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P43: History
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Subjects: Biochemistry & Molecular Biology
Contributor: François Casas

P43 is a truncated form of thyroid hormone receptor α localized in mitochondria, which stimulates mitochondrial respiratory chain activity. Previously, we showed that deletion of p43 led to reduction of pancreatic islet density and a loss of glucose-stimulated insulin secretion in adult mice. The present study was designed to determine whether p43 was involved in the processes of β cell development and maturation. We used neonatal, juvenile, and adult p43-/- mice, and we analyzed the development of β cells in the pancreas. Here, we show that p43 deletion affected only slightly β cell proliferation during the postnatal period. However, we found a dramatic fall in p43-/- mice of MafA expression (V-Maf Avian Musculoaponeurotic Fibrosarcoma Oncogene Homolog A), a key transcription factor of beta-cell maturation. Analysis of the expression of antioxidant enzymes in pancreatic islet and 4-hydroxynonenal (4-HNE) (a specific marker of lipid peroxidation) staining revealed that oxidative stress occurred in mice lacking p43. Lastly, administration of antioxidants cocktail to p43-/- pregnant mice restored a normal islet density but failed to ensure an insulin secretion in response to glucose. Our findings demonstrated that p43 drives the maturation of β cells via its induction of transcription factor MafA during the critical postnatal window.

  • thyroid hormone
  • p43
  • mitochondria
  • beta-cells
  • insulin
  • MafA
  • diabetes

1. Introduction

Thyroid hormone is a major regulator of metabolism and mitochondrial function [1][2] and also a key regulator of the postnatal maturation of many tissues. Thyroid hormone also affects different metabolic aspects of glucose and insulin metabolism. Hypothyroidism is associated with a decrease of normal glucose-stimulated insulin secretion by the beta-cells [3], while an increase of insulin secretion has been reported in hyperthyroidism [4]. In addition, Ligget and coworkers have observed an increase in insulin secretory rate after T3 administration in rats [5]. Thyroid hormone acts through nuclear receptors (T3Rs) encoded by the TRα and TRβ genes [6][7]. TRα and TRβ have been identified in adult islet cells [8][9]. Interestingly, a comparison of the expression of the isoforms shows that TRα predominates at early ages in β cells, whereas TRβ becomes the predominant isoform in adult islets [8]. Recently, Aguayo-Mazzucato and coworkers [10] have shown that thyroid hormone induces both maturation and aging effectors in β cells. Through direct binding on the promoter of the genes, they showed that TRα enhances p16Ink4a expression, a β cells senescent marker and effector, whereas TRβ drive the expression of MafA, a key transcription factor driving the maturation of the insulin secretory response to glucose in neonatal β cells. Moreover, Furuya et al. [11] have shown that liganded TRα enhances the proliferation of pancreatic β cells. The observation that thyroid hormone also regulates pancreatic islet maturation during zebrafish development suggests that the role of thyroid hormone in the functional maturation of β cells is preserved across species [12].

Previously, we have identified a truncated form of the nuclear receptor TRα1, with a molecular mass of 43 kDa (p43), which stimulates mitochondrial transcription and protein synthesis in the presence of T3 [13][14]. This protein is synthesized by the use of the internal initiation site of translation occurring in the TRα1 transcript and localized in mitochondria. This receptor, which stimulates mitochondrial respiratory chain activity, is expressed ubiquitously, but more particularly in the most metabolically active tissues [13][14]. It is notably involved in the regulation of skeletal muscle phenotype in adulthood [15][16][17] and during regeneration [18]. We also demonstrated recently that its absence induced an exacerbated age-related hearing loss in mice [19]. To assess the physiological importance of p43, we generated mice carrying specific p43 invalidation but that still express other TRα proteins [20]. We reported that p43 depletion in mice induced a decrease of the mitochondrial respiratory chain activities in the pancreatic islet, a reduction of islet density and a loss of glucose-stimulated insulin secretion [20]. In addition, during aging, p43 depletion in mice progressively induced all the characteristics of type 2 diabetes (hyperglycemia, glucose intolerance and insulin resistance) [21].

2. Discussion

We had previously shown that p43 depletion in mice led to a reduction of islet density and a loss of glucose-stimulated insulin secretion [20][21]. Here we have examined the relationship between the absence of p43 and islet β cells formation and function during the postnatal period, a critical window for the maturation and the acquisition of glucose-stimulated insulin secretion [22][23][24].

