Evidence for a role of proline and hypothalamic astrocytes in the regulation of glucose metabolism in rats

Isabel Arrieta-Cruz, Ya Su, Colette M. Knight, Tony K T Lam, Roger Gutiérrez-Juárez

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

The metabolism of lactate to pyruvate in the mediobasal hypothalamus (MBH) regulates hepatic glucose production. Because astrocytes and neurons are functionally linked by metabolic coupling through lactate transfer via the astrocyteneuron lactate shuttle (ANLS), we reasoned that astrocytes might be involved in the hypothalamic regulation of glucose metabolism. To examine this possibility, we used the gluconeogenic amino acid proline, which is metabolized to pyruvate in astrocytes. Our results showed that increasing the availability of proline in rats either centrally (MBH) or systemically acutely lowered blood glucose. Pancreatic clamp studies revealed that this hypoglycemic effect was due to a decrease of hepatic glucose production secondary to an inhibition of glycogenolysis, gluconeogenesis, and glucose-6-phosphatase flux. The effect of proline was mimicked by glutamate, an intermediary of proline metabolism. Interestingly, proline's action was markedly blunted by pharmacological inhibition of hypothalamic lactate dehydrogenase (LDH) suggesting that metabolic flux through LDH was required. Furthermore, short hairpin RNA-mediated knockdown of hypothalamic LDH-A, an astrocytic component of the ANLS, also blunted the glucoregulatory action of proline. Thus our studies suggest not only a new role for proline in the regulation of hepatic glucose production but also indicate that hypothalamic astrocytes are involved in the regulatory mechanism as well.

Original languageEnglish (US)
Pages (from-to)1152-1158
Number of pages7
JournalDiabetes
Volume62
Issue number4
DOIs
StatePublished - Apr 2013

Fingerprint

Proline
Astrocytes
Glucose
Lactic Acid
Pyruvic Acid
L-Lactate Dehydrogenase
Hypothalamus
Liver
Glycogenolysis
Glucose-6-Phosphatase
Gluconeogenesis
Hypoglycemic Agents
Small Interfering RNA
Blood Glucose
Glutamic Acid
Pharmacology
Neurons
Amino Acids

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

Cite this

Evidence for a role of proline and hypothalamic astrocytes in the regulation of glucose metabolism in rats. / Arrieta-Cruz, Isabel; Su, Ya; Knight, Colette M.; Lam, Tony K T; Gutiérrez-Juárez, Roger.

In: Diabetes, Vol. 62, No. 4, 04.2013, p. 1152-1158.

Research output: Contribution to journalArticle

Arrieta-Cruz, Isabel ; Su, Ya ; Knight, Colette M. ; Lam, Tony K T ; Gutiérrez-Juárez, Roger. / Evidence for a role of proline and hypothalamic astrocytes in the regulation of glucose metabolism in rats. In: Diabetes. 2013 ; Vol. 62, No. 4. pp. 1152-1158.
@article{7b34141d75eb482daceb031778e97229,
title = "Evidence for a role of proline and hypothalamic astrocytes in the regulation of glucose metabolism in rats",
abstract = "The metabolism of lactate to pyruvate in the mediobasal hypothalamus (MBH) regulates hepatic glucose production. Because astrocytes and neurons are functionally linked by metabolic coupling through lactate transfer via the astrocyteneuron lactate shuttle (ANLS), we reasoned that astrocytes might be involved in the hypothalamic regulation of glucose metabolism. To examine this possibility, we used the gluconeogenic amino acid proline, which is metabolized to pyruvate in astrocytes. Our results showed that increasing the availability of proline in rats either centrally (MBH) or systemically acutely lowered blood glucose. Pancreatic clamp studies revealed that this hypoglycemic effect was due to a decrease of hepatic glucose production secondary to an inhibition of glycogenolysis, gluconeogenesis, and glucose-6-phosphatase flux. The effect of proline was mimicked by glutamate, an intermediary of proline metabolism. Interestingly, proline's action was markedly blunted by pharmacological inhibition of hypothalamic lactate dehydrogenase (LDH) suggesting that metabolic flux through LDH was required. Furthermore, short hairpin RNA-mediated knockdown of hypothalamic LDH-A, an astrocytic component of the ANLS, also blunted the glucoregulatory action of proline. Thus our studies suggest not only a new role for proline in the regulation of hepatic glucose production but also indicate that hypothalamic astrocytes are involved in the regulatory mechanism as well.",
author = "Isabel Arrieta-Cruz and Ya Su and Knight, {Colette M.} and Lam, {Tony K T} and Roger Guti{\'e}rrez-Ju{\'a}rez",
year = "2013",
month = "4",
doi = "10.2337/db12-0228",
language = "English (US)",
volume = "62",
pages = "1152--1158",
journal = "Diabetes",
issn = "0012-1797",
publisher = "American Diabetes Association Inc.",
number = "4",

