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Endocrinology Vol. 148, No. 4 1928-1932
Copyright © 2007 by The Endocrine Society

Glucokinase Regulates Reproductive Function, Glucocorticoid Secretion, Food Intake, and Hypothalamic Gene Expression

Xue-jun Yang, Jason Mastaitis, Tooru Mizuno and Charles V. Mobbs

Fishberg Center for Neuroscience and Department of Geriatrics, Mount Sinai School of Medicine, New York, New York 10029

Address all correspondence and requests for reprints to: Dr. Charles V. Mobbs, Department of Neuroscience, Box 1639, Mt. Sinai School of Medicine, 1 Gustave Levy Place, New York, New York 10029-6574. E-mail: charles.mobbs{at}mssm.edu.


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Because appetite, hypothalamic gene expression, reproductive function, and adrenal function are highly sensitive to acute changes in plasma glucose levels, it has been hypothesized hypothalamic neurons sensitive to glucose play a role in regulating these functions. To assess this hypothesis, we examined these neuronendocrine functions in mice in which the glucokinase gene, which plays an essential role in neuroendocrine glucose sensing, has been ablated. Haploinsufficiency in heterozygous glucokinase knockout mice produced effects similar to those produced by hypoglycemia: impaired reproductive function, elevated plasma corticosterone, increased food intake, and hypothalamic gene expression similar to that observed in fasted or leptin-deficient obese mice (increased hypothalamic neuropeptide Y mRNA and reduced hypothalamic proopiomelanocortin mRNA). Plasma glucose was elevated 2-fold in glucokinase knockout mice, consistent with a maturity-onset diabetes of the young phenotype, but plasma insulin and leptin levels were normal. These data support the hypothesis that glucokinase plays a key role in the neuroendocrine regulation of metabolic economy.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
THE PHYSIOLOGICAL FUNCTIONS of glucose-sensitive hypothalamic neurons are unclear, although much evidence supports a role in energy balance and neuroendocrine regulation (1, 2). In an early discussion of this glucostatic hypothesis, Mayer (3) suggested that hypothalamic hexokinase activity might play a role in regulating appetite. One isoform of hexokinase, the enzyme glucokinase, constitutes a key element of the pancreatic glucose-sensing mechanism (4). This enzyme is also expressed in the hypothalamus (5, 6, 7) and apparently constitutes a key element in the hypothalamic glucose-sensing mechanism (6, 8, 9). These data suggest that manipulation of the glucokinase system may represent a novel strategy to assess the functional role of glucose-sensitive neurons. Thus, if glucokinase does constitute a key component of the neuroendocrine glucose-sensing system, as it does the pancreatic glucose sensing system, then genetic ablation of this gene should lead to impairments in functions regulated by glucose-sensing neurons. Although complete ablation of glucokinase is lethal, due to early postnatal development of fatal ketoacidosis, we now report that heterozygous ablation of the glucokinase gene produces neuroendocrine disturbances similar to those produced by hypoglycemia, fasting, and leptin deficiency.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Glucokinase knockout mice (GKKO), glucokinase transgenic mice, and genotyping
GKKO used in this study were originally produced in the laboratory of Stewart and colleagues (10) and purchased from The Jackson Laboratory (Bar Harbor, ME). The glucokinase (GK) gene in this line of mice is ablated by replacing part of exon 3, exon 5, and the whole of exon 4 of the GK gene with the neogene, resulting in deletion and frameshift (Fig. 1AGo). In the present study, mice were genotyped by Southern blot analysis. In brief, a glucokinase template was cloned from mouse liver using the cloning kit (Invitrogen, Carlsbad, CA). The probe was a 1433-bp fragment (GK sequence 9463–10876) produced by digestion with EcoR1 and EcoRV. Genomic DNA was extracted from neonatal mouse tail tissue using DNeasy tissue kit (QIAGEN, Valencia, CA). After digestion with BglII, the endogenous GK gene produces a 9.5-kb band and the knockout allele produces a 7.7-kb band (Fig. 1BGo).


Figure 1
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  		FIG. 1. Plasmid construction for GKKO and transgenic mice and the strategies for genotyping. A, Structures of the endogenous mouse glucokinase allele and the neogene knockout allele. B, Structure of the RIP-GK gene construct. C, Strategy for genotyping glucokinase transgenic (TG) mice by digesting with PvuII to obtain 0.79-kb single band and digesting with BglII to identify glucokinase wild-type (WT) allele by the 9.0-kb band and GKKO allele by the 0.77-kb band. Mouse 1, 2, heterozygous GKKO with GK transgene; mouse 3, homozygous GKKO mouse with insulin-driven glucokinase transgene; mouse 4, glucokinase transgenic mouse; mouse 5, 7, hGKKO mice; mouse 6, homozygous GKKO mouse; mouse 8, wild-type mouse.

