Central administration of metformin into the third ventricle of C57BL/6 mice decreases meal size and number and activates hypothalamic S6 kinase

2013 ◽  
Vol 305 (5) ◽  
pp. R499-R505 ◽  
Author(s):  
Hyun-Ju Kim ◽  
Eun-Young Park ◽  
Mi-Jeong Oh ◽  
Sung-Soo Park ◽  
Kyung-Ho Shin ◽  
...  
Keyword(s):  
Body Weight ◽  
Energy Balance ◽  
Food Intake ◽  
Third Ventricle ◽  
Meal Size ◽  
Dependent Manner ◽  
Central Administration ◽  
Mediobasal Hypothalamus ◽  
S6 Kinase ◽  
The Third

Administration of metformin is known to reduce both body weight and food intake. Although the hypothalamus is recognized as a critical regulator of energy balance and body weight, there is currently no evidence for an effect of metformin in the hypothalamus. Therefore, we sought to determine the central action of metformin on energy balance and body weight, as well as its potential involvement with key hypothalamic energy sensors, including adenosine monophosphate-activated protein kinase (AMPK) and S6 kinase (S6K). We used meal pattern analysis and a conditioned taste aversion (CTA) test and measured energy expenditure in C56BL/6 mice administered metformin (0, 7.5, 15, or 30 μg) into the third ventricle (I3V). Furthermore, we I3V-administered either control or metformin (30 μg) and compared the phosphorylation of AMPK and S6K in the mouse mediobasal hypothalamus. Compared with the control, I3V administration of metformin decreased body weight and food intake in a dose-dependent manner and did not result in CTA. Furthermore, the reduction in food intake induced by I3V administration of metformin was accomplished by decreases in both nocturnal meal size and number. Compared with the control, I3V administration of metformin significantly increased phosphorylation of S6K at Thr389 and AMPK at Ser485/491 in the mediobasal hypothalamus, while AMPK phosphorylation at Thr172 was not significantly altered. Moreover, I3V rapamycin pretreatment restored the metformin-induced anorexia and weight loss. These results suggest that the reduction in food intake induced by the central administration of metformin in the mice may be mediated by activation of S6K pathway.

scholarly journals Hyperphagia and obesity in OLETF rats lacking CCK-1 receptors

2006 ◽  
Vol 361 (1471) ◽  
pp. 1211-1218 ◽  
Author(s):  
Timothy H Moran ◽  
Sheng Bi
Keyword(s):  
Body Weight ◽  
Food Intake ◽  
Mrna Expression ◽  
Size Control ◽  
Insulin Dependent Diabetes Mellitus ◽  
Meal Size ◽  
Dependent Diabetes Mellitus ◽  
Central Administration ◽  
Oletf Rats ◽  
Oletf Rat

The brain–gut peptide cholecystokinin (CCK) inhibits food intake following peripheral or site directed central administration. Peripheral exogenous CCK inhibits food intake by reducing the size and duration of a meal. Antagonist studies have demonstrated that the actions of the exogenous peptide mimic those of endogenous CCK. Antagonist administration results in increased meal size and meal duration. The feeding inhibitory actions of CCK are mediated through interactions with CCK-1 receptors. The recent identification of the Otsuka–Long–Evans–Tokushima Fatty (OLETF) rat as a spontaneous CCK-1 receptor knockout model has allowed a more comprehensive evaluation of the feeding actions of CCK. OLETF rats become obese and develop non-insulin dependent diabetes mellitus (NIDDM). Consistent with the absence of CCK-1 receptors, OLETF rats do not respond to exogenous CCK. OLETF rats are hyperphagic and their increased food intake is characterized by a large increase in meal size with a decrease in meal frequency that is not sufficient to compensate for the meal size increase. Deficits in meal size control are evident in OLETF rats as young as 2 days of age. OLETF obesity is secondary to the increased food intake. Pair feeding to amounts consumed by intact control rats normalizes body weight, body fat and elevated insulin and glucose levels. Hypothalamic arcuate nucleus peptide mRNA expression in OLETF rats is appropriate to their obesity and is normalized by pair feeding. In contrast, pair fed and young pre-obese OLETF rats have greatly elevated dorsomedial hypothalamic (DMH) neuropeptide Y (NPY) mRNA expression. Elevated DMH NPY in OLETF rats appears to be a consequence of the absence of CCK-1 receptors. In intact rats NPY and CCK-1 receptors colocalize to neurons within the compact subregion of the DMH and local CCK administration reduces food intake and decreases DMH NPY mRNA expression. We have proposed that the absence of DMH CCK-1 receptors significantly contributes to the OLETF's inability to compensate for their meal size control deficit leading to their overall hyperphagia. Access to a running wheel and the resulting exercise normalizes food intake and body weight in OLETF rats. When given access to running wheels for 6 weeks shortly after weaning, OLETF rats do not gain weight to the same degree as sedentary OLETF rats and do not develop NIDDM. Exercise also prevents elevated levels of DMH NPY mRNA expression, suggesting that exercise exerts an alternative, non-CCK mediated, control on DMH NPY. The OLETF rat is a valuable model for characterizing actions of CCK in energy balance and has provided novel insights into interactions between exercise and food intake.