We showed that the islet density in p43-/- neonates were similar to the controls. In addition, the deletion of p43 affects only slightly proliferation of β cells during the postnatal period, which cannot explain the decrease in islet density observed in adult mice. These data indicate that the mechanisms involved in the reduction of islet density in adulthood in p43-/- mice occur after the neonatal period studied here. Moreover, the finding that antioxidant supplementation during pregnancy until weaning restores a normal islet density in offspring p43-/- mice suggests that the proliferation defect is at least in part mediated by the activation of ROS production.

We hypothesized that the lack of insulin secretion in response to glucose recorded in the absence of p43 results from a generalized low expression of genes characteristic of mature functional β cells. Among these genes, we focused our attention on two glucose-responsive transcription factors, MafA and Pdx1, known to regulate genes involved in insulin synthesis and secretion. In particular, studies conducted over the past decade by several groups strongly support that MafA [25] regulates β cells maturation and the acquisition of glucose-stimulated insulin secretion in vivo [26][27][28][29][30]. Interestingly, we found that MafA expression both at mRNA and protein levels remained dramatically low in p43-/- β cells in comparison to WT mice. Because MafA is known to induce endogenous insulin transcription [29], it was not a surprise to observe a decrease of insulin content, at least during the postnatal period in mice lacking p43. However, while the MafA messenger is well expressed at 2 and 7 days in both genotypes, we were unable to detect the protein by immunofluorescence at these two stages even in C57BL6/J mice in contrast to a previous publication [27]. Moreover, despite the fact that we used the same antibody, we observed that MafA is expressed in only 42% and 67% of β cells at 14 days and 3 months in WT mice, whereas Artner and coworkers found an expression level of 79% and 81% at the same stage [27]. The differences we observed are probably due to a difference in the breeding conditions (temperature, diet and enrichment).

Our results also revealed an increase of PDX1 expression at the protein level in the p43-/- pancreas during the neonatal period. Because overexpression of PDX1 is also known to increase insulin content [26][31], we postulate that this increase of PDX1 is most likely an adaptation to compensate in part for the decrease in insulin synthesis in beta-cells in response to the fall of MafA expression. However, as previously shown, this overexpression of PDX1 in neonatal islets was unable to stimulate insulin secretion in response to glucose [26]. This set of data demonstrates that p43 is a physiological regulator of functional maturation of beta-cells via its induction of MafA.

Mitochondria have emerged as central players in the regulation of adult beta-cell function [32][33]. We have previously shown that p43 deletion in mice induced a decrease of the mitochondrial respiratory chain activities and abolished beta-cell maturation [20]. Yoshihara and coworkers [34] have shown that an orphan nuclear receptor, Estrogen related receptors (ERRγ), is required to maintain mitochondrial function and drive the postnatal maturation of β cells. These observations emphasize that mitochondrial respiratory chain activities are also essential for beta-cell maturation. However, mitochondrial function and dysfunction have been implicated in many different aspects in the crosstalk with the nucleus, notably through ROS production and calcium signaling. Here, we have shown that p43 deletion induced oxidative stress in β cells detected two days after birth and that it was subsequently partly offset by an increase in the expression of the antioxidant enzymes in these cells. Since Kondo et al. showed that oxidative stress was responsible for a decrease in MafA stability via activation of p38 MAPK [35], we hoped to restore a glucose-stimulated insulin secretion with antioxidant supplementation in p43-/- mice. However, this was not the case. Perhaps the supplementation was a bit too drastic and inhibited normal favorable ROS signaling in β cells. This result also suggests that the retrograde signaling between the mitochondria and the nucleus induced by p43 and responsible for the regulation of MafA expression is not mediated by ROS.

Recently, the involvement of thyroid hormone in the functional maturation of the pancreatic beta-cells emerged. We reported that p43 depletion in mice induced a reduction of islet density and a loss of glucose-stimulated insulin secretion [20]. Aguayo-Mazzucato and coworkers have shown that TH drove the MafA expression through the direct binding of TRβ isoform on his promoter [8][10]. In addition, the authors found that TRα predominates at early ages in beta-cells, whereas TRβ becomes the predominant isoform in adult islets [10]. Moreover, Aguayo-Mazzucato et al. [26] have shown that MafA increases in expression in parallel to the acquisition of glucose responsiveness during the postnatal development before weaning and drove the beta-cell maturation. Altogether, these data indicate that in vivo, thyroid hormone regulates MafA expression in β cells differently depending on the temporal expression of TR isoforms. Before weaning, the TRα gene through the p43 and the regulation of mitochondrial activity induces the expression of MafA, whereas, in adult β cells, TRβ expression dominates and maintains the high levels of MafA. Lastly, during aging, TRα improves the expression of p16Ink4a, a marker and effector of senescence of β cells [10].

This entry is adapted from the peer-reviewed paper 10.3390/ijms22052489

References

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