 
Although complete ablation of the GK gene is lethal, due to the development of neonatal ketotic diabetes, expression of glucokinase driven by the insulin promoter [rat insulin promoter (RIP)] produces viable mice with complete ablation of the GK gene (10). Because this promoter can drive gene expression in hypothalamic neurons (11), the rescue of viability could be mediated in part by the expression of glucokinase in hypothalamic neurons. This hypothesis cannot be directly assessed because the original INS-GK transgenic line reported by Grupe et al. (10) no longer exists (Stewart, T., personal communication). We therefore undertook to reestablish INS-GK mice using the same transgenic construct used by Grupe et al. (generously supplied to us by T. Stewart). Using the same methodology as Grupe et al., we established several lines of RIP-GK transgenic mice (Fig. 1CGo) and crossed these mice with heterozygous GKKO (hGKKO) mice. Once RIP-GK x hGGKO heterozygous mice were produced, these mice were then crossed with each other to produce RIP-GK/(total)GKKO mice (Fig. 1CGo, mouse 3).

Physiological assessment
After weaning, all mice were housed singly and fed regular chow. Beginning at 11 wk of age, food intake was assessed in a total of 20 male and 20 female hGKKO mice as well as a similar number of wild-type littermates. Mice were housed singly from 11 wk until the mice were killed at 19 wk. Food intake, body weight, and plasma glucose level were assessed each week. Then the mice were killed, between 1200 and 1600 h (lights on 0600–1800 h) at 19 wk of age, at which time hypothalamic tissue and blood were taken for subsequent analysis. Males and females were segregated and all functions and gene expression were analyzed separately for each sex.

Quantitative real-time RT-PCR analysis
Total hypothalamic RNA was isolated using TRIzol (Invitrogen), and first-strand cDNA synthesis was carried out using the Superscript Choice system (Invitrogen). RNA was hybridized for 10 min at 70 C with 100 pmol/µl oligo-dT24, and first-strand synthesis was carried out at 42 C for 60 min using Superscript II reverse transcriptase. Primers for real-time PCR were first validated by standard PCR (94 C for 30 sec, 55 C for 1 min, and 72 C for 1 min/30 cycles) and agarose gel electrophoresis for correct product size and absence of primer/dimer formation. Real-time PCRs (95 C for 15 sec, 60 C for 30 sec, and 72 C for 30 sec/40 cycles) were carried out in an ABI-prism 7700 sequence detector (Applied Biosystems, Foster City, CA) (12). Samples were normalized using a ß-actin primer set. Primer pairs were: proopiomelanocortin (POMC): 5'-GCCCTCCTGCTTCAGACCTC-3' and 5'-CGTTGCCAGGAAACACGG-3'; neuropeptide Y (NPY): 5'-AGCAGAGGACATGGCCAGAT-3' and 5'-AAATCAGTGTCTCAGGGCTGGA-3'; c-fos: 5'-TTCCTGGCAATAGCGTGTTC-3' and 5'-TTCAGACCACCTCGAGACAATG-3'; and ß-actin: 5'-AGGTGACAGATTGCTTCTG-3' and 5'-GCTGCCTCAACACCTCAAC-3'.

Plasma chemistry analysis
Blood glucose levels were measured by Glucometer (Bayer, Elkhart, IN). Plasma insulin, leptin, and corticosterone levels were measured by ELISA (Crystal Chem Inc., Chicago, IL).

Statistical analysis
Each variable was analyzed by a two-way ANOVA, followed by Newman-Keul’s post hoc test (P < 0.05 was considered significant).


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Failure to rescue homozygous GKKO mice with RIP-GK transgene
Although we were able to produce nine homozygous GKKO mice expressing the RIP-GK transgene (Fig. 1CGo), all of these mice died within 5 d of birth due to diabetic ketoacidosis. We therefore concluded that although it is possible to rescue homozygous GKKO mice with this transgene (10), doing so is a rare event that may require expression of the GK gene in other cell types, possibly hypothalamic neurons (11), in addition to ß-cells. We therefore carried out the remainder of the studies with heterozygous glucokinase knockout mice, which are designated GKKO in subsequent descriptions.

