Recent controversy regarding the therapeutic potential of curcumin indicates the challenges to research in this field. Here, we highlight the investigations of curcumin and other plant-derived polyphenols that demonstrate their application to metabolic diseases, in particular, obesity and diabetes. Thus, a number of preclinical and clinical investigations have shown the beneficial effect of curcumin (and other dietary polyphenols) in attenuating body weight gain, improving insulin sensitivity, and preventing diabetes development in rodent models and prediabetic subjects. Other intervention studies with dietary polyphenols have also found improvements in insulin resistance. Recent studies suggest that the metabolic effects of curcumin/polyphenols are linked to changes in the gut microbiota. Thus, research into curcumin continues to provide novel insights into metabolic regulation that may ultimately translate into effective therapy.

Investigations on the metabolic role of the Wnt signaling pathway and hepatic transcription factor 7-like 2 (TCF7L2) have generated opposing views. While some studies demonstrated a repressive effect of TCF7L2 on hepatic gluconeogenesis, a recent study using liver-specific Tcf7l2 2/2 mice suggested the opposite. As a consequence of redundant and bidirectional actions of transcription factor (TCF) molecules and other complexities of the Wnt pathway, knockout of a single Wnt pathway component may not effectively reveal a complete metabolic picture of this pathway. To address this, we generated the liver-specific dominant-negative (DN) TCF7L2 (TCF7L2DN) transgenic mouse model LTCFDN. These mice exhibited progressive impairment in response to pyruvate challenge. Importantly, LTCFDN hepatocytes displayed elevated gluconeogenic gene expression, gluconeogenesis, and loss of Wnt-3a-mediated repression of gluconeogenesis. In C57BL/6 hepatocytes, adenovirus-mediated expression of TCF7L2DN, but not wild-type TCF7L2, increased gluconeogenesis and gluconeogenic gene expression. Our further mechanistic exploration suggests that TCF7L2DN-mediated inhibition of Wnt signaling causes preferential interaction of b-catenin (b-cat) with FoxO1 and increased binding of b-cat/FoxO1 to the Pck1 FoxO binding site, resulting in the stimulation of Pck1 expression and increased gluconeogenesis. Together, our results using TCF7L2DN as a unique tool revealed that the Wnt signaling pathway and its effector b-cat/TCF serve a beneficial role in suppressing hepatic gluconeogenesis.

Understanding mechanisms underlying adipogenic differentiation may lead to the discovery of novel therapeutic targets for obesity. Wnt signalling pathway activation leads to repressed adipogenic differentiation while certain microRNAs may regulate pre-adipocyte proliferation and differentiation. We show here that in mouse white adipose tissue, miR-17-5p level is elevated after high fat diet consumption. miR-17-5p upregulates adipogenic differentiation, as its over-expression increased while its inhibition repressed 3T3-L1 differentiation. The Tcf7l2 gene encodes a key Wnt signalling pathway effector, and its human homologue TCF7L2 is a highly regarded diabetes risk gene. We found that Tcf7l2 is an miR-17-5p target and confirmed the repressive effect of Tcf7l2 on 3T3-L1 adipogenic differentiation. The natural plant polyphenol compound curcumin possesses the body weight lowering effect. We observed that curcumin attenuated miR-17-5p expression and stimulated Tcf7l2 expression in 3T3-L1 cells. These, along with the elevation of miR-17-5p expression in mouse epididymal fat tissue in response to high fat diet consumption, allowed us to suggest that miR-17-5p is among central switches of adipogenic differentiation. It activates adipogenesis via repressing the Wnt signalling pathway effector Tcf7l2, and its own expression is likely nutritionally regulated in health and disease.