Possible role of creatine concentrations in the brain in regulating appetite and weight

doi:10.1016/j.brainres.2006.05.032

Brain Research

Volume 1101, Issue 1, 26 July 2006, Pages 85-91

https://doi.org/10.1016/j.brainres.2006.05.032 Get rights and content

Abstract

Cobaltic protoporphyrin IX (CoPP) is a synthetic heme analog which can elicit profound and prolonged decreases in appetite and body weight in several different animal species. Intracerebroventricular administration of CoPP in rats was found, by differential display and confirmed by Real-Time PCR, to result in an increase in expression of the creatine transporter when compared to vehicle-treated fed or vehicle-treated fasted control animals. In situ hybridization studies showed that creatine transporter mRNA concentrations were increased in several areas of the brain involved in the regulation of food intake, but creatine concentrations were decreased in hypothalamic homogenates in CoPP-treated animals compared to controls. Intracerebroventricular administration of β-guanidinopropionic acid, a compound known to decrease intracellular creatine concentration by competition for uptake, resulted in decreased food intake and body weight and increased Fos expression in the hypothalamus. Taken together, these findings suggest that creatine concentrations in the brain may play a role in regulating food intake and body weight.

Introduction

We have been engaged in study of a powerful experimental anorectic compound, cobaltic protoporphyrin IX (CoPP). This synthetic metalloporphyrin, with the exception of the cobalt which replaces the central iron atom, is otherwise identical to iron protoporphyrin IX (heme), the active prosthetic group in (to name but a few) hemoglobin, neuroglobin, the respiratory cytochromes, catalase, nitric oxide synthase and guanylate cyclase. CoPP (but not other metal-substituted porphyrins) is known to cause transient hypophagia and remarkably prolonged weight loss after subcutaneous, intracerebroventricular (icv) or intrahypothalamic administration in normal rats, mice, chickens and dogs and in obese Zucker rats which lack the leptin receptor (Galbraith and Kappas, 1989, Galbraith and Kappas, 1990, Galbraith and Kappas, 1991a, Galbraith and Kappas, 1991b, Galbraith and Kappas, 1991c, Galbraith et al., 1992). A single icv treatment with CoPP 0.2 μmol/kg body weight resulted in an approximately 20% (100 g) weight loss compared to vehicle-treated control rats, even when measured 300 days after treatment (Galbraith and Kappas, 1989). These duration and magnitude of weight loss after a single administration of an experimental compound are unprecedented.

We have previously reported that icv administration of CoPP leads to increased Fos expression in the hypothalamus of rats (Galbraith et al., 2004). Moreover, such treatments with CoPP also lead to decreased activity of nitric oxide synthase in hypothalamic homogenates when compared to vehicle-treated rats (Li et al., 2006). However, the exact mechanism of action of CoPP remains unclear. The purpose of the studies described in this manuscript was to try to further define the mechanism of action of CoPP on food ingestion and weight using a different approach, that of mRNA differential displays.

Section snippets

Results

During a series of mRNA differential display experiments, a particular band was identified (11G2L) which was reproducibly increased in the hypothalami of CoPP-treated rats compared to both vehicle-treated fed and vehicle-treated fasted rats (Figs. 1a, b). The band was excised from the gels, re-amplified and inserted into a cloning system. Using labeled cloned insert and freshly isolated mRNA from hypothalami of additional rats (saline-fed, saline-fasted, CoPP), the fidelity of the procedures

Discussion

Taken together, the above data strongly suggest that Cr and/or CrP concentrations play a role in the regulation of food intake and body weight. It cannot be definitively ruled out that the decrease in food intake characteristic of administration of CoPP itself causes a decrease in creatine levels. Although this possibility is not supported by the statistical analysis of our creatine data following treatment with CoPP or fasting (Fig. 1e), there appears to be a trend for reduction of creatine

Reagents

Cobaltic protoporphyrin was purchased from Porphyrin Products (Logan, UT) and β-guanidinopropionic acid from Sigma-Aldrich (St. Louis, MO).

Animals and surgery

Experiments were carried out in accordance with the University of Vermont Institutional Animal Use and Care guidelines. Measures were taken to minimize pain and discomfort. Adult Sprague–Dawley rats were housed singly in metabolic cages. Stereotactic surgery was used to implant indwelling cannulae into the III ventricle of the brain as previously described (

Acknowledgments

These studies were supported by National Institutes of Health Grant #R01 DK53479 to Richard A. Galbraith.

