Leptin Transcriptionally Enhances Peptide Transporter (hPepT1) Expression and Activity via the cAMP-response Element-binding Protein and Cdx2 Transcription Factors

Viennois

et al. 2016

Sci Rep

Self Cite

In the jejunum, PepT1 is particularly enriched in the well-differentiated absorptive epithelial cells in the villi. Studies of expression and function of PepT1 along the crypt-villus axis demonstrated that this protein is crucial to the process of di/tripeptide absorption. We recently exhibited that PepT1 plays an important role in multiple biological functions, including the ability to regulate the expression/secretion of specific microRNAs (miRNAs) and the expression levels of multiple proteins. In this study, we observed that PepT1 knockout (KO) mice exhibited reduced body weight and shorten intestinal microvilli. We then examined the expression levels of various miRNAs and their target proteins along the crypt-villi axis in the jejunum of PepT1 KO mice. We found that PepT1 KO altered the distribution of miRNAs along the crypt-villus axis and changed the miRNA profiles of both villi and crypts. Using miRNA-target prediction and 2D-DIGE/mass spectrometry on villi and crypts samples, we found that ablation of PepT1 further directly or indirectly altered expression levels of certain protein targets. Collectively, our results suggest that PepT1 contributes to maintain balance of homeostasis and proper functions in the small intestine, and dysregulated miRNAs and proteins along the crypt-villus axis are highly related to this process.

Section: Discussionsupporting

confidence: 78%

PepT1 Expression Helps Maintain Intestinal Homeostasis by Mediating the Differential Expression of miRNAs along the Crypt-Villus Axis

Viennois

et al. 2016

Sci Rep

Self Cite

The Journal of Pharmacology and Experimental Therapeutics

“…Thus, one can speculate that changes in growth hormone levels and in sympathetic nervous tone could be indirect regulators of PepT1 induced by leptin in our animals; however, this has yet to be demonstrated. Nduati et al (2007) reported that leptin can directly regulate PepT1 expression on enterocyte in an in vitro model. However, leptin concentrations used in this study were supraphysiological, and only a short-term effect was investigated.…”

mentioning

confidence: 99%

“…The promoter regions of the rat, mouse and human PepT1 gene (Shiraga et al, 1999;Fei et al, 2000;Shimakura et al, 2005) have been characterized, and they contain a number of potential binding sites for regulatory factors of gene transcription that can be targeted by leptin signaling pathways. Likewise, Nduati et al (2007) showed that cAMP response element-binding protein (CREB) and caudal-related homeobox 2 (Cdx2) are involved in PepT1 regulation by leptin in vitro. Future studies are needed to unravel the molecular mechanisms of activation of intestinal peptide transporter PepT1 expression by leptin in vivo.…”

mentioning

confidence: 99%

Long-Term Effect of Leptin on H+-Coupled Peptide Cotransporter 1 Activity and Expression in Vivo: Evidence in Leptin-Deficient Mice

Hindlet¹,

Bado²,

Farinotti³

et al. 2007

The Hϩ -coupled peptide cotransporter 1 (PepT1) mediates absorption of peptides and peptidomimetic drugs. Acute luminal leptin was reported to induce translocation of PepT1 to the enterocyte membrane in vitro and in vivo in the rat, resulting in enhanced peptide and peptidomimetic drug absorption. In this study, we analyzed chronic effects of leptin and leptin deficiency on PepT1 activity and expression in the small intestine. Wistar rats and ob/ob mice were used. Activity of PepT1 was determined by monitoring [3 H]glycyl-sarcosine (Gly-Sar) transport using the jejunal loop method. The levels of PepT1 mRNA and protein were quantified by real-time quantitative reverse transcription-polymerase chain reaction and Western blot analysis, respectively. Induction of chronic hyperleptinemia in rats (1 g/g/day for 7 days; subcutaneous continuous infusion), caused a significant 25% increase (P Ͻ 0.05 versus control) in Gly-Sar transport and uptake. This effect was associated with a significant 2-fold increase in the abundance of PepT1 protein and a 6-fold increase in the levels of PepT1 mRNA. In the leptin-deficient ob/ob mice, PepT1 activity and expression were significantly reduced, and replacement of leptin (10 g/ day for 7 days; subcutaneous continuous infusion) completely restored full PepT1 expression and activity. Moreover, we showed that a 7-day challenge of the Caco-2 cells with 0.2 nM leptin induced a significant increase in PepT1 activity and protein expression, arguing for a direct action. These data demonstrate, for the first time, an impaired activity/expression of PepT1 in leptin-deficient ob/ob mice that could be restored by leptin replacement. These findings may have relevance in modulation of dietary nitrogen supply and PepT1 substrate bioavailability in obesity.

