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Canonical Wnt signaling, which is transduced by β‐catenin and lymphoid enhancer factor 1/T cell‐specific transcription factors (LEF1/TCFs), regulates many aspects of metazoan development and tissue renewal. Although much evidence has associated canonical Wnt/β‐catenin signaling with mood disorders, the mechanistic links are still unknown. Many components of the canonical Wnt pathway are involved in cellular processes that are unrelated to classical canonical Wnt signaling, thus further blurring the picture. The present review critically evaluates the involvement of classical Wnt/β‐catenin signaling in developmental processes that putatively underlie the pathology of mental illnesses. Particular attention is given to the roles of LEF1/TCFs, which have been discussed surprisingly rarely in this context. Highlighting recent discoveries, we propose that alterations in the activity of LEF1/TCFs, and particularly of transcription factor 7‐like 2 (TCF7L2), result in defects previously associated with neuropsychiatric disorders, including imbalances in neurogenesis and oligodendrogenesis, the functional disruption of thalamocortical circuitry and dysfunction of the habenula.

Elevated levels of FFAs, often accompanied by obesity, have been considered as a major risk factor of ␤ -cell failure and insulin resistance, which contributes to the onset and progression of T2D ( 1 ). The FA-induced effect on ␤ -cell integrity and function depends on both the level of FA desaturation and the time of deposition ( 2 ). The prolonged exposure of ␤ -cells to high concentrations of FAs results in an impairment in insulin secretion, a decrease in insulin gene expression, the mitigation of proliferation, and subsequently the induction of lipoapoptosis ( 3 ). The molecular mechanisms that link FAs to ␤ -cell dysfunction still remain to be delineated. Several processes by which FAs mediate lipotoxicity have been suggested, including the generation of reactive oxygen species, de novo ceramide synthesis, endoplasmic reticulum (ER)-associated stress, and alterations in mitochondrial integrity and function ( 4-6 ). Saturated FAs (SFAs) were found to cause more severe effects on the insulin secretory capacity of ␤ -cells and rate of apoptosis compared with MUFAs ( 7,8 ).Stearoyl-CoA desaturase (SCD) is the pivotal lipid metabolism enzyme that catalyzes the biosynthesis of MUFAs by introducing a cis -double bond to a fatty-acyl CoA. The preferred desaturation substrates are palmitic acid (16:0) and stearic acid (18:0), which are converted to palmitoleate (16:1n-7) and oleate (18:1n-9), respectively ( 9 ). The resulting

Wnt signaling molecules are associated with obesity, hyperlipidemia, and type 2 diabetes (T2D). Here, we show that two Wnt proteins, WNT3a and WNT4, are specifically secreted by skeletal muscle and adipose tissue during the development of insulin resistance and play an important role in cross-talk between insulin-resistant tissues and pancreatic beta cells. The activation of Frizzled receptor and Wnt signaling in pancreatic islets via circulating WNT3a in blood resulted in higher insulin secretion and an increase in beta cell proliferation, thus leading to islet adaptation in a pre-diabetic state. Interestingly, in fully developed T2D, the expression profiles of Wnt3a and Wnt4 in adipose tissue and muscle cells and blood plasma levels of these proteins were opposite to the pre-diabetic state, thus favoring the downregulation of Wnt signaling in beta cells and resulting in dysfunctional pancreatic islets. These results demonstrate that alterations in the secretion profile of a canonical Wnt activator (WNT3a) and inhibitor (WNT4) from insulin-resistant tissues during the development of T2D are responsible for triggering progression from a pre-diabetic to a diabetic state. We also show here that WNT3a and WNT4 are potent myokines, and their expression and secretion are regulated in response to nutritional and metabolic changes.

