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Cell. 2014 Jan 30;156(3):495-509. doi: 10.1016/j.cell.2014.01.008. Epub 2014 Jan 23.

Neonatal insulin action impairs hypothalamic neurocircuit formation in response to maternal high-fat feeding.

Author information

1
Max Planck Institute for Neurological Research, 50931 Cologne, Germany; Department of Mouse Genetics and Metabolism, Institute for Genetics, University of Cologne, 50674 Cologne, Germany; Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases (CECAD) and Center of Molecular Medicine Cologne (CMMC), University of Cologne, 50674 Cologne, Germany.
2
Biocenter, Institute for Zoology, University of Cologne, 50674 Cologne, Germany; Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases (CECAD) and Center of Molecular Medicine Cologne (CMMC), University of Cologne, 50674 Cologne, Germany.
3
Biocenter, Institute for Zoology, University of Cologne, 50674 Cologne, Germany.
4
Program in Integrative Cell Signaling and Neurobiology of Metabolism, Section of Comparative Medicine, Department of Obstetrics/Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06510, USA. Electronic address: tamas.horvath@yale.edu.
5
Max Planck Institute for Neurological Research, 50931 Cologne, Germany; Department of Mouse Genetics and Metabolism, Institute for Genetics, University of Cologne, 50674 Cologne, Germany; Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases (CECAD) and Center of Molecular Medicine Cologne (CMMC), University of Cologne, 50674 Cologne, Germany; Center for Endocrinology, Diabetes and Preventive Medicine (CEDP), University Hospital Cologne, 50924 Cologne, Germany. Electronic address: bruening@nf.mpg.de.

Abstract

Maternal metabolic homeostasis exerts long-term effects on the offspring's health outcomes. Here, we demonstrate that maternal high-fat diet (HFD) feeding during lactation predisposes the offspring for obesity and impaired glucose homeostasis in mice, which is associated with an impairment of the hypothalamic melanocortin circuitry. Whereas the number and neuropeptide expression of anorexigenic proopiomelanocortin (POMC) and orexigenic agouti-related peptide (AgRP) neurons, electrophysiological properties of POMC neurons, and posttranslational processing of POMC remain unaffected in response to maternal HFD feeding during lactation, the formation of POMC and AgRP projections to hypothalamic target sites is severely impaired. Abrogating insulin action in POMC neurons of the offspring prevents altered POMC projections to the preautonomic paraventricular nucleus of the hypothalamus (PVH), pancreatic parasympathetic innervation, and impaired glucose-stimulated insulin secretion in response to maternal overnutrition. These experiments reveal a critical timing, when altered maternal metabolism disrupts metabolic homeostasis in the offspring via impairing neuronal projections, and show that abnormal insulin signaling contributes to this effect.

PMID:
24462248
PMCID:
PMC4101521
DOI:
10.1016/j.cell.2014.01.008
[Indexed for MEDLINE]
Free PMC Article

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