Differential Effect of Fatty Acids in Nervous Control of Energy Balance

Energy homeostasis is kept through a complex interplay of nutritional, neuronal and hormonal inputs that are integrated at the level of the central nervous system (CNS). A disruption of this regulation gives rise to life-threatening conditions that include obesity and type-2 diabetes, pathologies that are strongly linked epidemiologically and experimentally. The hypothalamus is a key integrator of nutrient-induced signals of hunger and satiety, crucial for processing information regarding energy stores and food availability. Much effort has been focused on the identification of hypothalamic pathways that control food intake but, until now, little attention has been given to a potential role for the hypothalamus in direct control of glucose homeostasis and nergy balance. Recent studies have cast a new light on the role of the CNS in regulating peripheral glucose via a hypothalamic fatty acid (FA)-sensing device that detects nutrient availability and relays, through the autonomic nervous system, a negative feedback signal on food intake, insulin sensitivity and insulin secretion. Indeed, accumulating evidences suggest that FA are used in specific areas of CNS not as nutrients, but as cellular messengers which inform “FA sensitive neurons” about the energy status of the whole body (Blouet & Schwartz, 2010; Migrenne et al., 2006; Migrenne et al., 2011). Thus it has been described that up to 70% of hypothalamic arcuate nucleus (ARC) and ventromedian nucleus (VMN) neurons are either excited or inhibited by long chain fatty acids such as oleic acid (Jo et al., 2009; Le Foll et al., 2009; Migrenne et al., 2011). Within the VMN, 90% of the glucosensing neurons also have their activity altered by FA. In a large percentage of these neurons, glucose and FA have opposing effects on neuronal activity, much as they do on intracellular metabolism in many other cells (Randle et al., 1994). Neuronal FA sensing mechanisms include activation of the KATP channel by long chain fatty acid acyl CoA (Gribble et al., 1998) or inactivation by generation of ATP or reactive oxygen species during mitochondrial ┚-oxidation (Jo et al., 2009; Le Foll et al., 2009; Migrenne et al., 2011; Wang et al., 2006). Many fatty acid sensing neurons are activated by interaction of long chain fatty acids with the fatty acid transporter/receptor, FAT/CD36, presumably by activation of store-operated calcium channels by a mechanism that is independent of fatty acid metabolism (Jo et al., 2009). Importantly, most neurons utilize FA primarily for membrane production rather than as a metabolic substrate (Rapoport et al., 2001; Smith & Nagura, 2001) and only nanomolar concentrations of fatty acid are required to