Adenovirus-mediated Suppression of Hypothalamic Glucokinase Affects Feeding Behavior

Overview

Journal Sci Rep

Specialty Science

Date 2017 Jun 18

PMID 28623340

Citations 17

Authors

Romina Maria Uranga

Carola Millan

Maria Jose Barahona

Antonia Recabal

Magdiel Salgado

Fernando Martinez

Patricio Ordenes

Roberto Elizondo-Vega

Fernando Sepulveda

Elena Uribe

Maria de Los Angeles Garcia-Robles

Affiliations

Soon will be listed here.

Abstract

Glucokinase (GK), the hexokinase involved in glucosensing in pancreatic β-cells, is also expressed in arcuate nucleus (AN) neurons and hypothalamic tanycytes, the cells that surround the basal third ventricle (3V). Several lines of evidence suggest that tanycytes may be involved in the regulation of energy homeostasis. Tanycytes have extended cell processes that contact the feeding-regulating neurons in the AN, particularly, agouti-related protein (AgRP), neuropeptide Y (NPY), cocaine- and amphetamine-regulated transcript (CART) and proopiomelanocortin (POMC) neurons. In this study, we developed an adenovirus expressing GK shRNA to inhibit GK expression in vivo. When injected into the 3V of rats, this adenovirus preferentially transduced tanycytes. qRT-PCR and Western blot assays confirmed GK mRNA and protein levels were lower in GK knockdown animals compared to the controls. In response to an intracerebroventricular glucose injection, the mRNA levels of anorexigenic POMC and CART and orexigenic AgRP and NPY neuropeptides were altered in GK knockdown animals. Similarly, food intake, meal duration, frequency of eating events and the cumulative eating time were increased, whereas the intervals between meals were decreased in GK knockdown rats, suggesting a decrease in satiety. Thus, GK expression in the ventricular cells appears to play an important role in feeding behavior.

Citing Articles

Circadian rhythm, glucose metabolism and diabetic complications: the role of glucokinase and the enlightenment on future treatment.

Zhang Z, Wang S, Gao L Front Physiol. 2025; 16:1537231.

PMID: 40061454 PMC: 11885239. DOI: 10.3389/fphys.2025.1537231.

Emerging roles of brain tanycytes in regulating blood-hypothalamus barrier plasticity and energy homeostasis.

Kannangara H, Cullen L, Miyashita S, Korkmaz F, Macdonald A, Gumerova A Ann N Y Acad Sci. 2023; 1525(1):61-69.

PMID: 37199228 PMC: 10524199. DOI: 10.1111/nyas.15009.

The ventromedial hypothalamic nucleus: watchdog of whole-body glucose homeostasis.

Tu L, Fukuda M, Tong Q, Xu Y Cell Biosci. 2022; 12(1):71.

PMID: 35619170 PMC: 9134642. DOI: 10.1186/s13578-022-00799-2.

Significance of Brain Glucose Hypometabolism, Altered Insulin Signal Transduction, and Insulin Resistance in Several Neurological Diseases.

Blazquez E, Hurtado-Carneiro V, LeBaut-Ayuso Y, Velazquez E, Garcia-Garcia L, Gomez-Oliver F Front Endocrinol (Lausanne). 2022; 13:873301.

PMID: 35615716 PMC: 9125423. DOI: 10.3389/fendo.2022.873301.

Tany-Seq: Integrated Analysis of the Mouse Tanycyte Transcriptome.

Sullivan A, Potthoff M, Flippo K Cells. 2022; 11(9).

PMID: 35563871 PMC: 9104898. DOI: 10.3390/cells11091565.

References

Leloup C, Allard C, Carneiro L, Fioramonti X, Collins S, Penicaud L . Glucose and hypothalamic astrocytes: More than a fueling role?. Neuroscience. 2015; 323:110-20. DOI: 10.1016/j.neuroscience.2015.06.007. View

Thomzig A, Laube G, Pruss H, Veh R . Pore-forming subunits of K-ATP channels, Kir6.1 and Kir6.2, display prominent differences in regional and cellular distribution in the rat brain. J Comp Neurol. 2005; 484(3):313-30. DOI: 10.1002/cne.20469. View

Schaeffer M, Langlet F, Lafont C, Molino F, Hodson D, Roux T . Rapid sensing of circulating ghrelin by hypothalamic appetite-modifying neurons. Proc Natl Acad Sci U S A. 2013; 110(4):1512-7. PMC: 3557016. DOI: 10.1073/pnas.1212137110. View

Schwartz M, Woods S, Porte Jr D, Seeley R, Baskin D . Central nervous system control of food intake. Nature. 2000; 404(6778):661-71. DOI: 10.1038/35007534. View

