Neuroscience Letters 534 (2013) 75–79 Contents lists available at SciVerse ScienceDirect Neuroscience Letters jou rn al h om epage: www.elsevier.com/locate/neulet Alteration of hypothalamic glucose and lactate sensing in 48 h hyperglycemic rats Camille Allard a,b,c , Lionel Carneiro a,b,c , Stephan C. Collins a,b,c , Chloé Chrétien a,b,c , Sylvie Grall a,b,c , Luc Pénicaud a,b,c , Corinne Leloup a,b,c,∗ a CNRS, UMR 6265, CSGA, F-21000 Dijon, France b INRA, UMR1324, CSGA, F-21000 Dijon, France c Université de bourgogne, CSGA, F-21000 Dijon, France h i g h l i g h t s ◮ Brain lactate injection, as for glucose, triggers insulin secretion in normal rats. ◮ 48 h-hyperglycaemia alters both hypothalamic glucose and lactate sensitivity. ◮ Protein levels of MCT1, 4 (glial) and 2 (neuronal) are not modified in this model. a r t i c l e i n f o Article history: Received 31 July 2012 Received in revised form 9 November 2012 Accepted 13 November 2012 Keywords: Hypothalamus Glucose sensing Lactate sensing Hyperglycemia Monocarboxylates transporters MCT1, 4 and 2 a b s t r a c t Hypothalamic detection of nutrients is involved in the control of energy metabolism and is altered in metabolic disorders. Although hypothalamic detection of blood lactate lowers hepatic glucose production and food intake, it is unknown whether it also modulates insulin secretion. To address this, a lactate injection via the right carotid artery (cephalad) was performed in Wistar rats. This triggered a transient increase in insulin secretion. Rats made hyperglycemic for 48 h exhibited prolonged insulin secretion in response to a glucose injection via the carotid artery, but lactate injection induced two types of responses: half of the HG rats showed no difference compared to controls and the other half had markedly decreased insulin secretion. Astroglial monocarboxylates transporters MCT1 and MCT4 isoforms transfer lactate from blood to astrocytes and release lactate to the extracellular space, whilst the neuronal MCT2 isoform permits neuronal lactate uptake. We found that astroglial MCT1 and MCT4, and neuronal MCT2 protein levels in the medio-basal hypothalamus (MBH) were not modified by 48 h-hyperglycemia. Together, these results indicate that hypothalamic sensing of circulating lactate triggers insulin secretion. Both glucose and lactate sensing are altered in a model of hyperglycemia, without alteration of MBH MCTs protein levels. © 2012 Elsevier Ireland Ltd. All rights reserved. 1. Introduction Central glucose sensing is mediated by gluco-sensitive neu- rons (GS neurons), mainly localized in the medio-basal part of the hypothalamus (MBH) constituted by the arcuate and the ventrome- dial nuclei. This detection participates in the control of food intake and energy balance [5,14]. Recent studies suggest that astrocytes are involved in this process [12,17,22]. Astroglial end-feet enwrap blood vessels, making astrocytes an obligatory pathway for nutri- ents such as glucose and lactate. Shuttling fuels to neurons via astrocytes may be important for hypothalamic nutrient sensing. ∗ Corresponding author at: CSGA, UMR6265 CNRS, UMR1324 INRA, Université de Bourgogne, F-21000 Dijon, France. Tel.: +33 380 681 665; fax: +33 380 681 601. E-mail address: leloup@cict.fr (C. Leloup). Astroglial GLUT1 and GLUT2 play important roles in central glu- cose sensing. Their disruption leads to metabolism dysfunctions [3,8,20,22]. Moreover, some MBH-GS neurons are also lactate- sensitive [29,33,34]. Lactate has been demonstrated to mimic glucose effects [17] and to regulate hepatic glucose production via hypothalamic sensing [15]. Lactate transport occurs through monocarboxylates transporters (MCTs). MCT1 is expressed by endothelial cells, ependymocytes and astrocytes. MCT4 appears specific to astrocytes. The predominant neuronal isoform is MCT2. These MCTs are crucial for the metabolic shuttle between blood, astrocytes and neurons [25]. Both high fat diet-induced obesity and diabetes models exhibit alterations of hypothalamic MCTs expression, suggesting that these transporters may be involved in impaired nutrient sensing [6,26]. Here we tested whether: (1) increased cerebral blood lactate might trigger insulin secretion in rats, (2) protracted hyperglycemia (48 h) affects cerebral glucose and lactate sensing in terms of insulin 0304-3940/$ – see front matter © 2012 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.neulet.2012.11.033