GKKO mice exhibit reduced fertility
In carrying out crosses with the GKKO mice, it became clear that these mice were less fertile than wild-type mice. Crosses of GKKO mice with wild-type mice consistently produced only about half as many pups as crosses with wild-type mice, regardless of whether the GKKO parent was male or female (Fig. 2Go). This reduction in fertility was not due to selective loss of offspring expressing the GKKO allele because this allele was obtained at the expected Mendelian frequency (e.g. a rate of about 50%) when GKKO mice were crossed with wild-type mice. However, the average birth weight of GKKO mice (1.42 ± 0.05 g) was lower than the birth weight of wild-type controls (1.89 ± 0.05 g; n = 30 P < 0.05), consistent with previous reports (13). The reduced fertility in hGKKO mice is consistent with previous reports that hypothalamic glucose metabolism regulates the secretion of gonadotropins (14, 15).


Figure 2
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  		FIG. 2. Heterozygous ablation of the GK gene reduces fertility in males and females. Number of mouse pups born (mean ± SEM) after each mating. WTmXWTf, Wild-type mother mated with wild-type father (n = 11 matings); WTmXKof, wild-type mother mated with hGKKO father (n = 12); WTfXKom, wild-type father mated with GKKO mother (n = 8); KomXKof, GKKO mother mated GKKO father (n = 17). *, P < 0.05 (ANOVA followed by Newman-Keul’s post hoc test).

 
GKKO mice exhibit mild hyperglycemia but normal plasma insulin and leptin
As indicated above, mice were segregated by sex, and mice of each sex were analyzed separately. The effects of the knockout were statistically the same in each sex. However, because reproductive cycles in female mice were not monitored, the results described below all refer to those observed in male mice.

As previously reported, GKKO mice exhibited a maturity-onset diabetes of the young-type phenotype, with plasma glucose levels approximately twice as high as in wild-type mice (Fig. 3AGo). Interestingly, consistent with effects of hypoglycemia, fasting, and leptin deficiency to cause elevated plasma glucocorticoid secretion (16, 17), GKKO mice also exhibited an elevation of plasma corticosterone (Fig. 3BGo). As previously reported (10), plasma insulin levels are normal in GKKO mice, presumably because the elevated glucose drives the single wild-type allele to compensate for the defective allele. Consistent with the wild-type insulin levels, plasma leptin levels were also normal (Fig. 3DGo). Consistent with normal leptin levels, although GKKO mice weighed less than wild-type mice at birth, by 11 wk of age, there was no longer a difference in body weight between GKKO mice and wild-type mice in either males or females.


Figure 3
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  		FIG. 3. Heterozygous ablation of the glucokinase gene (GKKO) increases ad libitum-fed levels of plasma glucose (A) and corticosterone (B) without influencing plasma insulin (C) or leptin (D). WT, Wild type; GKKO, heterozygous glucokinase knockout. *, P < 0.05 (ANOVA followed by Newman-Keul’s post hoc test).

 
GKKO mice exhibit hyperphagia and hypothalamic gene expression similar to that produced by hypoglycemia, fasting, and leptin deficiency
Although GKKO mice exhibited normal body weight, nevertheless, they did exhibit elevated food intake, eating about 20% more food than wild-type controls, as indicated by weekly weighing of food intake (Fig. 4Go). This hyperphagia was observed consistently throughout the entire study, in both males and females. Consistent with hyperphagia, ad libitum-fed GKKO mice also exhibited elevated expression of hypothalamic NPY (Fig. 5AGo) and reduced expression of hypothalamic POMC (Fig. 5BGo), similar to the profile of expression of fasted or leptin-deficient mice (18). Finally, we demonstrated that feeding induces c-fos in hypothalamic neurons, independent of leptin, consistent with the activation of hypothalamic neurons by glucose (19). Consistent with impaired hypothalamic responses to glucose, hypothalamic c-fos expression was also reduced in GKKO mice, compared with wild-type controls (Fig. 5CGo).


Figure 4
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  		FIG. 4. Heterozygous ablation of the GK gene increases food intake, measured weekly. WT, Wild type. *, P < 0.05; **, P < 0.005 (ANOVA followed by Newman-Keul’s post hoc test).

 

Figure 5
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  		FIG. 5. Heterozygous ablation of the GK gene increases hypothalamic expression of NPY (A) and reduces hypothalamic expression of POMC (B) and c-fos [without influencing plasma insulin (C) in ad libitum-fed mice]. WT, Wild type. *, P < 0.05 (ANOVA followed by Newman-Keul’s post hoc).

