Adipocyte CREB Promotes Insulin Resistance in Obesity

SummaryIncreases in adiposity trigger metabolic and inflammatory changes that interfere with insulin action in peripheral tissues, culminating in beta cell failure and overt diabetes. We found that the cAMP Response Element Binding protein (CREB) is activated in adipose cells under obese conditions, where it promotes insulin resistance by triggering expression of the transcriptional repressor ATF3 and thereby downregulating expression of the adipokine hormone adiponectin as well as the insulin-sensitive glucose transporter 4 (GLUT4). Transgenic mice expressing a dominant-negative CREB transgene in adipocytes displayed increased whole-body insulin sensitivity in the contexts of diet-induced and genetic obesity, and they were protected from the development of hepatic steatosis and adipose tissue inflammation. These results indicate that adipocyte CREB provides an early signal in the progression to type 2 diabetes

Rôle du facteur de transcription ChREBP dans la régulation transcriptionnelle par le glucose des gènes de la glycolyse et de la lipogenèse dans le foie (implication dans la physiopathologie de l'obésité et/ ou du diabète de type 2)

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Hidden variant of ChREBP in fat links lipogenesis to insulin sensitivity.

International audienceThe ChREBP transcription factor is regulated by glucose and plays a role in insulin sensitivity, but the mechanism underlying these effects remains unclear. In a recent Nature article, Herman et al. (2012) show that a shorter ChREBP isoform (ChREBP-β) links glucose transport to lipogenesis in white adipose tissue

Hepatic Gene Regulation by Glucose and Polyunsaturated Fatty Acids: A Role for ChREBP

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La régulation de l'expression des gènes par le glucose

Le glucose ne doit plus être considéré comme un simple carburant énergétique des cellules mais aussi comme une molécule de signalisation importante dans la régulation des gènes glycolytiques et lipogéniques impliqués dans la mise en réserve d'énergie sous forme de triglycérides. Les effets transcriptionnels du glucose sur les gènes des enzymes impliqués dans la glycolyse et la lipogenèse hépatiques impliquent un facteur de transcription spécifique, ChREBP, dont les caractéristiques et le mécanisme d'activation sont décrits en détail. Enfin, un exemple de l'implication possible de ChREBP dans la physiopathologie de l'obésité et du diabète de type 2 est présenté

Cooperation Between the NRF2 Pathway and Oncogenic β‐catenin During HCC Tumorigenesis

International audienceCTNNB1 (catenin beta 1)-mutated hepatocellular carcinomas (HCCs) account for a large proportion of human HCCs. They display high levels of respiratory chain activity. As metabolism and redox balance are closely linked, tumor cells must maintain their redox status during these metabolic alterations. We investigated the redox balance of these HCCs and the feasibility of targeting this balance as an avenue for targeted therapy. We assessed the expression of the nuclear erythroid 2 p45-related factor 2 (NRF2) detoxification pathway in an annotated human HCC data set and reported an enrichment of the NRF2 program in human HCCs with CTNNB1 mutations, largely independent of NFE2L2 (nuclear factor, erythroid 2 like 2) or KEAP1 (Kelch-like ECH-associated protein 1) mutations. We then used mice with hepatocyte-specific oncogenic β-catenin activation to evaluate the redox status associated with β-catenin activation in preneoplastic livers and tumors. We challenged them with various oxidative stressors and observed that the β-catenin pathway activation increased transcription of Nfe2l2, which protects β-catenin-activated hepatocytes from oxidative damage and supports tumor development. Moreover, outside of its effects on reactive oxygen species scavenging, we found out that Nrf2 itself contributes to the metabolic activity of β-catenin-activated cells. We then challenged β-catenin activated tumors pharmacologically to create a redox imbalance and found that pharmacological inactivation of Nrf2 was sufficient to considerably decrease the progression of β-catenin-dependent HCC development. Conclusion: These results demonstrate cooperation between oncogenic β-catenin signaling and the NRF2 pathway in CTNNB1-mediated HCC tumorigenesis, and we provide evidence for the relevance of redox balance targeting as a therapeutic strategy in CTNNB1-mutated HCC

The absence of hepatic glucose-6 phosphatase/ChREBP couple is incompatible with survival in mice.

International audienceObjective: Glucose production in the blood requires the expression of glucose-6 phosphatase (G6Pase), a key enzyme that allows glucose-6 phosphate (G6P) hydrolysis into free glucose and inorganic phosphate. We previously reported that the hepatic suppression of G6Pase leads to G6P accumulation and to metabolic reprogramming in hepatocytes from liver G6Pase-deficient mice (L.G6pc-/-). Interestingly, the activity of the transcription factor carbohydrate response element-binding protein (ChREBP), central for de novo lipid synthesis, is markedly activated in L.G6pc-/- mice, which consequently rapidly develop NAFLD-like pathology. In the current work, we assessed whether a selective deletion of ChREBP could prevent hepatic lipid accumulation and NAFLD initiation in L.G6pc-/- mice.Methods: We generated liver-specific ChREBP (L.Chrebp-/-)- and/or G6Pase (L.G6pc-/-)-deficient mice using a Cre-lox strategy in B6.SACreERT2 mice. Mice were fed a standard chow diet or a high-fat diet for 10 days. Markers of hepatic metabolism and cellular stress were analysed in the liver of control, L. G6pc-/-, L. Chrebp-/- and double knockout (i.e., L.G6pc-/-.Chrebp-/-) mice.Results: We observed that the deletion of ChREBP in liver of L.G6pc-/-.Chrebp-/- mice drastically decreased lipid accumulation. Importantly, it also exacerbated glycogen accumulation leading to hepatic water retention and aggravated hepatomegaly. At the mechanistic level, in the absence of ChREBP, elevated G6P concentrations caused by lack of G6Pase are rerouted towards glycogen synthesis. This caused animal distress and hepatocyte damage, characterised by ballooning and moderate fibrosis, paralleled with acute endoplasmic reticulum stress.Conclusions: Our study reveals the crucial role of the ChREBP-G6Pase duo in the regulation of G6P-regulated pathways in the liver