Molecular and Cellular Biology

“…Leptin has been shown to utilize the transcription factor cyclic AMP response element-binding protein (CREB) in enhancing the expression of cyclin D1 (17) and an intestinal epithelial apical membrane transporter, PepT1 (18). In particular, it has been demonstrated that the hypothalamic CREB mRNA level of Ob/Ob mice is lower than that of lean control mice and that leptin increases the hypothalamic CREB mRNA level in Ob/Ob mice (19).…”

Section: Nor1 Suppresses the Expression Of Agrp And Npy In The Arcmentioning

confidence: 99%

Control of Energy Balance by Hypothalamic Gene Circuitry Involving Two Nuclear Receptors, Neuron-Derived Orphan Receptor 1 and Glucocorticoid Receptor

Kim

Lee

Kim

et al. 2013

e Nuclear receptors (NRs) regulate diverse physiological processes, including the central nervous system control of energy balance. However, the molecular mechanisms for the central actions of NRs in energy balance remain relatively poorly defined. Here we report a hypothalamic gene network involving two NRs, neuron-derived orphan receptor 1 (NOR1) and glucocorticoid receptor (GR), which directs the regulated expression of orexigenic neuropeptides agouti-related peptide (AgRP) and neuropeptide Y (NPY) in response to peripheral signals. Our results suggest that the anorexigenic signal leptin induces NOR1 expression likely via the transcription factor cyclic AMP response element-binding protein (CREB), while the orexigenic signal glucocorticoid mobilizes GR to inhibit NOR1 expression by antagonizing the action of CREB. Also, NOR1 suppresses glucocorticoid-dependent expression of AgRP and NPY. Consistently, relative to wild-type mice, NOR1-null mice showed significantly higher levels of AgRP and NPY and were less responsive to leptin in decreasing the expression of AgRP and NPY. These results identify mutual antagonism between NOR1 and GR to be a key rheostat for peripheral metabolic signals to centrally control energy balance.T he first group of neurons that encounters peripheral metabolic signals, such as leptin, insulin, and ghrelin, thereby transducing their action to control energy balance to the rest of the central nervous system (CNS), is clustered in the arcuate nucleus region of the hypothalamus (ARC) (1, 2). Two types of metabolic neurons in the ARC have been particularly well characterized, i.e., neurons that express the orexigenic neuropeptides agouti-related peptide (AgRP) and neuropeptide Y (NPY), herein named AgRP neurons, and neurons expressing the anorexigenic neuropeptides ␣-melanocyte-stimulating hormone (␣MSH), a proteolytic product of pro-opiomelanocortin (POMC), and cocaine-and amphetamine-regulated transcript (CART), herein named POMC neurons. The anorexigenic signals insulin and leptin, which are critical adiposity signals that circulate in proportion to the body fat mass, stimulate POMC neurons and inactivate AgRP neurons to inhibit food intake and increase energy expenditure (1, 2). In contrast, the orexigenic signal ghrelin, a circulating peptide secreted from the stomach, activates AgRP neurons, thereby stimulating food intake. Thus, interplays among leptin, insulin, ghrelin, and AgRP and POMC neurons play important roles in maintaining normal energy balance, and deregulation of these communications leads to obesity and type II diabetes (1, 2).Nuclear receptors (NRs) have been extensively studied as critical regulators of a diverse array of physiological processes in the human body, including the CNS control of energy balance (3). In particular, recent progress has uncovered the roles of NRs in energy balance that involve the arcuate POMC and AgRP neurons. For example, it has been suggested that estrogen exerts its anorexigenic function through AgRP neurons and that, interestingly, this ...