p38α blocks brown adipose tissue thermogenesis through p38δ inhibition
| Autor: | Angel R. Nebreda, Elena Martín-García, Magdalena Leiva, Leticia Herrera-Melle, Ainoa Caballero, Jorge L Torres, Ayelén M Santamans, Lourdes Hernández-Cosido, Marta Pulgarín-Alfaro, Rebeca Acín-Pérez, Edgar Bernardo, Rubén Nogueiras, Ivana Nikolic, Nuria Matesanz, Alfonso Mora, Luis Leiva-Vega, José Antonio Enríquez, Miguel Marcos, Guadalupe Sabio, Daniel Beiroa, Elena Rodríguez, Francisco Centeno |
|---|---|
| Přispěvatelé: | European Foundation for the Study of Diabetes, Fundación Lilly, Unión Europea. Comisión Europea, Ministerio de Economía, Industria y Competitividad (España), Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF), European Research Council, Junta de Castilla y León (España), Xunta de Galicia (España), Fundación ProCNIC, Comunidad de Madrid (España), Government of Extremadura (España) |
| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
Male
0301 basic medicine Physiology Adipose tissue White adipose tissue Biochemistry Body Mass Index Fats Mitogen-Activated Protein Kinase 14 Mitogen-Activated Protein Kinase 13 Adipose Tissue Brown Animal Cells Brown adipose tissue Medicine and Health Sciences Adipocytes Biology (General) Uncoupling Protein 1 Connective Tissue Cells Mice Knockout 2. Zero hunger General Neuroscience Thermogenesis Lipids Thermogenin Adipocytes Brown medicine.anatomical_structure Adipose Tissue Physiological Parameters Connective Tissue Brown Adipose Tissue Anatomy Cellular Types General Agricultural and Biological Sciences Research Article Adult medicine.medical_specialty MAP Kinase Signaling System QH301-705.5 Context (language use) Biology Models Biological General Biochemistry Genetics and Molecular Biology Diabetes Mellitus Experimental 03 medical and health sciences Internal medicine medicine Animals Humans Obesity Protein kinase A Nutrition 030102 biochemistry & molecular biology General Immunology and Microbiology Body Weight Biology and Life Sciences Cell Biology medicine.disease Diet Enzyme Activation Mice Inbred C57BL Biological Tissue 030104 developmental biology Endocrinology Physiological Processes Energy Metabolism |
| Zdroj: | PLoS Biology, Vol 16, Iss 7, p e2004455 (2018) Repisalud Instituto de Salud Carlos III (ISCIII) PLoS Biology |
| ISSN: | 1545-7885 1544-9173 |
| Popis: | 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. 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 (p38δ Fab-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. Author summary Accumulation of fat in adipose tissue is essential to store energy and insulate the body; however, excessive body fat leads to obesity. Of the 2 existing types of adipose tissue, white adipose tissue (WAT) stores energy, whereas brown adipose tissue (BAT) can produce heat. Activation of BAT and transformation of WAT into brown-like ‘brite/beige’ adipocytes have recently emerged as novel strategies against obesity. The uncoupling protein 1 (UCP1) is a hallmark of BAT and is responsible for triggering these 2 processes under the regulation of the p38 MAP kinase (p38MAPK) pathway, but the underlying mechanisms remain unknown. Here, we have analysed this process in detail and demonstrate that a protein kinase called p38α directly correlates with UCP1 levels in human adipose tissue, while it inversely correlates with body mass index (BMI). We find that mice lacking p38α in adipose tissue are protected against diet-induced obesity due to increased body temperature. In addition, another p38 family member, p38δ, is activated in these adipocytes lacking p38α and reduces their thermogenic capacity. Our results suggest that these 2 members of the p38 family have opposite roles in controlling thermogenesis. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|