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. Author manuscript; available in PMC: 2019 Dec 1.
Published in final edited form as: Nat Rev Endocrinol. 2018 Dec;15(1):21–32. doi: 10.1038/s41574-018-0096-z

Fig. 4 |. Hypoxia-inducible factor 2α in metabolic disease.

Fig. 4 |

Under conditions of obesity, the small intestine becomes hypoxic, leading to the accumulation of hypoxia-inducible factor 2α (HIF2α) in epithelial cells. HIF2α activates the gene encoding sialidase 3 (NEU3), which hydrolyses gangliosides (located in the plasma membrane) to form ceramides. Increased levels of ceramides cause obesity as a result of decreased adipose browning, increased steatosis owing to upregulation of fatty acid synthesis and increased insulin resistance. Inhibition of HIF2α by PT2385 or inhibition of NEU3 by N-acetyl-2,3-didehydro-N-acetyl-neuraminic acid (DANA) or naringin decreases serum levels of ceramides, reduces obesity and fatty liver and increases insulin sensitivity. HRE, HIF regulating element.