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1.
Endocrinology ; 162(9)2021 09 01.
Article in English | MEDLINE | ID: mdl-34190328

ABSTRACT

Neurotensin (NT) is an anorexic gut hormone and neuropeptide that increases in circulation following bariatric surgery in humans and rodents. We sought to determine the contribution of NT to the metabolic efficacy of vertical sleeve gastrectomy (VSG). To explore a potential mechanistic role of NT in VSG, we performed sham or VSG surgeries in diet-induced obese NT receptor 1 (NTSR1) wild-type and knockout (ko) mice and compared their weight and fat mass loss, glucose tolerance, food intake, and food preference after surgery. NTSR1 ko mice had reduced initial anorexia and body fat loss. Additionally, NTSR1 ko mice had an attenuated reduction in fat preference following VSG. Results from this study suggest that NTSR1 signaling contributes to the potent effect of VSG to initially reduce food intake following VSG surgeries and potentially also on the effects on macronutrient selection induced by VSG. However, maintenance of long-term weight loss after VSG requires signals in addition to NT.


Subject(s)
Anorexia/etiology , Avoidant Restrictive Food Intake Disorder , Gastrectomy/adverse effects , Postoperative Complications/genetics , Receptors, Neurotensin/genetics , Animals , Anorexia/genetics , Dietary Fats , Gastrectomy/methods , Male , Mice , Mice, Knockout , Phobic Disorders/etiology , Phobic Disorders/genetics , Postoperative Complications/psychology
2.
Mol Metab ; 47: 101174, 2021 05.
Article in English | MEDLINE | ID: mdl-33549847

ABSTRACT

OBJECTIVE: The goal of this study was to investigate the importance of central hormone-sensitive lipase (HSL) expression in the regulation of food intake and body weight in mice to clarify whether intracellular lipolysis in the mammalian hypothalamus plays a role in regulating appetite. METHODS: Using pharmacological and genetic approaches, we investigated the role of HSL in the rodent brain in the regulation of feeding and energy homeostasis under basal conditions during acute stress and high-fat diet feeding. RESULTS: We found that HSL, a key enzyme in the catabolism of cellular lipid stores, is expressed in the appetite-regulating centers in the hypothalamus and is activated by acute stress through a mechanism similar to that observed in adipose tissue and skeletal muscle. Inhibition of HSL in rodent models by a synthetic ligand, global knockout, or brain-specific deletion of HSL prevents a decrease in food intake normally seen in response to acute stress and is associated with the increased expression of orexigenic peptides neuropeptide Y (NPY) and agouti-related peptide (AgRP). Increased food intake can be reversed by adeno-associated virus-mediated reintroduction of HSL in neurons of the mediobasal hypothalamus. Importantly, metabolic stress induced by a high-fat diet also enhances the hyperphagic phenotype of HSL-deficient mice. Specific deletion of HSL in the ventromedial hypothalamic nucleus (VMH) or AgRP neurons reveals that HSL in the VMH plays a role in both acute stress-induced food intake and high-fat diet-induced obesity. CONCLUSIONS: Our results indicate that HSL activity in the mediobasal hypothalamus is involved in the acute reduction in food intake during the acute stress response and sensing of a high-fat diet.


Subject(s)
Appetite/physiology , Homeostasis , Hypothalamus/metabolism , Sterol Esterase/metabolism , Agouti-Related Protein/metabolism , Animals , Body Weight , Diet, High-Fat/adverse effects , Eating , Energy Metabolism , Female , Hyperphagia/metabolism , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Neurons/metabolism , Neuropeptide Y/metabolism , Obesity/metabolism , RNA Splicing Factors , Sterol Esterase/genetics , Stress, Physiological/genetics , Transcriptome
3.
Nat Commun ; 11(1): 4458, 2020 09 07.
Article in English | MEDLINE | ID: mdl-32895383

