Notch signaling as a novel regulator of metabolism

• Inhibition of Notch signaling improves liver metabolism and ameliorates steatosis.
• Genetic or pharmacological inactivation of Notch signaling promotes beige adipogenesis and ameliorates obesity.
• HFDs activate Notch signaling in the brain and inhibit neurogenesis of central neuroendocrine cells.
• Notch signaling favors proinflammatory M1 macrophages over anti-inflammatory M2 macrophages.

Evolutionarily unprepared for modern high-calorie diets and sedentary lifestyles, humans are now unprecedentedly susceptible to metabolic disorders such as obesity, type 2 diabetes (T2D), nonalcoholic fatty liver, and cardiovascular disease. These metabolic conditions are intertwined, together known as metabolic syndrome, and compromise human life quality as well as lives. Notch signaling, a fundamental signal transduction pathway critical for cell–cell communication and development, has recently been recognized as a key player in metabolism. This review summarizes the emerging roles of Notch signaling in regulating the metabolism of various cell and tissue types, with emphasis on the underlying molecular mechanisms and the potential of targeting this signal axis to treat metabolic diseases.