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Category: Publications (page 1 of 4)

Adiponectin accounts for gender differences in hepatocellular carcinoma incidence

Elisa Manieri, Leticia Herrera-Melle, Alfonso Mora, Antonia Tomás-Loba, Luis Leiva-Vega, Delia I. Fernández, Elena Rodríguez, Laura Morán, Lourdes Hernández-Cosido, Jorge L. Torres, Luisa M. Seoane, Francisco Javier Cubero, Miguel Marcos & Guadalupe Sabio.

Hepatocellular carcinoma (HCC) is the sixth most common cancer type and the fourth leading cause of cancer-related death. This cancer appears with higher incidence in men and during obesity; however, the specific mechanisms underlying this correlation are unknown.

Adiponectin accounts for gender differences in liver cancer

HCC gender differences are driven by adiponectin (Image: Leticia Herrera-Melle).

Adipose tissue, a key organ in metabolic syndrome, shows evident gender disparities in the production of adipokines. Levels of the important adipokine adiponectin decrease in men during puberty, as well as in the obese state. Here, we show that this decrease in adiponectin levels is responsible for the increased liver cancer risk in males. We found that testosterone activates the protein JNK in mouse and human adipocytes. JNK-mediated inhibition of adiponectin secretion increases liver cancer cell proliferation, since adiponectin protects against liver cancer development through the activation of AMP-activated protein kinase (AMPK) and p38α.

This study provides insight into adipose tissue to liver crosstalk and its gender relation during cancer development, having the potential to guide strategies for new cancer therapeutics

Protein kinase D1 deletion in adipocytes enhances energy dissipation and protects against adiposity

Mona C. Löffler, Alexander E. Mayer, Jonathan Trujillo Viera, Angel Loza Valdes, Rabih El‐Merahbi, Carsten P. Ade, Till Karwen, Werner Schmitz, Anja Slotta, Manuela Erk, Sudha Janaki‐Raman, Nuria Matesanz, Jorge L. Torres, Miguel Marcos, Guadalupe Sabio, Martin Eilers, Almut Schulze, Grzegorz Sumara.

Nutrient overload in combination with decreased energy dissipation promotes obesity and diabetes. Obesity results in a hormonal imbalance, which among others activates G protein‐coupled receptors utilizing diacylglycerol (DAG) as secondary messenger. Protein kinase D1 (PKD1) is a DAG effector, which integrates multiple nutritional and hormonal inputs, but its physiological role in adipocytes is unknown.

Correlation between PKD1 and HOMA‐IR

Correlation between PKD1 expression and HOMA‐IR levels in human sWAT (Image: Nuria Matesanz).

Here, we show that PKD1 promotes lipogenesis and suppresses mitochondrial fragmentation, biogenesis, respiration, and energy dissipation in an AMP‐activated protein kinase (AMPK)‐dependent manner. Moreover, mice lacking PKD1 in adipocytes are resistant to diet‐induced obesity due to elevated energy expenditure. Beiging of adipocytes promotes energy expenditure and counteracts obesity. Consistently, deletion of PKD1 promotes expression of the β3‐adrenergic receptor (ADRB3) in a CCAAT/enhancer binding protein (C/EBP)‐α‐ and δ‐dependent manner, which leads to the elevated expression of beige markers in adipocytes and subcutaneous adipose tissue. Finally, deletion of PKD1 in adipocytes improves insulin sensitivity and ameliorates liver steatosis.

Our results showed that p38δ is activated in BAT by cold exposure, and lack of this kinase specifically in adipose tissue (p38δFab-KO) resulted in overweight together with reduced energy expenditure and lower body and skin surface temperature in the BAT region. These observations indicate that p38α probably blocks BAT thermogenesis through p38δ inhibition. Consistent with the results obtained in animals, p38α was reduced in visceral and subcutaneous adipose tissue of subjects with obesity and was inversely correlated with body mass index (BMI).

Thus, depletion of PKD1 in adipocytes increases energy dissipation by several complementary mechanisms and might represent an attractive strategy to treat obesity and its related complications.

p107 deficiency increases energy expenditure by inducing brown‐fat thermogenesis and browning of white adipose tissue

Juan Cunarro, Xabier Buque, Sabela Casado, Javier Lugilde, Anxo Vidal, Alfonso Mora, Guadalupe Sabio, Rubén Nogueiras, Patricia Aspichueta, Carlos Diéguez & Sulay Tovar.

The tumor suppressor p107, a pocket protein member of the retinoblastoma susceptibility protein family, plays an important role in the cell cycle and cellular adipocyte differentiation. Nonetheless, the mechanism by which it influences whole body energy homeostasis is unknown.

p107 during adipocyte differentiation

p107 is underexpressed in the stromal fraction (time 0) with the expression increasing during adipocyte differentiation (Image: Alfonso Mora).

The phenotype of p107 knockout (KO) mixed‐background C57BL6/129 mice phenotype is studied by focusing on the involvement of white and brown adipose tissue (WAT and BAT) in energy metabolism. It is shown that p107 KO mice are leaner and have high‐fat diet resistence. This phenomenon is explained by an increase of energy expenditure. The higher energy expenditure is caused by the activation of thermogenesis and may be mediated by both BAT and the browning of WAT. Consequently, it leads to the resistance of p107 KO mice to high‐fat diet effects, prevention of liver steatosis, and improvement of the lipid profile and glucose homeostasis.

These data allowed the unmasking of a mechanism by which a KO of p107 prevents diet‐induced obesity by increasing energy expenditure via increased thermogenesis in BAT and browning of WAT, indicating the relevance of p107 as a modulator of metabolic activity of both brown and white adipocytes. Therefore, it can be targeted for the development of new therapies to ameliorate the metabolic syndrome.

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