ABSTRACT

In rodent models of type 2 diabetes (T2D), sustained remission of hyperglycemia can be induced by a single intracerebroventricular (icv) injection of fibroblast growth factor 1 (FGF1), and the mediobasal hypothalamus (MBH) was recently implicated as the brain area responsible for this effect. To better understand the cellular response to FGF1 in the MBH, we sequenced >79,000 single-cell transcriptomes from the hypothalamus of diabetic Lepob/ob mice obtained on Days 1 and 5 after icv injection of either FGF1 or vehicle. A wide range of transcriptional responses to FGF1 was observed across diverse hypothalamic cell types, with glial cell types responding much more robustly than neurons at both time points. Tanycytes and ependymal cells were the most FGF1-responsive cell type at Day 1, but astrocytes and oligodendrocyte lineage cells subsequently became more responsive. Based on histochemical and ultrastructural evidence of enhanced cell-cell interactions between astrocytes and Agrp neurons (key components of the melanocortin system), we performed a series of studies showing that intact melanocortin signaling is required for the sustained antidiabetic action of FGF1. These data collectively suggest that hypothalamic glial cells are leading targets for the effects of FGF1 and that sustained diabetes remission is dependent on intact melanocortin signaling.


Subject(s)
Diabetes Mellitus, Experimental/diet therapy , Diabetes Mellitus, Type 2/drug therapy , Fibroblast Growth Factor 1/administration & dosage , Hypoglycemic Agents/administration & dosage , Hypothalamus/drug effects , Recombinant Proteins/administration & dosage , Agouti-Related Protein/metabolism , Animals , Astrocytes/drug effects , Astrocytes/metabolism , Blood Glucose/analysis , Cell Communication , Cell Nucleus/drug effects , Cell Nucleus/metabolism , Diabetes Mellitus, Experimental/blood , Diabetes Mellitus, Experimental/etiology , Diabetes Mellitus, Experimental/pathology , Diabetes Mellitus, Type 2/blood , Diabetes Mellitus, Type 2/etiology , Diabetes Mellitus, Type 2/pathology , Diet, High-Fat/adverse effects , Dietary Sucrose/administration & dosage , Dietary Sucrose/adverse effects , Humans , Hypothalamus/cytology , Hypothalamus/pathology , Injections, Intraventricular , Leptin/genetics , Male , Melanocortins/metabolism , Melanocyte-Stimulating Hormones/administration & dosage , Mice , Mice, Knockout , Neurons/drug effects , Neurons/metabolism , Oligodendroglia/drug effects , Oligodendroglia/metabolism , RNA-Seq , Receptor, Melanocortin, Type 4/genetics , Receptors, Melanocortin/antagonists & inhibitors , Receptors, Melanocortin/metabolism , Remission Induction/methods , Signal Transduction/drug effects , Single-Cell Analysis , Stereotaxic Techniques , Transcriptome/drug effects
4.
Acta Physiol (Oxf) ; 228(4): e13437, 2020 04.
Article in English | MEDLINE | ID: mdl-31900990

ABSTRACT

AIM: Neurons in the arcuate nucleus of the hypothalamus are involved in regulation of food intake and energy expenditure, and dysregulation of signalling in these neurons promotes development of obesity. The role of the rate-limiting enzyme in the NAD+ salvage pathway, nicotinamide phosphoribosyltransferase (NAMPT), for regulation energy homeostasis by the hypothalamus has not been extensively studied. METHODS: We determined whether Nampt mRNA or protein levels in the hypothalamus of mice were affected by diet-induced obesity, by fasting and re-feeding, and by leptin and ghrelin treatment. Primary hypothalamic neurons were treated with FK866, a selective inhibitor of NAMPT, or rAAV carrying shRNA directed against Nampt, and levels of reactive oxygen species (ROS) and mitochondrial respiration were assessed. Fasting and ghrelin-induced food intake was measured in mice in metabolic cages after intracerebroventricular (ICV)-mediated FK866 administration. RESULTS: NAMPT levels in the hypothalamus were elevated by administration of ghrelin and leptin. In diet-induced obese mice, both protein and mRNA levels of NAMPT decreased in the hypothalamus. NAMPT inhibition in primary hypothalamic neurons significantly reduced levels of NAD+ , increased levels of ROS, and affected the expression of Agrp, Pomc and genes related to mitochondrial function. Finally, ICV-induced NAMPT inhibition by FK866 did not cause malaise or anhedonia, but completely ablated fasting- and ghrelin-induced increases in food intake. CONCLUSION: Our findings indicate that regulation of NAMPT levels in hypothalamic neurons is important for the control of fasting- and ghrelin-induced food intake.


