Notch Signaling Mechanisms in Adipogenesis and Stem Cell Biology

Notch signalling is a conserved cell‐to‐cell communication pathway that directs the fate of multipotent precursors and stem cells. Engagement of Notch receptors by membrane-bound ligands triggers proteolytic cleavage and release of the Notch intracellular domain (NICD), which translocates to the nucleus and modulates transcriptional networks. In adipogenesis, Notch activity intersects with master regulators such as PPARγ and C/EBPα to balance preadipocyte maintenance against terminal differentiation. Depending on signal strength and ligand context, Notch can promote or inhibit the development of white versus brown adipocytes, thereby influencing tissue plasticity, energy expenditure and systemic metabolism. In stem cell biology, Notch signalling sustains the undifferentiated state of mesenchymal stromal cells, neural crest derivatives and adipose-derived stem cells by regulating genes involved in self-renewal and lineage commitment. Crosstalk with pathways such as Wnt, TGF-β and insulin integrates environmental and metabolic cues to govern tissue homeostasis and repair. Dysregulation of Notch underlies impaired adipose function, metabolic disease and compromised regenerative capacity, highlighting its potential as a therapeutic target in obesity, diabetes and regenerative medicine.

Research from Nature Portfolio

Recent studies have shown that SLC35D3, a transmembrane protein in adipocytes, binds the extracellular domain of Notch1 and sequesters it within the endoplasmic reticulum. This inhibition of Notch1 signalling enhances white adipose tissue browning, increases energy expenditure and improves insulin sensitivity in mouse models, suggesting a novel metabolic intervention point. Investigations into non-canonical ligands DLK1 and DLK2 have revealed their capacity to fine-tune global Notch receptor activity in 3T3-L1 preadipocytes. While overexpression of any Notch receptor drives adipogenesis, distinct combinations with DLK proteins bias cells towards thermogenic brown-like or lipid-storing white-like phenotypes. This work uncovers a ligand-dependent mechanism that determines adipocyte heterogeneity and highlights precise Notch modulation as key to tissue function.

Notch Signaling Mechanisms in Adipogenesis and Stem Cell Biology publication trend

The graph below shows the total number of articles in notch signaling mechanisms in adipogenesis and stem cell biology across all publications each year (not limited to Nature Index journals).

Technical terms

Notch signalling: A cell–cell communication cascade in which ligand binding triggers receptor cleavage and nuclear translocation of NICD to regulate gene expression.

Adipogenesis: The process by which mesenchymal progenitor cells undergo lineage commitment, growth arrest and lipid accumulation to become mature adipocytes.

Adipocyte browning: The conversion of energy-storing white fat cells into thermogenically active brown-like adipocytes characterised by mitochondrial enrichment and UCP1 expression.

Non-canonical ligand: A Notch ligand that modulates receptor activation in an atypical manner, affecting signal amplitude or duration rather than following classical activation routes.

Mesenchymal stromal cell: A multipotent progenitor found in various tissues, capable of differentiating into adipocytes, osteoblasts and other cell types, and regulated by Notch signalling.

References

1. SLC35D3 promotes white adipose tissue browning to ameliorate obesity by NOTCH signaling. Nature Communications (2023).
2. DLK proteins modulate NOTCH signaling to influence a brown or white 3T3-L1 adipocyte fate. Scientific Reports (2018).
3. TGFBI remodels adipose metabolism by regulating the Notch-1 signaling pathway. Experimental & Molecular Medicine (2023).
4. Notch-1 Controls the Expression of Fatty Acid-activated Transcription Factors and Is Required for Adipogenesis*. Journal of Biological Chemistry (1997).
5. Effects of Adipose Tissue-Specific Knockout of Delta-like Non-Canonical Notch Ligand 1 on Lipid Metabolism in Mice. International Journal of Molecular Sciences (2023).