][7][8]. In accordance with the pivotal role of the melanocortin system in the control of food intake, it has been shown that the disruption of the POMC and melanocortin receptor 4 (MC4R) genes in mice models causes obesity [9,10].…”

Section: Introductionmentioning

confidence: 99%

“…The miRNAs operate at the RNA level and play predominantly inhibitory regulatory roles by binding to cis-element in the 3ʹ untranslated region (3ʹUTR) of message-encoding RNAs [20,21]. Several studies have suggested that miRNAs play a critical role in lipid and glucid metabolism, adipogenesis, obesity-related diseases and also in the central control of energy homeostasis [1,[22][23][24]. For instance, the neuron-specific deletion of Dicer, a critical enzyme involved in miRNAs maturation, induced serious obesity [25].…”

Section: Introductionmentioning

confidence: 99%

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MicroRNAs are involved in the hypothalamic leptin sensitivity

et al. 2018

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The central nervous system monitors modifications in metabolic parameters or hormone levels (leptin) and elicits adaptive responses such as food intake and glucose homeostasis regulation. Particularly, within the hypothalamus, pro-opiomelanocortin (POMC) neurons are crucial regulators of energy balance. Consistent with a pivotal role of the melanocortin system in the control of energy homeostasis, disruption of the Pomc gene causes hyperphagia and obesity. Pomc gene expression is tightly controlled by different mechanisms. Interestingly, recent studies pointed to a key role for micro ribonucleic acid (miRNAs) in the regulation of gene expression. However, the role of miRNAs in the leptin sensitivity in hypothalamic melanocortin system has never been assessed. We developed a transgenic mouse model (PDKO) with a partial deletion of the miRNA processing enzyme DICER specifically in POMC neurons. PDKO mice exhibited a normal body weight but a decrease of food intake. Interestingly, PDKO mice had decreased metabolic rate by reduction of VO 2 consumption and CO 2 production which could explain that PDKO mice have normal weight while eating less. Interestingly, we observed an increase of leptin sensitivity in the POMC neurons of PDKO mice which could explain the decrease of food intake in this model. We also observed an increase in the expression of genes involved in the function of brown adipose tissue that is in polysynaptic contact with the POMC neurons. In summary, these results support the hypothesis that Dicer-derived miRNAs may be involved in the effect of leptin on POMC neurons activity.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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MicroRNAs are involved in the hypothalamic leptin sensitivity

et al. 2018

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“…In the developing hypothalamus, important changes in the expression pattern of miRNAs have been described, suggesting the involvement of miRNAs in the functional organisation of the melanocortin system . Also, there is evidence showing that leptin, a hormone whose signal transduction pathway is downregulated in DIHI, modulates the hypothalamic expression of miRNAs and, conversely, miRNAs could modulate leptin signalling . The importance of miRNA‐mediated control of gene expression is demonstrated by the conditional deletion of Dicer, a key enzyme in miRNA processing.…”

Section: New Cellular Mechanisms Involved In the Development Of Hypotmentioning

confidence: 99%

Cell and molecular mechanisms behind diet‐induced hypothalamic inflammation and obesity

Ávalos

Kerr

Maliqueo

et al. 2018

J Neuroendocrinology

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Diet-induced obesity (DIO) is associated with chronic, low-grade inflammation in the hypothalamus, a key regulator of energy homeostasis. Current studies have revealed the involvement of different cell types, as well as cell and molecular mechanisms, that contribute to diet-induced hypothalamic inflammation (DIHI) and DIO. Subsequent to the discovery that high-fat diet and saturated fatty acids increase the expression of hypothalamic cytokines prior to weight gain, research has focused on understanding the cellular and molecular mechanisms underlying these changes, in addition to the role of inflammation in the pathogenesis of obesity. Recent studies have proposed that the inhibition of pro-inflammatory pathways in microglia and astrocytes is sufficient to protect against DIHI and prevent obesity. In addition, impairment of intracellular and epigenetic mechanisms, such as hypothalamic autophagy and changes in the methylation pattern of certain genes, have been implicated in susceptibility to DIHI and DIO. Interestingly, a sexual dimorphism has been found during DIO in hypothalamic inflammation, glial activation and metabolic diseases, and recent data support an important role of sex steroids in DIHI. These new exciting findings uncover novel obesity pathogenic mechanisms and provide targets to develop therapeutic approaches.

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“…The regulation of energy expenditure involved hormonal (leptin and insulin), metabolic (nutrients), and nervous signals [1,2]. The various signals mentioned before are integrated by the hypothalamus and the brainstem [1,2].…”

Section: Introductionmentioning

confidence: 99%

Leptin Modulates the Expression of miRNAs-Targeting POMC mRNA by the JAK2-STAT3 and PI3K-Akt Pathways

Derghal

Astier

Sicard

et al. 2019

JCM

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The central control of energy balance involves a strongly regulated neuronal network within the hypothalamus and the brainstem. In these structures, pro-opiomelanocortin (POMC) neurons are known to decrease food intake and to increase energy expenditure. Thus, leptin, a peripheral signal that relays information regarding body fat content, modulates the activity of POMC neurons. MicroRNAs (miRNAs) are short non-coding RNAs of 22–26 nucleotides that post-transcriptionally interfere with target gene expression by binding to their mRNAs. It has been demonstrated that leptin is able to modulate the expression of miRNAs (miR-383, miR-384-3p, and miR-488) that potentially target POMC mRNA. However, no study has identified the transduction pathways involved in this effect of leptin on miRNA expression. In addition, miRNAs targeting POMC mRNAs are not clearly identified. In this work, using in vitro models, we have identified and confirmed that miR-383, miR-384-3p, and miR-488 physically binds to the 3′ untranslated (3′UTR) regions of POMC mRNA. Importantly, we show that leptin inhibits these miRNAs expression by different transduction pathways. Taken together, these results allowed us to highlight the miRNA involvement in the regulation of POMC expression downstream of the leptin signaling and satiety signal integration.

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The Role of MicroRNA in the Modulation of the Melanocortinergic System

Cited by 19 publications

References 70 publications

MicroRNAs are involved in the hypothalamic leptin sensitivity

MicroRNAs are involved in the hypothalamic leptin sensitivity

Cell and molecular mechanisms behind diet‐induced hypothalamic inflammation and obesity

Leptin Modulates the Expression of miRNAs-Targeting POMC mRNA by the JAK2-STAT3 and PI3K-Akt Pathways

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