Subject(s)
Fasting/metabolism , Ghrelin/metabolism , Hypothalamus/metabolism , Nicotinamide Phosphoribosyltransferase/metabolism , Acrylamides/administration & dosage , Agouti-Related Protein/genetics , Agouti-Related Protein/metabolism , Animals , Cell Line , Eating , Female , Male , Mice , Mice, Inbred C57BL , Phosphotransferases (Alcohol Group Acceptor)/metabolism , Piperidines/administration & dosage , Pro-Opiomelanocortin/genetics , Pro-Opiomelanocortin/metabolism
5.
J Neuroendocrinol ; 31(7): e12761, 2019 07.
Article in English | MEDLINE | ID: mdl-31237372

ABSTRACT

Dopamine-producing tyrosine hydroxylase (TH) neurones in the hypothalamic arcuate nucleus (ARC) have recently been shown to be involved in ghrelin signalling and body weight homeostasis. In the present study, we investigate the role of the intracellular regulator RhoA in hypothalamic TH neurones in response to peripheral hormones. Diet-induced obesity was found to be associated with increased phosphorylation of TH in ARC, indicating obesity-associated increased activity of ARC TH neurones. Mice in which RhoA was specifically knocked out in TH neurones (TH-RhoA-/- mice) were more sensitive to the orexigenic effect of peripherally administered ghrelin and displayed an abolished response to the anorexigenic hormone leptin. When TH-RhoA-/- mice were challenged with a high-fat high-sucrose (HFHS) diet, they became hyperphagic and gained more body weight and fat mass compared to wild-type control mice. Importantly, lack of RhoA prevented development of ghrelin resistance, which is normally observed in wild-type mice after long-term HFHS diet feeding. Patch-clamp electrophysiological analysis demonstrated increased ghrelin-induced excitability of TH neurones in lean TH-RhoA-/- mice compared to lean littermate control animals. Additionally, increased expression of the orexigenic hypothalamic neuropeptides agouti-related peptide and neuropeptide Y was observed in TH-RhoA-/- mice. Overall, our data indicate that TH neurones in ARC are important for the regulation of body weight homeostasis and that RhoA is both a central effector in these neurones and important for the development of obesity-induced ghrelin resistance. The obese phenotype of TH-RhoA-/- mice may be a result of increased sensitivity to ghrelin and decreased sensitivity to leptin, resulting in increased food intake.


Subject(s)
Arcuate Nucleus of Hypothalamus/metabolism , Body Weight , Eating , Ghrelin/metabolism , Neurons/metabolism , Tyrosine 3-Monooxygenase/metabolism , rhoA GTP-Binding Protein/metabolism , Animals , Female , Gene Expression , Male , Mice, Knockout , Obesity/metabolism , RNA, Messenger/metabolism , rhoA GTP-Binding Protein/genetics
6.
Diabetes ; 68(6): 1329-1340, 2019 06.
Article in English | MEDLINE | ID: mdl-30936142

ABSTRACT

Neurotensin (NT), a gut hormone and neuropeptide, increases in circulation after bariatric surgery in rodents and humans and inhibits food intake in mice. However, its potential to treat obesity and the subsequent metabolic dysfunctions have been difficult to assess owing to its short half-life in vivo. Here, we demonstrate that a long-acting, pegylated analog of the NT peptide (P-NT) reduces food intake, body weight, and adiposity in diet-induced obese mice when administered once daily for 6 days. Strikingly, when P-NT was combined with the glucagon-like peptide 1 mimetic liraglutide, the two peptides synergized to reduce food intake and body weight relative to each monotherapy, without inducing a taste aversion. Further, P-NT and liraglutide coadministration improved glycemia and reduced steatohepatitis. Finally, we show that the melanocortin pathway is central for P-NT-induced anorexia and necessary for the full synergistic effect of P-NT and liraglutide combination therapy. Overall, our data suggest that P-NT and liraglutide combination therapy could be an enhanced treatment for obesity with improved tolerability compared with liraglutide monotherapy.


