Resveratrol and HIV‐protease inhibitors control UCP1 expression through opposite effects on p38 MAPK phosphorylation in human adipocytes

• Published in: Journal of cellular physiology Vol. 235; no. 2; pp. 1184 - 1196
• Main Authors: Ravaud, Christophe, Paré, Martin, Yao, Xi, Azoulay, Stéphane, Mazure, Nathalie M., Dani, Christian, Ladoux, Annie
• Format: Journal Article
• Language: English
• Published: United States Wiley Subscription Services, Inc 01.02.2020; Wiley
• Subjects: Adipocytes; adipose tissue; aging; brown adipocytes; Browning; Cell differentiation; Drugs; Energy expenditure; energy metabolism; HIV; HIV protease inhibitors; Human immunodeficiency virus; Life Sciences; Lopinavir; MAP kinase; Mitochondria; Molecular modelling; p38 mitogen‐activated kinase; Phenotypes; Phosphorylation; Protease; Protease inhibitors; Proteinase inhibitors; Resveratrol; sirtuin‐1; Thermogenesis; UCP1; white adipocytes; white adipocytes; brown adipocytes; sirtuin-1; HIV protease inhibitors; p38 mitogen-activated kinase; UCP1; adipose tissue; aging; resveratrol; energy metabolism
• ISSN: 0021-9541; 1097-4652
• DOI: 10.1002/jcp.29032

Brown and brown‐like adipocytes (BBAs) control thermogenesis and are detected in adult humans. They express UCP1, which transforms energy into heat. They appear as promising cells to fight obesity. Deciphering the molecular mechanisms leading to the browning of human white adipocytes or the whitening of BBAs represents a goal to properly and safely control the pathways involved in these processes. Here, we analyzed how drugs endowed with therapeutic potential affect the differentiation of human adipose progenitor‐cells into BBAs and/or their phenotype. We showed that HIV‐protease inhibitors (PI) reduced UCP1 expression in BBAs modifying their metabolic profile and the mitochondria functionality. Lopinavir (LPV) was more potent than darunavir (DRV), a last PI generation. PPARγ and PGC‐1α were decreased in a PI or cell‐specific manner, thus altering UCP1's constitutive expression. In addition, LPV altered p38 MAPK phosphorylation, blunting then the β‐adrenergic responses. In contrast, low doses of resveratrol stimulated the activatable expression of UCP1 in a p38 MAPK‐dependent manner and counteracted the LPV induced loss of UCP1. This effect was independent of the resveratrol‐induced sirtuin‐1 expression. Altogether our results uncover how drugs impact crucial components of the networks regulating the expression of the thermogenic signature. They provide important information to control the relevant pathways involved in energy expenditure. We report here that HIV‐protease inhibitors impair browning in human adipocytes. In contrast, resveratrol promotes UCP1 expression. Despite their opposite effects, these drugs share a common target: p38 MAPK that plays a crucial role to control pathways involved in energy expenditure.