Intracerebroventricular infusions of 3-OHB and insulin in a rat model of dietary obesity

1988 ◽  
Vol 255 (6) ◽  
pp. R974-R981 ◽  
Author(s):  
K. Arase ◽  
J. S. Fisler ◽  
N. S. Shargill ◽  
D. A. York ◽  
G. A. Bray
Keyword(s):  
Body Weight ◽  
Food Intake ◽  
Dietary Fat ◽  
High Fat Diet ◽  
Third Ventricle ◽  
Sprague Dawley ◽  
High Fat ◽  
Low Fat ◽  
The Third ◽  
Intracerebroventricular Infusion

We examined the effect of dietary fat on the response to 3-hydroxybutyrate (3-OHB) and insulin infused chronically into the third ventricle in three strains of rats with differing susceptibility to obesity induced by a high-fat diet: Osborne-Mendel rats are most susceptible; Sprague-Dawley-rats are intermediate; and S 5B/Pl rats are most resistant. Ten days after implantation of cannulas into the third ventricle, rats were fed either a low-fat diet or a high-fat diet for 14 days. On day 7, osmotic minipumps were attached to the ventricular cannulas. 3-OHB infusions (3.6 mumol/24 h) reduced food intake and body weight in Sprague-Dawley and Osborne-Mendel rats eating either diet. The dietary fat-resistant S 5B/Pl rats did not respond to the intracerebroventricular infusion of 3-OHB. The infusion of insulin (10 mU/24 h) lowered food intake and body weight in animals eating the low-fat (high-carbohydrate) diet but not in animals eating the high-fat diet. Diet profoundly affects the response to intracerebroventricular infusions of insulin but is without effect on the response to 3-OHB.

Effects of corticotropin-releasing factor on food intake and brown adipose tissue thermogenesis in rats

1988 ◽  
Vol 255 (3) ◽  
pp. E255-E259 ◽  
Author(s):  
K. Arase ◽  
D. A. York ◽  
H. Shimizu ◽  
N. Shargill ◽  
G. A. Bray
Keyword(s):  
Body Weight ◽  
Adipose Tissue ◽  
Food Intake ◽  
Brown Adipose Tissue ◽  
Sympathetic Activity ◽  
Third Ventricle ◽  
Corticotropin Releasing Factor ◽  
Serum Corticosterone ◽  
The Third ◽  
Brown Adipose

Corticotropin-releasing factor (CRF) has been administered into the third ventricle of rats in acute and chronic experiments. Following a single 5-micrograms injection of CRF, there was an acute reduction in food intake at 30 and 60 min that was no longer significant at 3 h. Guanosine 5'-diphosphate (GDP) binding to mitochondria from interscapular brown adipose tissue (IBAT) of 21-h deprived rats was significantly increased 30 min after the acute infusion of 5 micrograms of CRF. Serum corticosterone was elevated in both groups but was significantly higher in the group treated with CRF. Serum glucose was unchanged. During a 7-day infusion of CRF (4.8 micrograms/day) into the third ventricle, the treated animals showed a slight, but significant, decrease in food intake but a progressive decline in body weight of 53 g over 7 days. Mitochondrial GDP binding was increased in the ad libitum-fed rats chronically treated with CRF. Serum corticosterone levels, although significantly higher than controls, were lower than following acute administration of CRF. These data show that CRF can acutely reduce food intake and increase sympathetic activity and that chronically it reduces body weight and may increase sympathetic activity without any consistent decrease in food intake.

scholarly journals Kisspeptin antagonist prevents RF9-induced reproductive changes in female rats

Reproduction ◽  
2015 ◽  
Vol 149 (5) ◽  
pp. 465-473 ◽  
Author(s):  
Zafer Sahin ◽  
Sinan Canpolat ◽  
Mete Ozcan ◽  
Tuba Ozgocer ◽  
Haluk Kelestimur
Keyword(s):  
Body Weight ◽  
Energy Balance ◽  
Food Intake ◽  
Female Rats ◽  
Central Administration ◽  
Vaginal Opening ◽  
Sprague Dawley ◽  
Sprague Dawley Rats ◽  
Induced Changes ◽  
Lh Secretion

