Editors' ChoiceMetabolism

Improving the health of newborns of obese mothers

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Science Signaling  25 Oct 2016:
Vol. 9, Issue 451, pp. ec246
DOI: 10.1126/scisignal.aal2588

Metabolic defects represent not only a health risk for adults and children but for newborns as well. For example, newborns of obese mothers have a higher mortality rate, and sudden infant death syndrome (SIDS) is associated with reduced brown adipose tissue (BAT). Yang et al. determined that the kinase AMPK, which functions as a cellular energy sensor that is activated when energy stores are depleted (when AMP abundance is high relative to that of ATP), was necessary for BAT development through a cell autonomous mechanism. Knockout of the AMPK subunit-encoding gene Prkaa1 impaired BAT development in mice, resulting in deficient body temperature regulation, phenotypes also observed in neonatal mice born of obese mothers. When transplanted into wild-type mice at the site where this tissue develops, wild-type BAT precursors integrated and grew into BAT. In contrast, Prkaa1-deficient precursors transplanted into wild-type mice integrated poorly and exhibited reduced thermogenic capacity, confirming that AMPK activity was required within BAT precursors. Expression of the gene encoding the transcription factor PRDM16, which is required for BAT specification and maintenance, was impaired in BAT precursor cells from Prkaa1 knockout mice, and overexpressing PRDM16 restored brown adipocyte differentiation in culture. Embryos from obese mothers had less phosphorylated and thus less active AMPK in developing BAT than did embryos from control mothers. Neonates and weaning mice from obese mothers also exhibited reduced Prdm16 expression in BAT and had impaired ability to regulate body temperature. DNA demethylation, which is mediated by enzymes of the α-ketoglutarate-dependent TET family and which promotes expression of the Prdm16 locus, was impaired in Prkaa1 knockout cells. BAT or brown adipocytes differentiated in vitro had higher α-ketoglutarate concentrations than progenitor cells. In contrast, Prkaa1 knockout cells failed to exhibit the increase in this metabolite because of deficient induction of the gene encoding isocitrate dehydrogenase 2 (IDH2), an enzyme involved in the production of α-ketoglutarate, and also because of increased inhibitory acetylation of IDH2. Adding a membrane-permeable analog of α-ketoglutarate enhanced TET activity in nuclear extracts of brown adipocyte precursors induced to differentiate and increased brown adipogenesis in culture, whereas a competitive inhibitor had the opposite effects. Compared with mice born to obese mothers that did not receive treatment, administration of AMPK activating drugs (AICAR or metformin) after birth resulted in partial recovery of BAT weight, restored the morphology of the BAT to “brown” rather than that resembling white adipose tissue, and reduced visceral fat weight. Thus, targeting AMPK with these clinically used drugs may be beneficial for the newborns of obese mothers.

Q. Yang, X. Liang, X. Sun, L. Zhang, X. Fu, C. J. Rogers, A. Berim, S. Zhang, S. Wang, B. Wang, M. Foretz, B. Viollet, D. R. Gang, B. D. Rodgers, M.-J. Zhu, M. Du, AMPK/α-ketoglutarate axis dynamically mediates DNA demethylation in the Prdm16 promoter and brown adipogenesis. Cell Metab. 24, 542–554 (2016). [PubMed]

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