Fatty Acid Signaling in the Hypothalamus and the Neural Control of Insulin Secretion

Fatty Acid Signaling in the Hypothalamus and the Neural Control of Insulin Secretion Stéphanie Migrenne 1 , Céline Cruciani-Guglielmacci 1 , Ling Kang 2 , Ruokun Wang 3 , Claude Rouch 1 , Anne-Laure Lefèvre 1 , Alain Ktorza 1 , Vanessa H. Routh 3 , Barry E. Levin 2 4 and Christophe Magnan 1 1 Laboratoire de Physiopathologie de la Nutrition, Université Paris 7, National Center of Scientific Research, Paris, France 2 Department of Neurology and Neurosciences, New Jersey Medical School, Newark, New Jersey 3 Department of Pharmacology and Physiology, New Jersey Medical School, Newark, New Jersey 4 Neurology Service, VA Medical Center, East Orange, New Jersey Address correspondence and reprint requests to Stéphanie Migrenne, Université Paris 7, CNRS UMR 7059, Case courier 712, 2, place Jussieu, 75251 Paris cedex 05, France. E-mail: stephanie.migrenne{at}paris7.jussieu.fr Abstract It is now clearly demonstrated that fatty acids (FAs) may modulate neural control of energy homeostasis and specifically affect both insulin secretion and action. Indeed, pancreatic β-cells receive rich neural innervation and FAs induce important changes in autonomic nervous activity. We previously reported that chronic infusion of lipids decreased sympathetic nervous system activity and led to exaggerated glucose-induced insulin secretion (GIIS), as would be expected from the known inhibitory effect of sympathetic splanchnic nerve activity on insulin secretion. Intracarotid infusion of lipids that do not change plasma FA concentrations also lead to increased GIIS. This effect of FAs on GIIS was prevented by inhibition of β-oxidation. It is noteworthy that a single intracarotid injection of oleic acid also induced a transient increase in plasma insulin without any change in plasma glucose, suggesting that FAs per se can regulate neural control of insulin secretion. Finally, using whole cell current clamp recordings in hypothalamic slices and calcium imaging in dissociated hypothalamic neurons, we identified a hypothalamic subpopulation of neurons either excited (13%) or inhibited (6%) by FAs. Thus, FAs per se or their metabolites modulate neuronal activity, as a means of directly monitoring ongoing fuel availability by central nervous system nutrient-sensing neurons involved in the regulation of insulin secretion. ARC, arcuate nucleus FA, fatty acid FLI, cfos-like immunoreactive GIIS, glucose-induced insulin secretion OA, oleic acid OAE, OA-excited OAI, OA-inhibited Footnotes This arti