The aim of this study was to determine the modulatory effects of peptide 234 (p234) (an antagonist of GPR54 receptors) on kisspeptin and RF9 (an RFamide-related peptide antagonist)-induced changes in reproductive functions and energy balance in female rats. Female Sprague–Dawley rats were weaned on postnatal day (pnd) 21. The animals were intracerebroventricularly cannulated under general anesthesia on pnd 23. Groups of female rats were injected with kisspeptin, RF9, p234, kisspeptin plus p234, or RF9 plus p234, daily. The experiments were ended on the day of first diestrus following pnd 60. Kisspeptin or RF9 alone advanced vaginal opening (VO), which was delayed by administration of kisspeptin antagonist alone. In the rats given kisspeptin plus p234 or RF9 plus p234, VO was not different from control rats. Kisspeptin and RF9 elicited significant elevations in circulating LH levels. Coadministrations of kisspeptin or RF9 with p234 decreased LH levels significantly. The use of p234 alone did not cause any significant change in LH secretion. Kisspeptin decreased both food intake and body weight while RF9 decreased only food intake without affecting body weight. The effects of kisspeptin on energy balance were also reversed by central administration of p234. In conclusion, kisspeptin antagonist, p234, modulates the effects of kisspeptin on reproductive functions and energy balance, whereas RF9 seems to exert only its effects on reproductive functions by means of GPR54 signaling in female rats.

Potent osmoregulatory actions of homologous adrenomedullins administered peripherally and centrally in eels

2008 ◽  
Vol 295 (6) ◽  
pp. R2075-R2083 ◽  
Author(s):  
Maho Ogoshi ◽  
Shigenori Nobata ◽  
Yoshio Takei
Keyword(s):  
Third Ventricle ◽  
Dependent Manner ◽  
Ang Ii ◽  
Central Administration ◽  
Seawater Adaptation ◽  
Induced Hypotension ◽  
The Third ◽  
Dose Dependent ◽  
The Brain ◽  
Freshwater Eels

The teleost adrenomedullin (AM) family consists of three groups, AM1/AM4, AM2/AM3, and AM5. In the present study, we examined the effects of homologous AM1, AM2, and AM5 on drinking and renal function after peripheral or central administration in conscious freshwater eels. AM2 and AM5, but not AM1, exhibited dose-dependent (0.01–1 nmol/kg) dipsogenic and antidiuretic effects after intra-arterial bolus injection. The antidiuretic effect was significantly correlated with the degree of associated hypotension. To avoid the potential indirect osmoregulatory effects of AM-induced hypotension, infusion of AMs was also performed at nondepressor doses. Drinking was enhanced dose-dependently at 0.1–3 pmol·kg−1·min−1 of AM2 and AM5, matching the potency and efficacy of angiotensin II (ANG II), the most potent dipsogenic hormone known thus far. AM2 and AM5 infusion also induced mild antidiuresis, while AM1 caused antinatriuresis. Additionally, AMs were injected into the third and fourth ventricles of conscious eels to assess their site of dipsogenic action. However, none of the AMs at 0.05–0.5 nmol induced drinking, while ANG II was highly dipsogenic. AM2 and ANG II injected into the third ventricle increased arterial pressure while AM5 decreased it in a dose-dependent manner, and both AM2 and AM5 decreased blood pressure when injected into the fourth ventricle. These data suggest that circulating AM2 and AM5 act on a target site in the brain that lacks the blood-brain barrier. Collectively, the present study showed that AM2 and AM5 are potent osmoregulatory hormones in the eel, and their actions imply involvement in seawater adaptation of this euryhaline species.

scholarly journals Appetite-modifying actions of pro-neuromedin U-derived peptides

2009 ◽  
Vol 297 (2) ◽  
pp. E545-E551 ◽  
Author(s):  
David A. Bechtold ◽  
Tina R. Ivanov ◽  
Simon M. Luckman
Keyword(s):  
Body Weight ◽  
Energy Balance ◽  
Food Intake ◽  
Energy Expenditure ◽  
Metabolic Rate ◽  
Knockout Mice ◽  
Gene Knockout ◽  
Central Administration ◽  
Reduced Body ◽  
Gene Knockout Mouse

