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Endocrine Abstracts (2015) 37 S7.2 | DOI: 10.1530/endoabs.37.S7.2

1MPI for Metabolism Research, Cologne, Germany; 2Biocenter, Institute for Zoology, University of Cologne, Cologne, Germany; 3Program 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, USA.

In light of the ever-increasing incidences of obesity and T2DM, development of novel therapeutic or preventative measures to combat these epidemics is of utmost importance. Identification of a causal relationship between an altered maternal metabolic homeostasis and an increased propensity for the unborn child to develop metabolic disorders throughout lifetime has shifted considerable amount of attention towards understanding the underlying cellular and molecular alterations. However, despite the multitude of studies already carried out in this field of research, to date we still know very little about the developmental alterations responsible for the increased propensity towards an impaired regulation of energy homeostasis.

By employing a thorough and physiological maternal high-fat diet (HFD) feeding paradigm in mice, we could demonstrate that nutritional and hormonal alterations specifically during lactation predispose the offspring for obesity and impaired glucose homeostasis. These metabolic defects are associated with malformations of the hypothalamic melanocortin circuitry in the offspring. 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 to the active neurotransmitter α-MSH remain unaffected in response to maternal HFD-feeding during lactation, the formation of POMC and AgRP projections to hypothalamic target sites is severely impaired. Moreover, abrogating insulin action in POMC neurons of the offspring prevents altered POMC projections specifically to the preautonomic paraventricular nucleus of the hypothalamus, restores pancreatic parasympathetic innervation and improves glucose-stimulated insulin-secretion in response to maternal overnutrition.

Taken together, these experiments reveal a critical developmental period of particular vulnerability towards altered maternal metabolic homeostasis. An abnormal developmental environment during exactly this period impairs hypothalamic neuronal projections at least in part by abnormal neuronal insulin signaling and thereby contributes to the increased propensity to develop obesity and impaired glucose homeostasis.

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