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. 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. a type of vascular disease characterized by plaque accumulation in arteries resulting from increased cytokines due to metabolic dysfunction, which leads to activation of the innate immune system and chronic inflammation. a newly defined type of adipocyte within the WAT. They are similar to brown adipocytes in that they express UCP1 and have the capacity for thermogenesis. Their gene expression signature is distinct from those of both brown adipocytes and white adipocytes. a type of adipocyte that is abundant in rodents and newborn humans but less abundant in adult humans and has a high capacity for adaptive thermogenesis. Brown adipocytes contain numerous mitochondria expressing UCP1, which uncouples the proton gradient from ATP production to generate heat. Due to their ability to burn lipids (through β-oxidation) to generate heat, brown adipocytes increase energy expenditure and are negatively associated with obesity. single-pass transmembrane proteins whose extracellular domain acts as a ligand for Notch receptors on a neighboring cell. In mammals, the family members include Delta-like (Dll1, Dll3, Dll4) and Jagged (Jag1, Jag2). a biochemical process that generates glucose from noncarbohydrate carbon substrates like pyruvate. a biochemical process whereby glycogen is broken down to glucose 1-phosphate. a biochemical process that converts glucose to pyruvate, releasing free energy in the form of ATP. a transcription repressor that belongs to the bHLH protein family with important roles in the Notch signaling pathway. a nuclear protein that belongs to the Hes-related (HESR) family of basic helix–loop–helix (bHLH)-type transcriptional repressors. Hey expression is induced by Notch signaling. a metabolic pathway that has two separate processes: fatty acid synthesis and triglyceride synthesis. also known as classically and alternatively activated macrophages, respectively. M1 macrophages are activated in response to bacterial infections or lipopolysaccharide and IFN-γ and are highly inflammatory. By contrast, M2 macrophages are activated in response to parasitic infections or IL-4 and -13 and are anti-inflammatory. a family of single-pass transmembrane receptors comprising an NECD, a TM domain, and an NICD. Activation of Notch receptors leads to release of the NICD, which then acts as a transcription factor to regulate gene expression. also known as CBF1 in humans; a highly conserved DNA-binding protein that mediates canonical Notch signaling. a major type of adipocyte in animals and humans that store energy in the form of triglycerides.