Preserved Energy Balance in Mice Lacking FoxO1 in Neurons of Nkx2.1 Lineage Reveals Functional Heterogeneity of FoxO1 Signaling within the Hypothalamus

  1. Domenico Accili
  1. Berrie Diabetes Center, Department of Medicine, College of Physicians & Surgeons of Columbia University, New York, NY 10032, USA
  1. Correspondence: Domenico Accili, Email: da230{at}


Transcription factor FoxO1 regulates energy expenditure, food intake, and hepatic glucose production. These activities have been mapped to specific hypothalamic neuronal populations using cell type-specific knockout experiments in mice. To parse out the integrated output of FoxO1-dependent transcription from different neuronal populations and multiple hypothalamic regions, we used transgenic mice expressing Cre recombinase from the Nkx2.1 promoter to ablate loxP-flanked Foxo1 alleles from a majority of hypothalamic neurons (Foxo1KONkx2.1 mice). This strategy resulted in the expected inhibition of FoxO1 expression, but only produced a transient reduction of body weight as well as decreased body length. The transient decrease of body weight in male mice was accompanied by decreased fat mass. Male Foxo1KONkx2.1 mice show similar food intake to wild-type controls, and while female knockouts eat less, they do so in proportion to reduced body size. Energy expenditure is unaffected in Foxo1KONkx2.1 mice, though small increases in body temperature are present. Unlike other neuron-specific Foxo1 knockouts, Foxo1KONkx2.1 mice are not protected from diet-induced obesity. These studies indicate that, unlike the metabolic effects of highly restricted neuronal subsets (POMC, NPY/AgRP, Sf-1), those of neurons derived from the Nkx2.1 lineage occur in either a FoxO1-independent fashion or are compensated for through developmental plasticity.

  • Received April 23, 2013.
  • Accepted January 24, 2014.

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