Subject(s)
Adiposity/drug effects , Blood Glucose/drug effects , Body Weight/drug effects , Eating/drug effects , Hypoglycemic Agents/pharmacology , Liraglutide/pharmacology , Neurotensin/pharmacology , Obesity/metabolism , Animals , Blood Glucose/metabolism , Delayed-Action Preparations , Drug Synergism , Fatty Liver/metabolism , Fatty Liver/pathology , Liver/drug effects , Liver/metabolism , Liver/pathology , Melanocortins/metabolism , Mice , Mice, Knockout , Polyethylene Glycols
7.
Int J Mol Sci ; 18(5)2017 Apr 26.
Article in English | MEDLINE | ID: mdl-28445429

ABSTRACT

Ghrelin receptor (Ghr-R) signaling in neurons of the ventral tegmental area (VTA) can modulate dopaminergic function and the reward-related effects of both palatable foods and drugs of abuse. In this study, we re-introduced the Ghr-R in VTA neurons in Ghr-R knockout mice (Ghr-RVTA mice) to specifically study the importance of the constitutively active Ghr-R for VTA neuronal signaling. Our results showed that re-introduction of the Ghr-R in the VTA had no impact on body weight or food intake under basal conditions. However, during novel environment stress Ghr-RVTA mice showed increased food intake and energy expenditure compared to Ghr-R knockout mice, demonstrating the significance of Ghr-R signaling in the response to stress. Ghr-RVTA mice also showed increased cocaine-induced locomotor activity compared to Ghr-R knockout mice, highlighting the importance of ghrelin signaling for the reward-related effects of activation of VTA neurons. Overall, our data suggest that re-introduction of the Ghr-R in the mesolimbic reward system of Ghr-R knockout mice increases the level of activation induced by both cocaine and novelty stress.


Subject(s)
Behavior, Animal/physiology , Receptors, Ghrelin/metabolism , Ventral Tegmental Area/metabolism , Animals , Body Weight , Dependovirus/genetics , Dopamine Plasma Membrane Transport Proteins/metabolism , Eating , Energy Metabolism , Genetic Vectors/genetics , Genetic Vectors/metabolism , Humans , Locomotion , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Oxygen Consumption , Receptors, Dopamine D2/metabolism , Receptors, Ghrelin/deficiency , Receptors, Ghrelin/genetics , Tyrosine 3-Monooxygenase/metabolism
8.
Endocrinology ; 157(9): 3482-92, 2016 09.
Article in English | MEDLINE | ID: mdl-27580810

ABSTRACT

Neurotensin (NT) is a peptide expressed in the brain and in the gastrointestinal tract. Brain NT inhibits food intake, but the effects of peripheral NT are less investigated. In this study, peripheral NT decreased food intake in both mice and rats, which was abolished by a NT antagonist. Using c-Fos immunohistochemistry, we found that peripheral NT activated brainstem and hypothalamic regions. The anorexigenic effect of NT was preserved in vagotomized mice but lasted shorter than in sham-operated mice. This in combination with a strong increase in c-Fos activation in area postrema after ip administration indicates that NT acts both through the blood circulation and the vagus. To improve the pharmacokinetics of NT, we developed a pegylated NT peptide, which presumably prolonged the half-life, and thus, the effect on feeding was extended compared with native NT. On a molecular level, the pegylated NT peptide increased proopiomelanocortin mRNA in the arcuate nucleus. We also investigated the importance of NT for the decreased food intake after gastric bypass surgery in a rat model of Roux-en-Y gastric bypass (RYGB). NT was increased in plasma and in the gastrointestinal tract in RYGB rats, and pharmacological antagonism of NT increased food intake transiently in RYGB rats. Taken together, our data suggest that NT is a metabolically active hormone, which contributes to the regulation of food intake.