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Aims/hypothesisWe aimed to identify microRNAs (miRNAs) under transcriptional control of the HNF1β transcription factor, and investigate whether its effect manifests in serum.MethodsThe Polish cohort (N = 60) consisted of 11 patients with HNF1B-MODY, 17 with HNF1A-MODY, 13 with GCK-MODY, an HbA1c-matched type 1 diabetic group (n = 9) and ten healthy controls. Replication was performed in 61 clinically-matched British patients mirroring the groups in the Polish cohort. The Polish cohort underwent miRNA serum level profiling with quantitative real-time PCR (qPCR) arrays to identify differentially expressed miRNAs. Validation was performed using qPCR. To determine whether serum content reflects alterations at a cellular level, we quantified miRNA levels in a human hepatocyte cell line (HepG2) with small interfering RNA knockdowns of HNF1α or HNF1β.ResultsSignificant differences (adjusted p < 0.05) were noted for 11 miRNAs. Five of them differed between HNF1A-MODY and HNF1B-MODY, and, amongst those, four (miR-24, miR-27b, miR-223 and miR-199a) showed HNF1B-MODY-specific expression levels in the replication group. In all four cases the miRNA expression level was lower in HNF1B-MODY than in all other tested groups. Areas under the receiver operating characteristic curves ranged from 0.79 to 0.86, with sensitivity and specificity reaching 91.7% (miR-24) and 82.1% (miR-199a), respectively. The cellular expression pattern of miRNA was consistent with serum levels, as all were significantly higher in HNF1α- than in HNF1β-deficient HepG2 cells.Conclusions/interpretationWe have shown that expression of specific miRNAs depends on HNF1β function. The impact of HNF1β deficiency was evidenced at serum level, making HNF1β-dependent miRNAs potentially applicable in the diagnosis of HNF1B-MODY.Electronic supplementary materialThe online version of this article (doi:10.1007/s00125-016-3945-0) contains peer-reviewed but unedited supplementary material, which is available to authorised users.

Neuronal phenotypes are controlled by terminal selector transcription factors in invertebrates, but only a few examples of such regulators have been provided in vertebrates. We hypothesised that TCF7L2 regulates different stages of postmitotic differentiation in the thalamus, and functions as a thalamic terminal selector. To investigate this hypothesis, we used complete and conditional knockouts of Tcf7l2 in mice. The connectivity and clustering of neurons were disrupted in the thalamo-habenular region in Tcf7l2−/− embryos. The expression of subregional thalamic and habenular transcription factors was lost and region-specific cell migration and axon guidance genes were downregulated. In mice with a postnatal Tcf7l2 knockout, the induction of genes that confer thalamic terminal electrophysiological features was impaired. Many of these genes proved to be direct targets of TCF7L2. The role of TCF7L2 in terminal selection was functionally confirmed by impaired firing modes in thalamic neurons in the mutant mice. These data corroborate the existence of master regulators in the vertebrate brain that control stage-specific genetic programmes and regional subroutines, maintain regional transcriptional network during embryonic development, and induce terminal selection postnatally.

The Wnt signaling pathway plays an important role in morphogenesis, differentiation, cell survival and proliferation. Wnt activators are secreted proteins that work in an auto-, para- and endocrine manner and their synthesis, secretion and transport are tightly regulated. Frizzled/LRP is the main receptor complex in the canonical Wnt pathway. Its activation triggers β-catenin translocation to the nucleus and increases activity of TCF transcription factor. Disruption in Wnt signaling has been found in many pathophysiological states such as different types of cancer, neurodegenerative diseases and metabolic disorders. Recent studies revealed the important role of Wnt signaling in maintaining carbohydrate and lipid homeostasis. Activation of the Frizzled/LRP receptor complex leads to increase in the activity of transcription factors and nuclear receptors that regulate expression of genes involved in lipid utilization (PPARδ, RAR, LXR) and inhibits adipogenesis. The Wnt signaling pathway is also involved in the regulation of gluconeogenesis and glycolysis. This review summarizes the current state of knowledge about mechanisms that regulate canonical Wnt signaling and its role in cell metabolism regulation.