Oral Presentation The International Congress of Neuroendocrinology 2014

Insulin receptor and hypothalamic programming (#5)

Sophie Steculorum 1
  1. Brüning Lab, Max Planck Institute for Metabolism Research, Cologne, Germany

It is increasingly accepted that the metabolic future of an individual can be programmed as early as during developmental stages. For instance, offspring of diabetic and/or obese mothers have a greater risk to become obese and diabetic later in life. Numerous evidence from animal studies demonstrated that alterations of the hormonal status during perinatal life can permanently affect the development and therefore the long-term function of hypothalamic circuits that control energy balance and glucose homeostasis. In a recent study published by our laboratory (Vogt et al., Cell, 2014), we investigated the mechanisms that underlie the predisposition to metabolic dysfunctions observed in offspring of mother fed a high-fat diet (HFD). We found that specific deletion of insulin action in POMC neurons of the offspring rescues decreased POMC projections to the preautonomic region of the paraventricular nucleus of the hypothalamus (PVH). Prevention of hypothalamic neuroanatomical defects in response to maternal HFD-feeding is associated with a rescue of altered pancreatic parasympathetic innervation as well as an improvement of glucose-stimulated insulin secretion. Thus, our study provides additional evidence toward the existence of critical period of vulnerability to abnormal developmental-milieu and pinpoints a novel cell- autonomous mechanism by revealing that insulin action in POMC neurons contributes to impaired glucose homeostasis in offspring raised by HFD-fed mother. This study further reveals the importance of hormonal signaling in the ontogeny of hypothalamic neuronal circuitry. Interestingly, in addition to insulin, recent discoveries in the field suggest that other hormones known to modulate the function of hypothalamic metabolic circuits in adult, also act on the same circuits during perinatal life to modulate their development.