No abstract

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.