Subject(s)
Appetite Regulation/drug effects , Gastric Bypass , Neurotensin/administration & dosage , Animals , Eating/drug effects , Female , Male , Mice, Inbred C57BL , Neurotensin/antagonists & inhibitors , Neurotensin/blood , Rats, Sprague-Dawley , Sucrose , Vagotomy
9.
Cell Metab ; 23(2): 335-43, 2016 Feb 09.
Article in English | MEDLINE | ID: mdl-26724858

ABSTRACT

The liver is an important integrator of nutrient metabolism, yet no liver-derived factors regulating nutrient preference or carbohydrate appetite have been identified. Here we show that the liver regulates carbohydrate intake through production of the hepatokine fibroblast growth factor 21 (FGF21), which markedly suppresses consumption of simple sugars, but not complex carbohydrates, proteins, or lipids. Genetic loss of FGF21 in mice increases sucrose consumption, whereas acute administration or overexpression of FGF21 suppresses the intake of both sugar and non-caloric sweeteners. FGF21 does not affect chorda tympani nerve responses to sweet tastants, instead reducing sweet-seeking behavior and meal size via neurons in the hypothalamus. This liver-to-brain hormonal axis likely represents a negative feedback loop as hepatic FGF21 production is elevated by sucrose ingestion. We conclude that the liver functions to regulate macronutrient-specific intake by producing an endocrine satiety signal that acts centrally to suppress the intake of "sweets."


Subject(s)
Endocrine System/metabolism , Fibroblast Growth Factors/metabolism , Food Preferences/drug effects , Liver/metabolism , Sucrose/pharmacology , Taste/drug effects , Animals , Basic Helix-Loop-Helix Leucine Zipper Transcription Factors , Endocrine System/drug effects , Feeding Behavior/drug effects , Liver/drug effects , Male , Mice, Knockout , Nuclear Proteins/metabolism , Signal Transduction/drug effects , Transcription Factors/metabolism
10.
Article in English | MEDLINE | ID: mdl-26578081

ABSTRACT

BACKGROUND: Besides the well-known effects of ghrelin on adiposity and food intake regulation, the ghrelin system has been shown to regulate aspects of behavior including anxiety and stress. However, the effect of virus-mediated overexpression of the ghrelin receptor in the amygdala has not previously been addressed directly. METHODS: First, we examined the acute effect of peripheral ghrelin administration on anxiety- and depression-like behavior using the open field, elevated plus maze, forced swim, and tail suspension tests. Next, we examined the effect of peripheral ghrelin administration and ghrelin receptor deficiency on stress in a familiar and social environment using the Intellicage system. Importantly, we also used a novel approach to study ghrelin receptor signaling in the brain by overexpressing the ghrelin receptor in the amygdala. We examined the effect of ghrelin receptor overexpression on anxiety-related behavior before and after acute stress and measured the modulation of serotonin receptor expression. RESULTS: We found that ghrelin caused an anxiolytic-like effect in both the open field and elevated plus maze tests. Additionally, it attenuated air-puff-induced stress in the social environment, while the opposite was shown in ghrelin receptor deficient mice. Finally, we found that overexpression of the ghrelin receptor in the basolateral division of the amygdala caused an anxiolytic-like effect and decreased the 5HT1a receptor expression. CONCLUSIONS: Ghrelin administration and overexpression of the ghrelin receptor in the amygdala induces anxiolytic-like behavior. Since the ghrelin receptor has high constitutive activity, ligand-independent signaling in vivo may be important for the observed anxiolytic-like effects. The anxiolytic effects seem to be mediated independently from the HPA axis, potentially engaging the central serotonin system.


Subject(s)
Amygdala/drug effects , Anti-Anxiety Agents/pharmacology , Anxiety/prevention & control , Behavior, Animal/drug effects , Ghrelin/pharmacology , Receptors, Ghrelin/agonists , Signal Transduction/drug effects , Amygdala/metabolism , Amygdala/physiopathology , Animals , Anxiety/genetics , Anxiety/metabolism , Anxiety/psychology , Disease Models, Animal , Dose-Response Relationship, Drug , Female , Hindlimb Suspension , Humans , Locomotion/drug effects , Male , Maze Learning/drug effects , Mice, Inbred C57BL , Mice, Knockout , Motor Activity/drug effects , Receptor, Serotonin, 5-HT1A/metabolism , Receptors, Ghrelin/genetics , Receptors, Ghrelin/metabolism , Social Behavior , Stress, Psychological/complications , Stress, Psychological/metabolism , Stress, Psychological/psychology , Swimming , Time Factors
11.
Endocrinology ; 157(1): 176-94, 2016 Jan.
Article in English | MEDLINE | ID: mdl-26469136

