Current Nutrition & Food Science, 2012, 8, 45-48 45 The Role of Gut Glucose Metabolism in the Control of Food Intake Mithieux Gilles 1,2, * 1 Institut National de la Santé et de la Recherche Médicale, U855, Lyon, F-69372, France 2 Université de Lyon, Lyon, F-69008, France 3 Université Lyon I, Villeurbanne, F-69622, France Abstract: Glucose homeostasis is a crucial physiological function of the living organisms. A system of plasma glucose sensing present in the portal vein plays a key role in this homeostasis. Connected to the hypothalamus via the peripheral nervous system, it allows the body to adapt its response to any variation in portal glycemia. The hypothalamus notably controls food intake. Intestinal gluconeogenesis, via the release of glucose into the portal vein, plays a key role in the con- trol of hunger and satiety. The induction of intestinal gluconeogenesis has provided a physiological explanation to the sa- tiety effects induced by protein-enriched diets. Intestinal gluconeogenesis has also provided an explanation to the early curbing of hunger and improvement in glucose control observed in obese diabetic patients treated by gastric bypass sur- gery. These data have emphasized the importance of the gut gluconeogenesis to brain axis in the control of the sensations of hunger and satiety and in glucose homeostasis. Keywords: Portal glucose signal, intestinal gluconeogenesis, hypothalamus, energy homeostasis, insulin sensitivity. 1. INTRODUCTION The upholding of plasma glucose concentration around 1g/L (i.e. glucose homeostasis) is a crucial function of the body. It is widely believed that the reason is that “glucose is a major energy source” for living cells. However, it is prob- able that a key explanation of the importance of glucose for cells is that the glycolytic function is essential for the life of every cell, beyond energy supply. Glycolysis is indeed the “biological skeleton” to which are ultimately connected all specialized biochemical pathways. It is thus essential for the body to sense plasma glucose permanently, so as to be able to rapidly and adequately respond in case of insufficient sup- ply. Food intake is an immediate way to restore plasma glu- cose in response to a fall in glucose concentration. Thus, it makes sense that glucose itself should be a key determinant of the sensation of hunger. A drop in plasma glucose concen- tration by no more than 5 % is able to trigger meal onset in the rat [1]. Since it receives blood coming from the whole gut, the portal vein appears as a key site for the sensing of plasma glucose concentrations, before the final integration of glycemia information by the central nervous system. The portal vein was indeed demonstrated as a critical site for the detection of slowly induced hypoglycaemia [2, 3]. Several studies also established that infusions of glucose into the portal vein can induce a wide array of physiological and be- havioural effects, among which: 1/ a decrease in spontaneous food intake [4-7], 2/ the acquisition of a food preference [4], 3/ a rapid-phase secretion of insulin [8] and the induction of glucose uptake [9,10], and 4/ the inhibition of a hypogly- caemia-induced sympathoadrenal response [11, 12]. These *Address correspondence to this author at the INSERM U855, Faculté de Médecine Laennec, 69372 Lyon Cedex 08, France; Tel: 33 4 78 77 87 88; Fax : 33 4 78 77 87 62; E-mail: gilles.mithieux@inserm.fr effects depend on the integrity of portal innervation [3, 13], as the detection of glucose decreases the electrical activity of hepatoportal vagal and spinal afferents [14]. Few studies also demonstrated that this portal glucose signal influences the impulse activity of central neurons, in areas involved in the control of food intake and metabolism, the nucleus of the solitary tract [15] and the lateral hypothalamus [16, 17]. Physiological variations in portal glucose concentration occur in the fasted-to-fed transition. Therefore, it has been generally hypothesized that the activation of the portal glu- cose signal should have a key role in the decrease of hunger taking place under postprandial conditions, that is, among satiation phenomena. In keeping with this rationale, the works cited above have been performed under conditions of high rates of portal glucose appearance, matching those oc- curring during postprandial periods, i.e. comparable to (or even higher than) total endogenous glucose production (EGP) of the animal studied. However, various studies rather suggested that portal delivery of glucose does not determine the termination of an ongoing meal [18, 19], but rather de- termines the size of the following meal [19]. This strongly suggested that the portal glucose signal should range among satiety phenomena, not among satiation phenomena. This also raised the following intriguing question: what could be the source of portal glucose involved in a physiological sati- ety phenomenon, i.e. occuring at a distance from the absorp- tion of dietary glucose? This has led to the attractive hy- pothesis of the activation of intestinal gluconeogenesis, oc- curing during the post-absorptive period under some nutri- tional conditions. In line with this hypothesis, glucose-6- phosphatase (Glc6Pase), the key enzyme of EGP, is regu- lated by nutrients and hormones at the level of gene expres- sion and enzymatic activity in the liver, kidney and small intestine [20-27]. - /12 $58.00+.00 © 2012 Bentham Science Publishers