Expression Levels of Genes Likely Involved in Glucose-sensing in the Obese Zucker Rat Brain

Abstract

It has been suggested that certain cells in the brain, like pancreatic beta-cells, use glucose transporter-2 (GLUT-2), glucokinase and glucagon-like peptide-1 receptor (GLP-1R) to sense glucose in the service of multiple aspects of energy balance. The obese Zucker rat displays numerous disturbances in energy homeostasis and may provide a model of dysfunctional expression of genes related to nutrient control systems. Using real-time RT-PCR we measured gene expression for three of the pancreatic glucose-sensing markers and neuropeptide Y (NPY) in the medial, lateral hypothalamus and hindbrain of lean and obese Zucker rats of both genders. Additionally, we measured circulating levels of glucose, leptin, insulin, corticosterone and glucagon. The results indicate that GLUT-2 mRNA expression is decreased, whereas glucokinase is increased in the hindbrain of obese rats. NPY mRNA level is significantly higher, whereas GLP-1R is significantly lower in the medial hypothalamus in obese individuals. Gender-related differences were found in the hindbrain and medial hypothalamus for GLUT-2 and in the lateral hypothalamus for GLP-1R and they may be related to the fact that the female Zucker rats do not develop diabetes as readily as males. Furthermore, the hindbrain may be an important site for glucose-sensing where major phenotypic changes occur for glucose-sensing genes expression.

Modulation of olfactory sensitivity and glucose-sensing by the feeding state in obese Zucker rats

“…However in the present study, it remains difficult to decipher the respective role of obesity and of glucose-sensing alteration related to hyperglycemia on olfactory sensitivity. In order to go further, it will be intriguing to study olfactory sensitivity and expression of glucose-sensing genes on female Zucker rats because numerous gender-related metabolic differences exist in peripheral (Clark et al, 1983; Corsetti et al, 2000; Gustavsson et al, 2011) as well as in central tissues (Bogacka et al, 2004). Indeed, females develop obesity and insulin resistance but remain normoglycemic (Clark et al, 1983; Corsetti et al, 2000) and express differently glucose-sensing genes in hypothalamus compared to males (Bogacka et al, 2004).…”

“…These neurons cannot adapt their firing to fluctuations of interstitial glucose concentration and cannot take part in the regulation of feeding behavior according to the metabolic needs of the organism (Rowe et al, 1996; Spanswick et al, 1997, 2000; Colombani et al, 2009). Among the molecules involved in glucose-sensing, the mRNA expression of glucokinase, a glucose metabolizing enzyme and of GLUT2, a glucose transporter is altered in the hypothalamus of fa/fa Zucker rats (Bogacka et al, 2004). Moreover, the regional brain glucose utilization is modified in obese Zuckers, compared to lean controls (Tsujii et al, 1988; Marfaing-Jallat et al, 1992; Doyle et al, 1993).…”

Leptin transport in the central nervous system

“…82,91 Nevertheless, extra-hypothalamic distribution and thalamic and cerebellar localization of leptin show that it can be effective on specific sensory and motor systems. 84 Furthermore, non-neuronal localization of leptin receptors (localization in meninges, choroid plexus, and vessel walls) suggests that these receptors have a role in both leptin transport to the brain and its reabsorption by blood from the CSF.…”

“…81 They are found in modest amounts in the periventricular hypothalamic area, medial mamillary nucleus, posterior hypothalamic nucleus, and lateral ophthalmic nucleus, as well as in substantia nigra pars compacta. 82 They are seen in concentrated amounts in several thalamic nuclei too (mediodorsal, ventral anterior, medial submedial, ventral posterior, and dorsal thalamic nuclei). 83 Leptin receptors are observed in medial and geniculate nuclei, and purkinje and granular cell layers of the cerebellum.…”

Molecular connexions between dementia and diabetes

“…The effects of insulin on NPY and POMC expression are less rapid, peaking between 6 and 12 h, and are independent of glucose. Meanwhile, abnormally high NPY mRNA levels have been found in the hypothalamic neurons of the obese Zucker rats, presumably reflecting the leptin and insulin resistance of these animals (Bogacka et al, 2004). Therefore, there appears to be a complex interplay between food intake, body adiposity and hypothalamic neuropeptide expression.…”