ABSTRACT

The 2 gut hormones glucagon-like peptide-1 (GLP-1) and peptide YY (PYY) are well known to be coexpressed, costored, and released together to coact in the control of key metabolic target organs. However, recently, it became clear that several other gut hormones can be coexpressed in the intestinal-specific lineage of enteroendocrine cells. Here, we focus on the anatomical and functional consequences of the coexpression of neurotensin with GLP-1 and PYY in the distal small intestine. Fluorescence-activated cell sorting analysis, laser capture, and triple staining demonstrated that GLP-1 cells in the crypts become increasingly multihormonal, ie, coexpressing PYY and neurotensin as they move up the villus. Proglucagon promoter and pertussis toxin receptor-driven cell ablation and reappearance studies indicated that although all the cells die, the GLP-1 cells reappear more quickly than PYY- and neurotensin-positive cells. High-resolution confocal fluorescence microscopy demonstrated that neurotensin is stored in secretory granules distinct from GLP-1 and PYY storing granules. Nevertheless, the 3 peptides were cosecreted from both perfused small intestines and colonic crypt cultures in response to a series of metabolite, neuropeptide, and hormonal stimuli. Importantly, neurotensin acts synergistically, ie, more than additively together with GLP-1 and PYY to decrease palatable food intake and inhibit gastric emptying, but affects glucose homeostasis in a more complex manner. Thus, neurotensin is a major gut hormone deeply integrated with GLP-1 and PYY, which should be taken into account when exploiting the enteroendocrine regulation of metabolism pharmacologically.


Subject(s)
Enteroendocrine Cells/metabolism , Gene Expression Regulation , Glucagon-Like Peptide 1/metabolism , Ileum/metabolism , Intestinal Mucosa/metabolism , Neurotensin/metabolism , Peptide YY/metabolism , Animals , Biomarkers/metabolism , Bombesin/pharmacology , Enteroendocrine Cells/drug effects , Enteroendocrine Cells/ultrastructure , Female , Gene Expression Regulation/drug effects , Genes, Reporter , Glucagon-Like Peptide 1/genetics , Humans , Ileum/drug effects , Ileum/ultrastructure , Intestinal Mucosa/drug effects , Intestinal Mucosa/ultrastructure , Luminescent Proteins/genetics , Luminescent Proteins/metabolism , Male , Mice, Inbred C57BL , Mice, Transgenic , Neurotensin/genetics , Peptide Fragments/pharmacology , Peptide YY/genetics , Rats, Wistar , Receptors, G-Protein-Coupled/genetics , Receptors, G-Protein-Coupled/metabolism , Recombinant Fusion Proteins/genetics , Recombinant Fusion Proteins/metabolism , Secretory Vesicles/drug effects , Secretory Vesicles/metabolism , Secretory Vesicles/ultrastructure , Tissue Culture Techniques , Red Fluorescent Protein
12.
Am J Physiol Regul Integr Comp Physiol ; 308(11): R973-82, 2015 Jun 01.
Article in English | MEDLINE | ID: mdl-25855307

ABSTRACT

To characterize mechanisms responsible for fat accumulation we used a selectively bred obesity-prone (OP) and obesity-resistant (OR) rat model where the rats were fed a Western diet for 76 days. Body composition was assessed by magnetic resonance imaging scans, and as expected, the OP rats developed a higher degree of fat accumulation compared with OR rats. Indirect calorimetry showed that the OP rats had higher respiratory exchange ratio (RER) compared with OR rats, indicating an impaired ability to oxidize fat. The OP rats had lower expression of carnitine palmitoyltransferase 1b in intra-abdominal fat, and higher expression of stearoyl-CoA desaturase 1 in subcutaneous fat compared with OR rats, which could explain the higher fat accumulation and RER values. Basal metabolic parameters were also examined in juvenile OP and OR rats before and during the introduction of the Western diet. Juvenile OP rats likewise had higher RER values, indicating that this trait may be a primary and contributing factor to their obese phenotype. When the adult obese rats were exposed to the orexigenic and adipogenic hormone ghrelin, we observed increased RER values in both OP and OR rats, while OR rats were more sensitive to the orexigenic effects of ghrelin as well as ghrelin-induced attenuation of activity and energy expenditure. Thus increased fat accumulation characterizing obesity may be caused by impaired oxidative capacity due to decreased carnitine palmitoyltransferase 1b levels in the white adipose tissue, whereas ghrelin sensitivity did not seem to be a contributing factor.