Neuromedin U (NMU) is known to have potent actions on appetite and energy expenditure. Deletion of the NMU gene in mice leads to an obese phenotype, characterized by hyperphagia and decreased energy expenditure. Conversely, transgenic mice that overexpress proNMU exhibit reduced body weight and fat storage. Here, we show that central administration of NMU or the related peptide neuromedin S (NMS) dose-dependently decreases food intake, increases metabolic rate, and leads to significant weight loss in mice. The effects of NMU and NMS on both feeding and metabolism are almost completely lost in mice lacking the putative CNS receptor for NMU and NMS, NMUr2. However, NMUr2 knockout mice do not exhibit overt differences in body weight or energy expenditure compared with wild-type mice, suggesting that the dramatic phenotype of the NMU gene knockout mouse is not due simply to the loss of NMU/NMUr2 signaling. Putative proteolytic cleavage sites indicate that an additional peptide is produced from the NMU precursor protein, which is extremely well conserved between human, mouse, and rat. Here, we demonstrate that this peptide, proNMU104-136, has a pronounced effect on energy balance in mice. Specifically, central administration of proNMU104-136 causes a significant but transient (∼4 h) increase in feeding, yet both food intake and body weight are decreased over the following 24 h. proNMU104-136 administration also significantly increased metabolic rate. These results suggest that proNMU104-136 is a novel modulator of energy balance and may contribute to the phenotype exhibited by NMU knockout mice.

Secretin as a satiation whisperer with the potential to turn into an obesity-curbing knight

Endocrinology ◽  
2021 ◽  
Author(s):  
Katharina Schnabl ◽  
Yongguo Li ◽  
Mueez U-Din ◽  
Martin Klingenspor
Keyword(s):  
Bariatric Surgery ◽  
Body Weight ◽  
Energy Balance ◽  
Food Intake ◽  
Weight Control ◽  
Therapeutic Potential ◽  
Physiological Mechanism ◽  
Gut Hormones ◽  
Metabolic Effects ◽  
Beneficial Effects

Abstract The obesity pandemic requires effective preventative and therapeutic intervention strategies. Successful and sustained obesity treatment is currently limited to bariatric surgery. Modulating the release of gut hormones is considered promising to mimic bariatric surgery with its beneficial effects on food intake, body weight and blood glucose levels. The gut peptide secretin was the first molecule to be termed a hormone; nevertheless, it only recently has been established as a legitimate anorexigenic peptide. In contrast to gut hormones that crosstalk with the brain either directly or by afferent neuronal projections, secretin mediates meal-associated brown fat thermogenesis to induce meal termination, thereby qualifying this physiological mechanism as an attractive, peripheral target for the treatment of obesity. In this perspective, it is of pivotal interest to deepen our yet superficial knowledge on the physiological roles of secretin as well as meal-associated thermogenesis in energy balance and body weight regulation. Of note, the emerging differences between meal-associated thermogenesis and cold-induced thermogenesis must be taken into account. In fact, there is no correlation between these two entities. In addition, the investigation of potential effects of secretin in hedonic-driven food intake, bariatric surgery as well as chronic treatment using suitable application strategies to overcome pharmacokinetic limitations will provide further insight into its potential to influence energy balance. The aim of this article is to review the facts on secretin’s metabolic effects, address prevailing gaps in our knowledge, and provide an overview on the opportunities and challenges of the therapeutic potential of secretin in body weight control.

scholarly journals Murine neuronatin deficiency is associated with a hypervariable food intake and bimodal obesity

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Irene Cimino ◽  
Debra Rimmington ◽  
Y. C. Loraine Tung ◽  
Katherine Lawler ◽  
Pierre Larraufie ◽  
...  
Keyword(s):  
Body Weight ◽  
Energy Balance ◽  
Food Intake ◽  
Energy Expenditure ◽  
Positive Energy ◽  
Chow Diet ◽  
Chromatin Regulator ◽  
Positive Energy Balance ◽  
The Impact ◽  
Deficient Mice

AbstractNeuronatin (Nnat) has previously been reported to be part of a network of imprinted genes downstream of the chromatin regulator Trim28. Disruption of Trim28 or of members of this network, including neuronatin, results in an unusual phenotype of a bimodal body weight. To better characterise this variability, we examined the key contributors to energy balance in Nnat+/−p mice that carry a paternal null allele and do not express Nnat. Consistent with our previous studies, Nnat deficient mice on chow diet displayed a bimodal body weight phenotype with more than 30% of Nnat+/−p mice developing obesity. In response to both a 45% high fat diet and exposure to thermoneutrality (30 °C) Nnat deficient mice maintained the hypervariable body weight phenotype. Within a calorimetry system, food intake in Nnat+/−p mice was hypervariable, with some mice consuming more than twice the intake seen in wild type littermates. A hyperphagic response was also seen in Nnat+/−p mice in a second, non-home cage environment. An expected correlation between body weight and energy expenditure was seen, but corrections for the effects of positive energy balance and body weight greatly diminished the effect of neuronatin deficiency on energy expenditure. Male and female Nnat+/−p mice displayed subtle distinctions in the degree of variance body weight phenotype and food intake and further sexual dimorphism was reflected in different patterns of hypothalamic gene expression in Nnat+/−p mice. Loss of the imprinted gene Nnat is associated with a highly variable food intake, with the impact of this phenotype varying between genetically identical individuals.

