Notch signaling as a novel regulator of metabolism

Abstract

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.

Keywords: insulin resistance; notch signaling; obesity; type 2 diabetes.

Figure 1. Notch regulates gluconeogenesis and lipogenesis of hepatocytes

Notch signaling regulates hepatic glucose production through synergy with FoxO1, which directly activates the transcription of G6pc and Pck1, the rate-limiting enzymes in hepatic glycogenolysis and gluconeogenesis, respectively. Transcriptionally active FoxO1 is phosphorylated by AKT and excluded from nucleus. In addition, Notch signaling promotes hepatic lipogenesis through an unknown factor that stabilizes mTORC1, which is normally activated by amino acids, as well as the insulin-PI3K-AKT pathway. mTORC1 in turn activates Srebp1c, a key factor that turns on transcription of Fasn, which encodes a rate limiting enzyme in lipogenesis. In obesity, high levels of glucose and free fatty acids (FFA) activate the AMPK-mTOC1-STAT3 pathway, which eventually upregulates Jag1 and activates Notch signaling in the neighbor hepatocyte. Dotted line indicates indirect effect. G6pc, glucose-6-phosphatase, catalytic subunit; Pck1, phosphoenolpyruvate carboxykinase; AMPK, AMP-activated protein kinase; mTORC1, mammalian target of rapamycin complex 1; STAT3, signal transducer and activator of transcription 3; Srebp1c, sterol regulatory element-binding protein 1c; FoxO1, forkhead box protein O1; TG, triglyceride; Fasn, fatty acid synthase; PI3K, phosphatidylinositol 3-kinase.

Figure 2. Notch signaling regulates adipocyte thermogenesis

In response to cold ambient temperature, sympathetic nervous system releases catecholamine, which binds with β-adrenergic receptor and activates lipolysis through the cAMP pathway. Fatty acids (FAs) can directly activate uncoupling protein 1 (UCP1) for heat production. Notch target gene Hes1 directly binds to the promoter region of Prdm16, Ppargc1a and Pparγ, and inhibit their transcription. This leads to reduced mitochondria numbers and expression of UCP1. Notch signaling promotes activation and production of proinflammatory cytokines mediated by NF-κB, which attracts macrophages and together cause low-grade systematic inflammation and exacerbates insulin resistance. In obesity, infiltrated macrophages activate transcription of Notch ligand Dll4 through NF-κB. Dotted line indicates indirect effect. IL-1β, interleukin 1β; TNFα, tumor necrosis factor α; IL-1R, interleukin 1 receptor; TNFR, tumor necrosis factor receptor; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells; Dll4, delta-like 4; Pparγ, peroxisome proliferator-activated receptor gamma; PGC1α, Pparγ coactivator 1-alpha; Prdm16, PR domain containing 16;.

Figure 3. Notch signaling and macrophage polarization

M1 (classically activated) and M2 (alternatively activated) macrophages are activated by distinct and mutually exclusive activation programs. Notch signaling promotes M1 macrophage polarization through synergy with NF-κB and by upregulating expression of the M1 macrophage regulator IRF8. Notch signaling inhibits M2 macrophage polarization through repressing JMJD3, a M2 macrophage regulator. M1 and M2 macrophages have distinct secretory profiles, which oppositely control inflammation and impact systematic insulin sensitivity. Abbreviation: IFNγ, Interferon gamma; LPS, Lipopolysaccharide; IRF8, Interferon regulatory factor 8; JMJD3, Jumonji domain containing 3; MCP-1, monocyte chemotactic protein 1.