Editors' ChoiceMetabolism

Going a Notch More Beige

Sci. Signal.  12 Aug 2014:
Vol. 7, Issue 338, pp. ec211
DOI: 10.1126/scisignal.2005783

Activation of the Notch receptor triggers γ-secretase–mediated cleavage of the receptor, generating the Notch intracellular domain, which translocates to the nucleus, binds to the Rbpj transcriptional complex, and activates transcription of target genes, such as those in the Hes family. Studies with cultured cells have generated conflicting results about the role of Notch signaling in adipocyte differentiation. Bi et al. generated mice with white adipocyte–specific knockout of Notch1 (aNotch1 mice) or Rbpj (aRbpj mice). In aNotch1 mice, white adipose tissue depots weighed less, contained smaller cells, and showed increased amounts of UCP1, a protein that is abundant in brown adipose tissue, compared with wild-type mice. Both aNotch1 and aRbpj mice showed increased expression of brown fat–specific genes (such as Ucp1, Ppargc1a, and Prdm16) in white adipose tissue depots and increased body temperature, suggesting greater thermogenesis. These results suggested that ablation of Notch signaling in white adipocytes enabled these cells to acquire some of the characteristics of brown adipocytes, which dissipate energy in the form of heat. Such white adipocytes are called beige adipocytes. aNotch1 and aRbpj mice showed improved insulin sensitivity and blood glucose tolerance compared with wild-type mice, and inguinal white adipose tissue explants from aNotch1 mice showed increased insulin-stimulated uptake of glucose. Furthermore, aNotch1 mice were more metabolically active (which suggested that they had increased numbers of beige adipocytes) and generated more beige adipocytes in response to cold stress. When fed a high-fat diet, aNotch1 mice gained less weight and had better insulin sensitivity and glucose tolerance than did wild-type mice. In the white adipose tissue of wild-type mice fed a high-fat diet, the mRNA and protein abundance of Notch receptors, targets, or both was increased, as was the abundance of Lep, which encodes leptin, a hormone produced by white adipose tissue. Inhibition of Notch signaling in adipocytes from wild-type mice with a γ-secretase inhibitor resulted in increased expression of brown fat–specific genes, whereas mice that overexpressed the Notch1 intracellular domain in white adipose tissue showed decreased expression of brown fat–specific genes. The transcriptional repressor Hes1, which is encoded by a Notch target gene, bound to the promoters of Ppargc1a and Prdm16 and repressed their expression. Administration of the γ-secretase inhibitor DBZ to ob/ob mice (which are a genetic model of obesity) reduced body weight gain, the size and weight of white adipose tissue depots, and lipid accumulation in the liver; improved insulin sensitivity and glucose tolerance; and resulted in decreased expression of various Notch target genes and increased expression of Ucp1 and Ppargc1a in white adipose tissue. In the accompanying commentary, Gridley and Kajimura suggest that inhibiting Notch ligand-receptor interactions may reduce the incidence of serious side effects seen with γ-secretase inhibitors that are undergoing clinical testing for other conditions.

P. Bi, T. Shan, W. Liu, F. Yue, X. Yang, X.-R. Liang, J. Wang, J. Li, N. Carlesso, X. Liu, S. Kuang, Inhibition of Notch signaling promotes browning of white adipose tissue and ameliorates obesity. Nat. Med. 20, 911–918 (2014).[PubMed]

T. Gridley, S. Kajimura, Lightening up a notch: Notch regulation of energy metabolism. Nat. Med. 20, 811–812 (2014). [PubMed]

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