scholarly journals Body composition and appetite: fat-free mass (but not fat mass or BMI) is positively associated with self-determined meal size and daily energy intake in humans

2011 ◽  
Vol 107 (3) ◽  
pp. 445-449 ◽  
Author(s):  
John E. Blundell ◽  
Phillipa Caudwell ◽  
Catherine Gibbons ◽  
Mark Hopkins ◽  
Erik Näslund ◽  
...  
Keyword(s):  
Body Composition ◽  
Body Weight ◽  
Food Intake ◽  
Energy Intake ◽  
Fat Mass ◽  
Meal Size ◽  
Fat Free Mass ◽  
Daily Energy Intake ◽  
Molecular Control ◽  
Daily Energy

The idea of body weight regulation implies that a biological mechanism exerts control over energy expenditure and food intake. This is a central tenet of energy homeostasis. However, the source and identity of the controlling mechanism have not been identified, although it is often presumed to be some long-acting signal related to body fat, such as leptin. Using a comprehensive experimental platform, we have investigated the relationship between biological and behavioural variables in two separate studies over a 12-week intervention period in obese adults (totaln92). All variables have been measured objectively and with a similar degree of scientific control and precision, including anthropometric factors, body composition, RMR and accumulative energy consumed at individual meals across the whole day. Results showed that meal size and daily energy intake (EI) were significantly correlated with fat-free mass (FFM,Pvalues < 0·02–0·05) but not with fat mass (FM) or BMI (Pvalues 0·11–0·45) (study 1,n58). In study 2 (n34), FFM (but not FM or BMI) predicted meal size and daily EI under two distinct dietary conditions (high-fat and low-fat). These data appear to indicate that, under these circumstances, some signal associated with lean mass (but not FM) exerts a determining effect over self-selected food consumption. This signal may be postulated to interact with a separate class of signals generated by FM. This finding may have implications for investigations of the molecular control of food intake and body weight and for the management of obesity.

scholarly journals Circulating Peptide YY Concentrations Are Higher in Preterm than Full-Term Infants and Correlate Negatively with Body Weight and Positively with Serum Ghrelin Concentrations

2005 ◽  
Vol 51 (11) ◽  
pp. 2131-2137 ◽  
Author(s):  
Tania Siahanidou ◽  
Helen Mandyla ◽  
Maria Vounatsou ◽  
Dimitris Anagnostakis ◽  
Ioannis Papassotiriou ◽  
...  
Keyword(s):  
Body Mass Index ◽  
Body Weight ◽  
Energy Balance ◽  
Food Intake ◽  
Preterm Infants ◽  
Gestational Age ◽  
Peptide Yy ◽  
Full Term ◽  
Term Infants ◽  
Serum Ghrelin

Abstract Background: Peptide YY (PYY) and ghrelin are gastrointestinal tract–derived hormones that play roles in the regulation of food intake and energy balance. Negative energy balance often occurs in hospitalized preterm infants. Methods: To measure serum concentrations of PYY in preterm and full-term infants and to investigate their correlations with anthropometric characteristics, food intake, and serum ghrelin concentrations, we measured serum PYY and ghrelin concentrations by RIA in 62 healthy preterm infants [mean (SD) gestational age, 32.0 (2.1) weeks; postnatal age, 40.9 (14.8) days] and 15 healthy full-term infants of comparable postnatal age. All of the infants were formula-fed every 3 h. Results: PYY concentrations were significantly higher in preterm [1126.2 (215.4) ng/L] than in full-term infants [825.3 (234.4) ng/L; P &lt;0.001]. In the entire study population, serum PYY concentrations correlated negatively with gestational age and anthropometric measurements (birth weight, body weight, body length, body mass index, and head circumference) and positively with serum ghrelin concentrations, whereas there was no significant correlation between PYY concentration and caloric intake or weight gain. Multiple regression analysis, after correction for prematurity, revealed that serum PYY concentrations correlated independently with serum ghrelin concentrations and infant body weight or body mass index. Conclusions: Circulating concentrations of PYY may increase in preterm infants to compensate for the negative body-weight balance. The physiologic mechanisms behind the correlation between PYY and ghrelin remain to be elucidated.

Sign in / Sign up

Export Citation Format

Share Document