Exploring the Mechanisms of Recovery in Anorexia Nervosa through a Translational Approach: From Original Ecological Measurements in Human to Brain Tissue Analyses in Mice.

International audienceAnorexia nervosa (AN) is a severe eating disorder where caloric restriction, excessive physical activity and metabolic alterations lead to life-threatening situations. Despite weight restoration after treatment, a significant part of patients experience relapses. In this translational study, we combined clinical and preclinical approaches. We describe preliminary data about the effect of weight gain on the symptomatology of patients suffering from acute AN ( = 225) and partially recovered ( = 41). We measured more precisely physical activity with continuous cardiac monitoring in a sub-group ( = 68). Using a mouse model, we investigated whether a long-term food restriction followed by nutritional recovery associated or not with physical activity may differentially impact peripheral and central homeostatic regulation. We assessed the plasma concentration of acyl ghrelin, desacyl ghrelin and leptin and the mRNA expression of hypothalamic neuropeptides and their receptors. Our data show an effect of undernutrition history on the level of physical activity in AN. The preclinical model supports an important role of physical activity in the recovery process and points out the leptin system as one factor that can drive a reliable restoration of metabolic variables through the hypothalamic regulation of neuropeptides involved in feeding behavior

Astrocytic Insulin Signaling Couples Brain Glucose Uptake with Nutrient Availability

We report that astrocytic insulin signaling co-regulates hypothalamic glucose sensing and systemic glucose metabolism. Postnatal ablation of insulin receptors (IRs) in glial fibrillary acidic protein (GFAP)-expressing cells affects hypothalamic astrocyte morphology, mitochondrial function, and circuit connectivity. Accordingly, astrocytic IR ablation reduces glucose-induced activation of hypothalamic pro-opio-melanocortin (POMC) neurons and impairs physiological responses to changes in glucose availability. Hypothalamus-specific knockout of astrocytic IRs, as well as postnatal ablation by targeting glutamate aspartate transporter (GLAST)-expressing cells, replicates such alterations. A normal response to altering directly CNS glucose levels in mice lacking astrocytic IRs indicates a role in glucose transport across the blood-brain barrier (BBB). This was confirmed in vivo in GFAP-IR KO mice by using positron emission tomography and glucose monitoring in cerebral spinal fluid. We conclude that insulin signaling in hypothalamic astrocytes co-controls CNS glucose sensing and systemic glucose metabolism via regulation of glucose uptake across the BBB.This work was funded, in part, by the Helmholtz Alliance ICEMED – Imaging and Curing Environmental Metabolic Diseases, the Humboldt Foundation (to M.H.T.), through the Initiative and Networking Fund of the Helmholtz Association and Deutsches Zentrum für DiabetesForschung (DZD). This work also received funding from the Institute of Advanced Studies of Technische Universität München (IAS-TUM Hans-Fischer Senior Fellowship to T.L.H.) and from DFG funding (SFB 1123 to M.H.T; SFB 870 and SPP 1757 to M.G.)