Subject(s)
Adiposity , Carnitine O-Palmitoyltransferase/metabolism , Energy Metabolism , Intra-Abdominal Fat/enzymology , Obesity/enzymology , Subcutaneous Fat/enzymology , Adiposity/drug effects , Animals , Calorimetry, Indirect , Carnitine O-Palmitoyltransferase/genetics , Diet, High-Fat , Disease Models, Animal , Down-Regulation , Eating , Energy Metabolism/drug effects , Gene Expression Regulation , Ghrelin/administration & dosage , Hypothalamus/enzymology , Insulin/blood , Intra-Abdominal Fat/drug effects , Intra-Abdominal Fat/physiopathology , Leptin/blood , Magnetic Resonance Imaging , Male , Muscle, Skeletal/enzymology , Obesity/blood , Obesity/etiology , Obesity/genetics , Obesity/physiopathology , Oxidation-Reduction , Rats , Subcutaneous Fat/drug effects , Subcutaneous Fat/physiopathology , Time Factors , Weight Gain
13.
Physiol Behav ; 118: 144-51, 2013 Jun 13.
Article in English | MEDLINE | ID: mdl-23680430

ABSTRACT

GPRC6A is an amino acid-sensing receptor highly expressed in the brain and in skeletal muscle. Although recent evidence suggests that genetically engineered GPRC6A receptor knockout (KO) mice are susceptible to develop subtle endocrine and metabolic disturbances, the underlying disruptions in energy metabolism are largely unexplored. Based on GPRC6A's expression pattern and ligand preferences, we hypothesize that the receptor may impact energy metabolism via regulating physical activity levels. Thus, in the present study, we exposed GPRC6A receptor KO mice and their wild-type (WT) littermates to voluntary wheel running and forced treadmill exercise. Moreover, we assessed energy expenditure in the basal state, and evaluated the effects of wheel running on food intake, body composition, and a range of exercise-induced central and peripheral biomarkers. We found that adaptation to voluntary wheel running is affected by GPRC6A, as ablation of the receptor significantly enhances wheel running in KO relative to WT mice. Both genotypes responded to voluntary exercise by increasing food intake and improving body composition to a similar degree. In conclusion, these data demonstrate that the GPRC6A receptor is involved in regulating exercise behaviour. Future studies are highly warranted to delineate the underlying molecular details and to assess if these findings hold any translational value.


Subject(s)
Motor Activity/genetics , Motor Activity/physiology , Receptors, G-Protein-Coupled/genetics , Animals , Blotting, Western , Body Composition/genetics , Body Composition/physiology , Calorimetry, Indirect , Corticosterone/blood , Eating/physiology , Energy Metabolism/genetics , Energy Metabolism/physiology , Heat-Shock Proteins/metabolism , Hippocampus/metabolism , Mice , Mice, Knockout , Muscle, Skeletal/metabolism , Neural Pathways/physiology , Nucleus Accumbens/physiology , Reward , Running/physiology
14.
Synapse ; 67(9): 620-5, 2013 Sep.
Article in English | MEDLINE | ID: mdl-23536493