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
Several lines of evidence suggest that glucose-sensing hypothalamic neurons play a role in the regulation of neuroendocrine functions, including appetite (1, 2). However, in contrast to the leptin system, whose importance in determining chronic metabolic status can easily be demonstrated by ablation of either leptin or its receptor, it has been difficult to assess the importance of glucose signaling because complete removal of either glucose or its signaling system, i.e. glucokinase, is lethal. Although it has been reported that expression of glucokinase in ß-cells only is sufficient to maintain viability (10), we were not able to replicate this result because expression of the RIP-GK (Fig. 1Go) was never able, in our hands, to produce viable homozygous GKKO mice. Therefore, we hypothesize that the rescue of the homozygous GKKO mice by a RIP-GK transgene (10) entailed expression of glucokinase in glucose-sensing neurons as well as pancreatic ß-cells. Such a phenomenon has precedent because homozygous insulin receptor knockout mice can be rescued only with transgenic expression of the insulin receptor in neurons as well as liver and ß-cells (20). Furthermore, recent studies have demonstrated the importance of hypothalamic neuronal activity (especially melanocortinergic neurons) in directly regulating acute (21, 22) and chronic (23) glucose homeostasis. Further support for this hypothesis is that GKKO knockout mice exhibited hyperglycemia, even after fasting (data not shown), whereas under no circumstances did we observe reduced plasma insulin levels in GKKO mice (Fig. 3CGo). These results raise the possibility that the hyperglycemia is not due to reduced insulin secretion or hyperphagia but to impairments in the hypothalamic regulation of peripheral glucose homeostasis (23).

Although we were unable to examine neuroendocrine functions in homozygous GKKO mice, we were nevertheless able to demonstrate that even heterozygous ablation of the GK gene produced a phenotype similar to that produced by hypoglycemia, fasting, or leptin deficiency. These phenotypes included impaired fertility, hyperphagia, elevated glucocorticoid secretion, elevated hypothalamic NPY mRNA, and reduced POMC mRNA. These results are all the more impressive because plasma glucose levels were elevated sufficiently to drive normal levels of insulin (and leptin) secretion, and this elevated plasma glucose is sufficient to compensate for the impaired pancreatic sensing of glucose characteristic of these GKKO mice (24). Apparently, however, even this markedly elevated level of plasma glucose was insufficient to completely compensate for impaired neuronal sensing of glucose. In view of the observed phenotypes, so reminiscent of leptin deficiency (16, 17, 18, 25, 26), it is surprising that the GKKO mice are not obese. Although we did measure thermogenesis by indirect calorimetry, effects of genotype on total heat production, VO2, VCO2, or respiratory quotient were not statistically significant (data not shown). We hypothesize that there are two reasons that we did not observe obesity. First, the effect of heterozygous ablation of the GK gene on food intake is only about half as large as the effect of homozygous ablation of the leptin gene (26). Second, the development of obesity due to leptin deficiency entails profound hyperinsulinemia and extremely elevated glucocorticoid secretion, normalization of which largely prevents the obese phenotype (26). Although GKKO mice exhibit normal insulin levels due to hyperstimulation by elevated glucose, we hypothesize that further stimulation of insulin secretion might be impaired in GKKO mice (due to pancreatic glucokinase deficiency), which may therefore be resistant to obesity. Similarly, the relative modest elevation in plasma glucocortoid levels observed in GKKO mice may be insufficient to support the extreme obesity of completely leptin-deficient mice (26).

Taken together, these data support the hypothesis that glucokinase mediates not only insulin secretion but also neuroendocrine regulation of metabolic economy, including regulation of other hormones and appetite. We hypothesize that the relatively modest perturbations in neuroendocrine function observed in GKKO mice would be enhanced if glucokinase could be more fully and specifically deleted from neurons or if glucose levels were normalized [because the 2-fold elevation of plasma glucose levels largely compensates for the roughly 50% decrease in glucokinase activity (24)]. Such studies, currently underway, would more fully address the hypothesis that reduced sensitivity to glucose in hypothalamic neurons could contribute to the development of obesity in some individuals.


   Acknowledgments
 
We thank Dr. Tim Stewart for his generous sharing of the GKKO mice and the RIP-GK construct.


   Footnotes
 
This work was supported by the Juvenile Diabetes Foundation International and the National Institutes on Aging (AG19934-01).

Disclosure Statement: X.Y., J.M., T.M., and C.V.M. have nothing to declare.

First Published Online January 11, 2007

Abbreviations: GK, Glucokinase; GKKO, glucokinase knockout; hGKKO, heterozygous GKKO; NPY, neuropeptide Y; POMC, proopiomelanocortin; RIP, rat insulin promoter.

Received September 25, 2006.

Accepted for publication December 29, 2006.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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