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Tag: diabetes (Page 1 of 8)

Conventional type 1 dendritic cells protect against age-related adipose tissue dysfunction and obesity

Elena Hernández-García, Francisco J. Cueto, Emma C. L. Cook, Ana Redondo-Urzainqui, Sara Charro-Zanca, Iñaki Robles-Vera, Ruth Conde-Garrosa, Ivana Nikolić, Guadalupe Sabio, David Sancho & Salvador Iborra.

Conventional dendritic cells (cDCs) scan and integrate environmental cues in almost every tissue, including exogenous metabolic signals. While cDCs are critical in maintaining immune balance, their role in preserving energy homeostasis is unclear.

Body composition by MRI.

Here, we showed that Batf3-deficient mice lacking conventional type 1 DCs (cDC1s) had increased body weight and adiposity during aging. This led to impaired energy expenditure and glucose tolerance, insulin resistance, dyslipidemia, and liver steatosis. cDC1 deficiency caused adipose tissue inflammation that was preceded by a paucity of NK1.1+ invariant NKT (iNKT) cells. Accordingly, among antigen-presenting cells, cDC1s exhibited notable induction of IFN-γ production by iNKT cells, which plays a metabolically protective role in lean adipose tissue. Flt3L treatment, which expands the dendritic cell (DC) compartment, mitigated diet-induced obesity and hyperlipidemia in a Batf3-dependent manner. This effect was partially mediated by NK1.1+ cells.

These results reveal a new critical role for the cDC1-iNKT cell axis in the regulation of adipose tissue homeostasis.

p38γ and p38δ regulate postnatal cardiac metabolism through glycogen synthase 1

Ayelén M. Santamans, Valle Montalvo-Romeral, Alfonso Mora, Juan Antonio Lopez, Francisco González-Romero, Daniel Jimenez-Blasco, Elena Rodríguez, Aránzazu Pintor-Chocano, Cristina Casanueva-Benítez, Rebeca Acín-Pérez, Luis Leiva-Vega, Jordi Duran, Joan J. Guinovart, Jesús Jiménez-Borreguero, José Antonio Enríquez, María Villlalba-Orero, Juan P. Bolaños, Patricia Aspichueta, Jesús Vázquez, Bárbara González-Terán, Guadalupe Sabio.

During the first weeks of postnatal heart development, cardiomyocytes undergo a major adaptive metabolic shift from glycolytic energy production to fatty acid oxidation. This metabolic change is contemporaneous to the up-regulation and activation of the p38γ and p38δ stress-activated protein kinases in the heart.

Cardiac fibrosis (Image: Ayelén Santamans/CNIC).

We demonstrate that p38γ/δ contribute to the early postnatal cardiac metabolic switch through inhibitory phosphorylation of glycogen synthase 1 (GYS1) and glycogen metabolism inactivation. Premature induction of p38γ/δ activation in cardiomyocytes of newborn mice results in an early GYS1 phosphorylation and inhibition of cardiac glycogen production, triggering an early metabolic shift that induces a deficit in cardiomyocyte fuel supply, leading to whole-body metabolic deregulation and maladaptive cardiac pathogenesis. Notably, the adverse effects of forced premature cardiac p38γ/δ activation in neonate mice are prevented by maternal diet supplementation of fatty acids during pregnancy and lactation.

These results suggest that diet interventions have a potential for treating human cardiac genetic diseases that affect heart metabolism.

O-GlcNAcylated p53 in the liver modulates hepatic glucose production

Maria J. Gonzalez-Rellan, Marcos F. Fondevila, Uxia Fernandez, Amaia Rodríguez, Marta Varela-Rey, Christelle Veyrat-Durebex, Samuel Seoane, Ganeko Bernardo, Fernando Lopitz-Otsoa, David Fernández-Ramos, Jon Bilbao, Cristina Iglesias, Eva Novoa, Cristina Ameneiro, Ana Senra, Daniel Beiroa, Juan Cuñarro, Maria DP Chantada-Vazquez, Maria Garcia-Vence, Susana B. Bravo, Natalia Da Silva Lima, Begoña Porteiro, Carmen Carneiro, Anxo Vidal, Sulay Tovar, Timo D. Müller, Johan Ferno, Diana Guallar, Miguel Fidalgo, Guadalupe Sabio, Stephan Herzig, Won Ho Yang, Jin Won Cho, Maria Luz Martinez-Chantar, Roman Perez-Fernandez, Miguel López, Carlos Dieguez, Jose M. Mato, Oscar Millet, Roberto Coppari, Ashwin Woodhoo, Gema Fruhbeck & Ruben Nogueiras.

p53 regulates several signaling pathways to maintain the metabolic homeostasis of cells and modulates the cellular response to stress. Deficiency or excess of nutrients causes cellular metabolic stress, and we hypothesized that p53 could be linked to glucose maintenance.

Pyruvate tolerance test.

We show here that upon starvation hepatic p53 is stabilized by O-GlcNAcylation and plays an essential role in the physiological regulation of glucose homeostasis. More specifically, p53 binds to PCK1 promoter and regulates its transcriptional activation, thereby controlling hepatic glucose production. Mice lacking p53 in the liver show a reduced gluconeogenic response during calorie restriction. Glucagon, adrenaline and glucocorticoids augment protein levels of p53, and administration of these hormones to p53 deficient human hepatocytes and to liver-specific p53 deficient mice fails to increase glucose levels.

Moreover, insulin decreases p53 levels, and over-expression of p53 impairs insulin sensitivity. Finally, protein levels of p53, as well as genes responsible of O-GlcNAcylation are elevated in the liver of type 2 diabetic patients and positively correlate with glucose and HOMA-IR.

Overall these results indicate that the O-GlcNAcylation of p53 plays an unsuspected key role regulating in vivo glucose homeostasis.

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