References (35)

O. Braissant et al.
Endogenous synthesis and transport of creatine in the rat brain: an in situ hybridization study
Mol. Brain Res.
(2001)
D. Carling
The AMP-activated protein kinase cascade—A unifying system for energy control
Trends Biochem. Sci.
(2004)
A.J. Carter et al.
Application and validation of an ionic exchange high performance liquid chromatographic method for measuring adenine nucleotides, creatine and creatine phosphate in mouse brain
J. Chromatogr.
(1990)
C.D. Fitch et al.
Inhibition of creatine and phosphocreatine accumulation in skeletal muscle and heart
Metabolism
(1980)
D. Holtzman et al.
Brain creatine phosphate and creatine kinase in mice fed an analogue of creatine
Brain Res.
(1989)
B. Walzel et al.
Novel mitochondrial creatine transport activity
J. Biol. Chem.
(2002)
M. Wyss et al.
Health implications of creatine: can oral creatine supplementation protect against neurological and atherosclerotic disease?
Neuroscience
(2002)
C. Bachmann et al.
Ammonia toxicity to the brain and creatine
Mol. Genet. Metab.
(2004)
N.G. Bowery et al.
[³H]γ-Aminobutyric acid uptake into neuroglial cells of rat superior cervical sympathetic ganglia
J. Physiol.
(1979)
N. Brustovetsky et al.
On the mechanisms of neuroprotection by creatine and phosphocreatine
J. Neurochem.
(2001)

A.J. Defalco et al.

The synthesis of creatine by the brain of the intact rat

J. Neurochem.

(1961)

R. Dringen et al.

Metabolism of glycine in primary astroglial cells: synthesis of creatine, serine, and glutathione

J. Neurochem.

(1998)

R.A. Galbraith et al.

Regulation of food intake and body weight by cobalt porphyrins in animals

Proc. Natl. Acad. Sci. U. S. A.

(1989)

R.A. Galbraith et al.

Cobalt-protoporphyrin suppresses expression of genetic obesity in homozygous (fa/fa) Zucker rats

Pharmacology

(1990)

R.A. Galbraith et al.

Cobalt protoporphyrin regulates body weight in beagle dogs: induction of weight loss in normal animals of stable adult weight

Pharmacology

(1991)

R.A. Galbraith et al.

Intracerebroventricular administration of cobalt protoporphyrin elicits prolonged weight reduction in rats

Am. J. Physiol.

(1991)

R.A. Galbraith et al.

The effects of cobalt-protoporphyrin on food intake, body weight and metabolism in adult male rats

Am. J. Physiol.

(1991)

Cited by (30)

