Review A novel function of intestinal gluconeogenesis: Central signaling in glucose and energy homeostasis Gilles Mithieux, Ph.D. a,b,c, * a Institut National de la Sante ´ et de la Recherche Me ´dicale, U 855, Lyon, France b Universite ´ de Lyon, Lyon, France c Universite ´ Lyon 1, Villeurbanne, France Manuscript received June 10, 2009; accepted June 17, 2009. Abstract The gut can contribute to the control of glucose homeostasis by its high glycolytic capacity and a re- cently described function, gluconeogenesis. In addition to its quantitative role in endogenous glucose production, a qualitative role of central signaling was recently described for intestinal gluconeogenesis. Relating to the control of energy homeostasis, intestinal gluconeogenesis, by its detection by a hepato- portal glucose sensor, is able to generate a central signal promoting a decrease in food intake. This mechanism may contribute to the well-known satiety effect initiated by food protein. In relation to the control of glucose homeostasis, intestinal gluconeogenesis has been suggested to be a key factor of the central enhancement of insulin sensitivity for the whole body. It may account for the rapid ame- lioration of insulin resistance occurring after gastric bypass, a specific type of surgery for morbid obe- sity. Because these beneficial effects may take place in the context of established physiopathology, they allow one to envision new strategies of prevention or treatment of obesity and type 2 diabetes in humans. Ó 2009 Elsevier Inc. All rights reserved. Keywords: Intestinal gluconeogenesis; Small intestine; Endogenous glucose production; Glucose-6-phosphatase; Phosphoenolpyruvate carboxyki- nase-cytosolic form; Gastric banding; Gastric bypass Introduction The existence of intestinal gluconeogenesis (IGNG) has been uncovered only within the past 10 y [1–4]. The mecha- nisms of its induction during fasting and experimental diabetes and their consequences in the redistribution of gluconeogenic substrates to the liver have been subsequently documented [5– 8]. Over the past 5 y, this previously unsuspected function of the small intestine (SI) has received further accreditation from several groups and several approaches in animal and hu- man studies [9–15]. It has been known since the 1980s that glucose may be a key signaling molecule able to modulate food intake when it is directly infused into the portal vein. The effects in- duced might be quantitative, i.e., a decreased amount of food ingested [16–18], and also qualitative, i.e., a preference for the food associated to the infusion [16]. It has also been suggested, over the same period, that the delivery of glucose into the portal vein is detected within the walls of the portal vein, in which it initiates a nervous signal [19–21]. The signal is further transmitted to the nucleus of the solitary tract and/or the hypothalamus by autonomous nervous afferents [19–21]. This particular location of the system of detection of glucose into the portal vein putatively conferred on IGNG the capac- ity to be a key signal in the control of food intake. Intestinal gluconeogenesis in nutritional control of energy homeostasis It has been known, from animal and human studies, that di- ets enriched in food protein induce satiety phenomena [22– 24]. The mechanisms underlying these effects were, however, poorly understood. An important breakthrough was achieved when it was shown that protein feeding in rats markedly in- creases the expression of the three key regulatory enzymes in- volved in IGNG, i.e., glutaminase, phosphoenolpyruvate carboxykinase–cytosolic form, and glucose-6-phosphatase *Corresponding author. Tel.: þ33-4-7877-8788; Fax: þ33-4-7877- 8762. E-mail address: mithieux@sante.univ-lyon1.fr (G. Mithieux). 0899-9007/09/$ – see front matter Ó 2009 Elsevier Inc. All rights reserved. doi:10.1016/j.nut.2009.06.010 Nutrition 25 (2009) 881–884 www.nutritionjrnl.com