Obesity is a chronic and debilitating disorder that originates from alterations in energy-sensing brain circuits controlling body weight gain and food intake. The dysregulated syntheses and actions of lipid mediators in the hypothalamus induce weight gain and overfeeding, but the molecular and cellular underpinnings of these alterations remain elusive. In response to changes in the nutritional status, different lipid sensing pathways in the hypothalamus direct body energy needs in a Yin-Yang model. Endocannabinoids orchestrate the crosstalk between hypothalamic circuits and the sympathetic nervous system to promote food intake and energy accumulation during fasting, whereas bile acids act on the same top-down axis to reduce energy intake and possibly storage after the meal. In obesity, the bioavailability and downstream cellular actions of endocannabinoids and bile acids are altered in hypothalamic neurons involved in body weight and metabolic control. Thus, the onset and progression of this disease might result from an imbalance in hypothalamic sensing of multiple lipid signals, which are possibly integrated by common molecular nodes. In this viewpoint, we discuss a possible model that explains how bile acids and endocannabinoids may exert their effects on energy balance regulation via interconnected mechanisms at the level of the hypothalamic neuronal circuits. Therefore, we propose a new conceptual framework for understanding and treating central mechanisms of maladaptive lipid action in obesity. © 2022 Elsevier B.V. and Société Française de Biochimie et Biologie Moléculaire (SFBBM)< Réduire