}

TY - JOUR

T1 - Evidence for a role of proline and hypothalamic astrocytes in the regulation of glucose metabolism in rats

AU - Arrieta-Cruz, Isabel

AU - Su, Ya

AU - Knight, Colette M.

AU - Lam, Tony K T

AU - Gutiérrez-Juárez, Roger

PY - 2013/4

Y1 - 2013/4

N2 - The metabolism of lactate to pyruvate in the mediobasal hypothalamus (MBH) regulates hepatic glucose production. Because astrocytes and neurons are functionally linked by metabolic coupling through lactate transfer via the astrocyteneuron lactate shuttle (ANLS), we reasoned that astrocytes might be involved in the hypothalamic regulation of glucose metabolism. To examine this possibility, we used the gluconeogenic amino acid proline, which is metabolized to pyruvate in astrocytes. Our results showed that increasing the availability of proline in rats either centrally (MBH) or systemically acutely lowered blood glucose. Pancreatic clamp studies revealed that this hypoglycemic effect was due to a decrease of hepatic glucose production secondary to an inhibition of glycogenolysis, gluconeogenesis, and glucose-6-phosphatase flux. The effect of proline was mimicked by glutamate, an intermediary of proline metabolism. Interestingly, proline's action was markedly blunted by pharmacological inhibition of hypothalamic lactate dehydrogenase (LDH) suggesting that metabolic flux through LDH was required. Furthermore, short hairpin RNA-mediated knockdown of hypothalamic LDH-A, an astrocytic component of the ANLS, also blunted the glucoregulatory action of proline. Thus our studies suggest not only a new role for proline in the regulation of hepatic glucose production but also indicate that hypothalamic astrocytes are involved in the regulatory mechanism as well.

AB - The metabolism of lactate to pyruvate in the mediobasal hypothalamus (MBH) regulates hepatic glucose production. Because astrocytes and neurons are functionally linked by metabolic coupling through lactate transfer via the astrocyteneuron lactate shuttle (ANLS), we reasoned that astrocytes might be involved in the hypothalamic regulation of glucose metabolism. To examine this possibility, we used the gluconeogenic amino acid proline, which is metabolized to pyruvate in astrocytes. Our results showed that increasing the availability of proline in rats either centrally (MBH) or systemically acutely lowered blood glucose. Pancreatic clamp studies revealed that this hypoglycemic effect was due to a decrease of hepatic glucose production secondary to an inhibition of glycogenolysis, gluconeogenesis, and glucose-6-phosphatase flux. The effect of proline was mimicked by glutamate, an intermediary of proline metabolism. Interestingly, proline's action was markedly blunted by pharmacological inhibition of hypothalamic lactate dehydrogenase (LDH) suggesting that metabolic flux through LDH was required. Furthermore, short hairpin RNA-mediated knockdown of hypothalamic LDH-A, an astrocytic component of the ANLS, also blunted the glucoregulatory action of proline. Thus our studies suggest not only a new role for proline in the regulation of hepatic glucose production but also indicate that hypothalamic astrocytes are involved in the regulatory mechanism as well.

UR - http://www.scopus.com/inward/record.url?scp=84875454496&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84875454496&partnerID=8YFLogxK

U2 - 10.2337/db12-0228

DO - 10.2337/db12-0228

M3 - Article

VL - 62

SP - 1152

EP - 1158

JO - Diabetes

JF - Diabetes

SN - 0012-1797

IS - 4

ER -