Current and potential new treatment strategies for creatine deficiency syndromes
2022, Molecular Genetics and Metabolism
Citation Excerpt :
Cr was also suggested as appetite and weight regulator in hypothalamic nuclei. Intracerebroventricular administration, in adult rats, of cobaltic protoporphyrin IX (CoPP, an anorectic compound), resulted in decreased Cr concentrations paralleled by increased expression of SLC6A8 in several hypothalamic areas involved in the regulation of food intake, as compared to vehicle-treated fed or fasted controls animal [29]. Recent studies also proposed new roles for Cr in peripheral tissues.
Creatine deficiency syndromes (CDS) are inherited metabolic disorders caused by mutations in GATM, GAMT and SLC6A8 and mainly affect central nervous system (CNS). AGAT- and GAMT-deficient patients lack the functional brain endogenous creatine (Cr) synthesis pathway but express the Cr transporter SLC6A8 at blood-brain barrier (BBB), and can thus be treated by oral supplementation of high doses of Cr. For Cr transporter deficiency (SLC6A8 deficiency or CTD), current treatment strategies benefit one-third of patients. However, as their phenotype is not completely reversed, and for the other two-thirds of CTD patients, the development of novel more effective therapies is needed. This article aims to review the current knowledge on Cr metabolism and CDS clinical aspects, highlighting their current treatment possibilities and the most recent research perspectives on CDS potential therapeutics designed, in particular, to bring new options for the treatment of CTD.
Cobalt protoporphyrin decreases food intake, body weight, and the number of neurons in the Nucleus Accumbens in female rats
2021, Brain Research
Cobalt protoporphyrin (CoPP) is a potent heme oxygenase-1 inductor that produces temporary hypophagia and chronic weight loss. A complete description of this effect and the underlying mechanisms are unknown. In this work, we challenged the ability of CoPP to produce changes in rat behavior and cellular alterations in the Nucleus Accumbens that would explain those effects. We subcutaneously administered 25 µmol/kg_{body weight} CoPP in female rats and determined body weight, food intake, hyperactivity, and anxiety-like behavior, as well as the number of neurons and glial cells in the Nucleus Accumbens. CoPP significantly reduced food intake, water consumption, and body weight. Behavioral tests showed that anxiety-like behaviors and locomotor activity were not modified five days after the administration of CoPP. We also found a reduced number of neurons in the Nucleus Accumbens Shell. The above results could be relevant to diseases like anorexia, so it is necessary to deepen the study about the molecular mechanisms involved in reducing the food intake and weight loss elicited by CoPP.
Dietary supplementation of guanidinoacetic acid improves growth, biochemical parameters, antioxidant capacity and cytokine responses in Nile tilapia (Oreochromis niloticus)
2020, Fish and Shellfish Immunology
Citation Excerpt :
Furthermore, GAA favored the production of growth promoting polyamines (putrescine, spermidine and spermine), that have anabolic functions in synthesis of DNA, RNA, and proteins [44], along with its hydration effect on the muscle cells, bringing water into the cells, which promotes protein synthesis, reduces proteolysis, and enhances glycogen synthesis [45]. In addition, several studies reported that GAA supplementation has a role in increasing insulin-like growth factor 1 (IGF-1) in plasma, which led to the enhancement of protein synthesis and growth improvement [45,46]. Further, GAA supplementation could improve energy utilization with subsequent enhanced body weight [47,48].
A total of 180 unsexed Nile Tilapia fish (initial weight, 21 g) fed isonitrogenous (32%), isocaloric (3000 kcal/kg) diets containing different levels of guanidinoacetic acid (GAA) at levels of (GAA1, 0.06%, GAA2, 0.12%, GAA3, 0.18%); for 60 days. Results showed higher final body weight (FBW) and body weight gain (BWG) in groups supplemented with different levels of GAA. Specific growth rate (SGR) was the highest in groups supplemented with 0.12% and 0.18% GAA. Lipid % of whole-body composition was higher in all groups excluding GAA3 group. Serum creatine kinase (CK) activity, cholesterol, and creatinine levels showed a marked significant (P < 0.05) increase in all GAA supplemented groups compared to the control one. Triglycerides level demonstrated a higher elevation (P < 0.05) in both GAA2 and GAA3 supplemented groups. No significant observed in total protein, albumin, globulin, and A/G ratio. Lipid peroxidation marker (malondialdehyde/MDA) is markedly decreased along with a significant increase of superoxide dismutase (SOD), reduced glutathione (GSH), and nitric oxide (NO) levels in both GAA2 and GAA3 compared to other groups. Similarly, interleukin 1β (IL-1β) and tumor necrosis factor (TNF-α) gene expression levels were downregulated along with upregulation of transforming growth factor β1 (TGF-β1) at higher GAA levels, particularly at 0.18%. Our findings give important insights for the growth promoting, antioxidant and immunomodulatory effects of GAA supplemented diet particularly at level of 0.18%.
Effects of guanidinoacetic acid supplementation on growth performance, nutrient digestion, rumen fermentation and blood metabolites in Angus bulls
2020, Animal
Citation Excerpt :
Allen (2000) reported that the DMI of cows was positively related to dietary NDF digestion. Galbraith et al. (2006) found that creatine could stimulate food intake in rats. Similarly, Li et al. (2018) found that the feed intake of pigs increased with GAA addition.
Guanidinoacetic acid (GAA) can improve the growth performance of bulls. This study investigated the influences of GAA addition on growth, nutrient digestion, ruminal fermentation and serum metabolites in bulls. Forty-eight Angus bulls were randomly allocated to experimental treatments, that is, control, low-GAA (LGAA), medium-GAA (MGAA) and high-GAA (HGAA), with GAA supplementation at 0, 0.3, 0.6 and 0.9 g/kg DM, respectively. Bulls were fed a basal diet containing 500 g/kg DM concentrate and 500 g/kg DM roughage. The experimental period was 104 days, with 14 days for adaptation and 90 days for data collection. Bulls in the MGAA and HGAA groups had higher DM intake and average daily gain than bulls in the LGAA and control groups. The feed conversion ratio was lowest in MGAA and highest in the control. Bulls receiving 0.9 g/kg DM GAA addition had higher digestibility of DM, organic matter, NDF and ADF than bulls in other groups. The digestibility of CP was higher for HGAA than for LGAA and control. The ruminal pH was lower for MGAA, and the total volatile fatty acid concentration was greater for MGAA and HGAA than for the control. The acetate proportion and acetate-to-propionate ratio were lower for MGAA than for LGAA and control. The propionate proportion was higher for MGAA than for control. Bulls receiving GAA addition showed decreased ruminal ammonia N. Bulls in MGAA and HGAA had higher cellobiase, pectinase and protease activities and Butyrivibrio fibrisolvens, Prevotella ruminicola and Ruminobacter amylophilus populations than bulls in LGAA and control. However, the total protozoan population was lower for MGAA and HGAA than for LGAA and control. The total bacterial and Ruminococcus flavefaciens populations increased with GAA addition. The blood level of creatine was higher for HGAA, and the activity of l-arginine glycine amidine transferase was lower for MGAA and HGAA, than for control. The blood activity of guanidine acetate N-methyltransferase and the level of folate decreased in the GAA addition groups. The results indicated that dietary addition of 0.6 or 0.9 g/kg DM GAA improved growth performance, nutrient digestion and ruminal fermentation in bulls.
Potential therapeutic implications of ergogenic compounds on pathophysiology induced by traumatic brain injury: A narrative review
2019, Life Sciences
Citation Excerpt :
Decreased cerebral creatine was also demonstrated in an in vivo model of hepatic encephalopathy [47]. Finally, creatine has also been suggested as a potential regulator of the appetite and weight in hypothalamic nuclei [48–50]. Our current knowledge on creatine importance in normal neurological function and diseases is evidenced in a myriad of roles.
Traumatic brain injury (TBI) is a devastating condition that often triggers a sequel of neurological disorders that can last throughout lifespan. From a metabolic viewpoint, the compromising of the energy metabolism of the brain has produced evidence linking the severity of brain injury to the extent of disturbances in the cerebral metabolism. The cerebral metabolic crisis, however, displays that regional heterogeneity varies temporally post-injury. It is important to note that energy generation and mitochondrial function are closely related and interconnected with delayed secondary manifestations of brain injury, including early neuromotor dysfunction, cognitive impairment, and post-traumatic epilepsy (PTE). Given the extent of post-traumatic changes in neuronal function and the possibility of amplifying secondary cascades, different therapies designed to minimize damage and retain/restore cellular function after TBI are currently being studied. One of the possible strategies may be the inclusion of ergogenic compounds, which is a class of supplements that typically includes ingredients used by athletes to enhance their performance. The combination of these compounds offers specific physiological advantages, which include enhanced energy availability/metabolism and improved buffering capacity. However, the literature on their effects in certain biological systems and neurological diseases, such as TBI, has yet to be determined. Thus, the present review aims to discuss the role of ergogenic compounds popularly used in secondary damage induced by this neurological injury. In this narrative review, we also discuss how the results from animal studies can be applied to TBI clinical settings.
Creatine in the central nervous system: From magnetic resonance spectroscopy to creatine deficiencies
2017, Analytical Biochemistry
Creatine (Cr) is an important organic compound acting as intracellular high-energy phosphate shuttle and in energy storage. While located in most cells where it plays its main roles in energy metabolism and cytoprotection, Cr is highly concentrated in muscle and brain tissues, in which Cr also appears to act in osmoregulation and neurotransmission. This review discusses the basis of Cr metabolism, synthesis and transport within brain cells. The importance of Cr in brain function and the consequences of its impaired metabolism in primary and secondary Cr deficiencies are also discussed. Cr and phosphocreatine (PCr) in living systems can be well characterized using in vivo magnetic resonance spectroscopy (MRS). This review describes how ¹H MRS allows the measurement of Cr and PCr, and how ³¹P MRS makes it possible to estimate the creatine kinase (CK) rate constant and so detect dynamic changes in the Cr/PCr/CK system. Absolute quantification by MRS using creatine as internal reference is also debated. The use of in vivo MRS to study brain Cr in a non-invasive way is presented, as well as its use in clinical and preclinical studies, including diagnosis and treatment follow-up in patients.