Garcia M, Millan C, Balmaceda-Aguilera C, Castro T, Pastor P, Montecinos H . Hypothalamic ependymal-glial cells express the glucose transporter GLUT2, a protein involved in glucose sensing. J Neurochem. 2003; 86(3):709-24. DOI: 10.1046/j.1471-4159.2003.01892.x. View

Marty N, Dallaporta M, Foretz M, Emery M, Tarussio D, Bady I . Regulation of glucagon secretion by glucose transporter type 2 (glut2) and astrocyte-dependent glucose sensors. J Clin Invest. 2005; 115(12):3545-53. PMC: 1297256. DOI: 10.1172/JCI26309. View

Akmayev I, Popov A . Morphological aspects of the hypothalamic-hypophyseal system. VII. The tanycytes: Their relation to the hypophyseal adrenocorticotrophic function. An ultrastructural study. Cell Tissue Res. 1977; 180(2):263-82. DOI: 10.1007/BF00231958. View

Yang X, Mastaitis J, Mizuno T, Mobbs C . Glucokinase regulates reproductive function, glucocorticoid secretion, food intake, and hypothalamic gene expression. Endocrinology. 2007; 148(4):1928-32. DOI: 10.1210/en.2006-1312. View

Millan C, Martinez F, Cortes-Campos C, Lizama I, Yanez M, Llanos P . Glial glucokinase expression in adult and post-natal development of the hypothalamic region. ASN Neuro. 2010; 2(3):e00035. PMC: 2881537. DOI: 10.1042/AN20090059. View

10.

Boychuk C, Gyarmati P, Xu H, Smith B . Glucose sensing by GABAergic neurons in the mouse nucleus tractus solitarii. J Neurophysiol. 2015; 114(2):999-1007. PMC: 4725103. DOI: 10.1152/jn.00310.2015. View

11.

Vaughan C, Moore M, Haskell-Luevano C, Rowland N . Meal patterns and foraging in melanocortin receptor knockout mice. Physiol Behav. 2005; 84(1):129-33. DOI: 10.1016/j.physbeh.2004.10.016. View

12.

Printz R, Magnuson M, GRANNER D . Mammalian glucokinase. Annu Rev Nutr. 1993; 13:463-96. DOI: 10.1146/annurev.nu.13.070193.002335. View

13.

Balland E, Dam J, Langlet F, Caron E, Steculorum S, Messina A . Hypothalamic tanycytes are an ERK-gated conduit for leptin into the brain. Cell Metab. 2014; 19(2):293-301. PMC: 3936883. DOI: 10.1016/j.cmet.2013.12.015. View

14.

Lamy C, Sanno H, Labouebe G, Picard A, Magnan C, Chatton J . Hypoglycemia-activated GLUT2 neurons of the nucleus tractus solitarius stimulate vagal activity and glucagon secretion. Cell Metab. 2014; 19(3):527-38. DOI: 10.1016/j.cmet.2014.02.003. View

15.

Langlet F, Levin B, Luquet S, Mazzone M, Messina A, Dunn-Meynell A . Tanycytic VEGF-A boosts blood-hypothalamus barrier plasticity and access of metabolic signals to the arcuate nucleus in response to fasting. Cell Metab. 2013; 17(4):607-17. PMC: 3695242. DOI: 10.1016/j.cmet.2013.03.004. View

16.

Frayling C, Britton R, Dale N . ATP-mediated glucosensing by hypothalamic tanycytes. J Physiol. 2011; 589(Pt 9):2275-86. PMC: 3098703. DOI: 10.1113/jphysiol.2010.202051. View

17.

Thorens B . Molecular and cellular physiology of GLUT-2, a high-Km facilitated diffusion glucose transporter. Int Rev Cytol. 1992; 137:209-38. DOI: 10.1016/s0074-7696(08)62677-7. View

18.

Ritter S, Strang M . Fourth ventricular alloxan injection causes feeding but not hyperglycemia in rats. Brain Res. 1982; 249(1):198-201. DOI: 10.1016/0006-8993(82)90190-1. View

19.

Bali D, Svetlanov A, Lee H, Leiser M, Li B, Barzilai N . Animal model for maturity-onset diabetes of the young generated by disruption of the mouse glucokinase gene. J Biol Chem. 1995; 270(37):21464-7. DOI: 10.1074/jbc.270.37.21464. View

20.

Rodriguez E, Blazquez J, Pastor F, Pelaez B, Pena P, Peruzzo B . Hypothalamic tanycytes: a key component of brain-endocrine interaction. Int Rev Cytol. 2005; 247:89-164. DOI: 10.1016/S0074-7696(05)47003-5. View