Sabio lab

at the CNIC

Tag: thermogenesis

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.

p38α blocks brown adipose tissue thermogenesis through p38δ inhibition

Nuria Matesanz, Ivana Nikolić, Magdalena Leiva, Marta Pulgarín-Alfaro, Ayelén M. Santamans, Edgar Bernardo, Alfonso Mora, Leticia Herrera-Melle, Elena Rodríguez, Daniel Beiroa, Ainoa Caballero, Elena Martín-García, Rebeca Acín-Pérez, Lourdes Hernández-Cosido, Luis Leiva-Vega, Jorge L. Torres, Francisco Centeno, Angel R. Nebreda, José Antonio Enríquez, Rubén Nogueiras, Miguel Marcos & Guadalupe Sabio.

Adipose tissue has emerged as an important regulator of whole-body metabolism, and its capacity to dissipate energy in the form of heat has acquired a special relevance in recent years as potential treatment for obesity. In this context, the p38MAPK pathway has arisen as a key player in the thermogenic program because it is required for the activation of brown adipose tissue (BAT) thermogenesis and participates also in the transformation of white adipose tissue (WAT) into BAT-like depot called beige/brite tissue.

Regulation of browning and BAT activation by p38 pathway (Image: Ivana Nikolić).

Here, using mice that are deficient in p38α specifically in adipose tissue (p38αFab-KO), we unexpectedly found that lack of p38α protected against high-fat diet (HFD)-induced obesity. We also showed that p38αFab-KO mice presented higher energy expenditure due to increased BAT thermogenesis. Mechanistically, we found that lack of p38α resulted in the activation of the related protein kinase family member p38δ.

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).

Altogether, we have elucidated a mechanism implicated in physiological BAT activation that has potential clinical implications for the treatment of obesity and related diseases such as diabetes.


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