View all citing articles on Scopus

View full text

Research ReportPossible role of creatine concentrations in the brain in regulating appetite and weight

Abstract

Introduction

Section snippets

Results

Discussion

Reagents

Animals and surgery

Acknowledgments

Mol. Brain Res.

Trends Biochem. Sci.

J. Chromatogr.

Metabolism

Brain Res.

J. Biol. Chem.

Neuroscience

Ammonia toxicity to the brain and creatine

Mol. Genet. Metab.

[3H]γ-Aminobutyric acid uptake into neuroglial cells of rat superior cervical sympathetic ganglia

J. Physiol.

On the mechanisms of neuroprotection by creatine and phosphocreatine

J. Neurochem.

The synthesis of creatine by the brain of the intact rat

J. Neurochem.

Metabolism of glycine in primary astroglial cells: synthesis of creatine, serine, and glutathione

J. Neurochem.

Regulation of food intake and body weight by cobalt porphyrins in animals

Proc. Natl. Acad. Sci. U. S. A.

Cobalt-protoporphyrin suppresses expression of genetic obesity in homozygous (fa/fa) Zucker rats

Pharmacology

Cobalt protoporphyrin regulates body weight in beagle dogs: induction of weight loss in normal animals of stable adult weight

Pharmacology

Intracerebroventricular administration of cobalt protoporphyrin elicits prolonged weight reduction in rats

Am. J. Physiol.

The effects of cobalt-protoporphyrin on food intake, body weight and metabolism in adult male rats

Am. J. Physiol.

Research Report
Possible role of creatine concentrations in the brain in regulating appetite and weight

[³H]γ-Aminobutyric acid uptake into neuroglial cells of rat superior cervical sympathetic ganglia