Abstract
The central nervous system (CNS) monitors modifications in metabolic parameters or hormone levels and elicits adaptive responses such as food intake regulation. Particularly, within the hypothalamus, leptin modulates the activity of pro-opiomelanocortin (POMC) neurons which are critical 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. MicroRNAs (miRNAs) are short noncoding RNA molecules that post-transcriptionally repress the expression of genes by binding to 3′-untranslated regions (3′UTR) of the target mRNAs. However, little is known regarding the role of miRNAs that target POMC 3′UTR in the central control energy homeostasis. Particularly, their interaction with the leptin signaling pathway remain unclear. First, we used common prediction programs to search for potential miRNAs target sites on 3′UTR of POMC mRNA. This screening identified a set of conserved miRNAs seed sequences for mir-383, mir-384-3p, and mir-488. We observed that mir-383, mir-384-3p, and mir-488 are up-regulated in the hypothalamus of leptin deficient ob/ob mice. In accordance with these observations, we also showed that mir-383, mir-384-3p, and mir-488 were increased in db/db mice that exhibit a non-functional leptin receptor. The intraperitoneal injection of leptin down-regulated the expression of these miRNAs of interest in the hypothalamus of ob/ob mice showing the involvement of leptin in the expression of mir-383, mir-384-3p, and mir-488. Finally, the evaluation of responsivity to intracerebroventricular administration of leptin exhibited that a chronic treatment with leptin decreased mir-488 expression in hypothalamus of C57BL/6 mice. In summary, these results suggest that leptin modulates the expression of miRNAs that target POMC mRNA in hypothalamus.
Highlights
The control of energy homeostasis is finely tuned by endocrine and neural mechanisms that cooperate to maintain the balance between caloric intake and energy expenditure
The relevance of miRNAs in the function of melanocortin pathways has been recently highlighted by the deletion of Dicer in POMC-expressing cells which led to a postnatal ablation of POMC neurons resulting in obesity (Schneeberger et al, 2012; Greenman et al, 2013)
It is already established that these miRNAs are highly expressed in the brain (Chiang et al, 2010). In agreement with this data, we have found by using Quantitative RT-PCR (qRT-PCR) that the highest concentrations of mir-383 occurred in the hypothalamus, brainstem, and cortex
Summary
The control of energy homeostasis is finely tuned by endocrine and neural mechanisms that cooperate to maintain the balance between caloric intake and energy expenditure. Within the arcuate nucleus of the hypothalamus, pro-opiomelanocortin (POMC) neurons are critical regulators of energy balance and glucose homeostasis (Porte et al, 2002; Mounien et al, 2005, 2009, 2010; Parton et al, 2007; Hill et al, 2010) In accordance with this aspect, it has been shown that the disruption of the POMC and melanocortin receptor 4 (MC4R) genes in mice models causes obesity (Huszar et al, 1997; Yaswen et al, 1999), while MC3R gene-deficient mice have normal food consumption but accumulate fat (Chen et al, 2000). Obesity can result from genetic deficiencies which produce a lack in the leptin receptor, POMC, or MC3/4R (Lee, 2009)
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