ABSTRACT

The beneficial effect of exercise on hippocampal plasticity is possibly mediated by increased angiogenesis and neurogenesis. In angiogenesis, insulin-like growth factor-1 (IGF-1), vascular endothelial growth factor (VEGF), and hypoxia-inducible factor 1, alpha subunit (HIF1α) are important factors, while the induction of neurogenesis requires signaling through the VEGF receptor, Flk-1 (VEGFR-2). VEGF expression is believed to be regulated by two distinct mTOR (mammalian target of Rapamycin)-containing multiprotein complexes mTORC1 and mTORC2, respectively. This study was initiated to investigate the effect of exercise on the expression of VEGF, cognate receptors, HIF1α, mTORC1, and mTORC2 in hippocampus and frontal cortex. To this end, we measured messenger RNA (mRNA) levels in rat brain using quantitative real-time polymerase chain reaction (real-time qPCR) after forced treadmill exercise for 1 day, 2 weeks, and 8 weeks. Rats were euthanized either immediately (0 h) or 24 h after last exercise session. Here, we show that exercise affected mRNA levels of VEGF, VEGFR2, and the coreceptor neuropilin 2 (NRP2) when the rats were euthanized immediately, whereas at 24 h only the expression of mTOR was regulated after a single bout of exercise. In conclusion, the effect of treadmill exercise on the VEGF system is acute rather than chronic and there is a transient activation of mTOR. More studies are needed to understand whether this could be beneficial in the treatment of neuropsychiatric disorders.


Subject(s)
Multiprotein Complexes/metabolism , Physical Exertion , TOR Serine-Threonine Kinases/metabolism , Animals , Exercise Test , Frontal Lobe/metabolism , Hippocampus/metabolism , Hypoxia-Inducible Factor 1, alpha Subunit/genetics , Hypoxia-Inducible Factor 1, alpha Subunit/metabolism , Male , Mechanistic Target of Rapamycin Complex 1 , Mechanistic Target of Rapamycin Complex 2 , Multiprotein Complexes/genetics , Neuropilin-2/genetics , Neuropilin-2/metabolism , Rats , Rats, Wistar , TOR Serine-Threonine Kinases/genetics , Transcription, Genetic , Vascular Endothelial Growth Factor A/genetics , Vascular Endothelial Growth Factor A/metabolism , Vascular Endothelial Growth Factor Receptor-2/genetics , Vascular Endothelial Growth Factor Receptor-2/metabolism
15.
Synapse ; 67(6): 328-37, 2013 Jun.
Article in English | MEDLINE | ID: mdl-23390031

ABSTRACT

Imaging the cerebral serotonin 2A (5-HT2A ) receptors with positron emission tomography (PET) has been carried out in humans with [(11) C]MDL 100907 and [(18) F]altanserin. Recently, the MDL 100907 analogue [(18) F]MH.MZ was developed combining the selectivity profile of MDL 100907 and the favourable radiophysical properties of fluorine-18. Here, we present a direct comparison of [(18) F]altanserin and [(18) F]MH.MZ. 5-HT2A receptor binding in pig cortex and cerebellum was investigated by autoradiography with [(3) H]MDL 100907, [(18) F]MH.MZ, and [(18) F]altanserin. [(18) F]MH.MZ and [(18) F]altanserin were investigated in Danish Landrace pigs by brain PET scanning at baseline and after i.v. administration of blocking doses of ketanserin. Full arterial input function and high performance liquid chromatography (HPLC) analysis allowed for tissue-compartment kinetic modeling of PET data. In vitro autoradiography showed high binding in cortical regions with both [(18) F]MH.MZ and [(18) F]altanserin. Significant 5-HT2A receptor binding was also found in the pig cerebellum, thus making this region unsuitable as a reference region for in vivo data analysis in this species. The cortical binding of [(18) F]MH.MZ and [(18) F]altanserin was blocked by ketanserin supporting that both radioligands bind to 5-HT2A receptors in the pig brain. In the HPLC analysis of pig plasma, [(18) F]MH.MZ displayed a fast and reproducible metabolism resulting in hydrophilic radiometabolites only whereas the metabolic profile of [(18) F]altanserin as expected showed lipophilic radiometabolites. Due to the slow kinetics of [(18) F]MH.MZ in high-binding regions in vivo, we suggest that [(18) F]MH.MZ will be an appropriate tracer for low binding regions where kinetics will be faster, whereas [(18) F]altanserin is a suitable tracer for high-binding regions.


Subject(s)
Fluorobenzenes/pharmacokinetics , Ketanserin/analogs & derivatives , Piperidines/pharmacokinetics , Positron-Emission Tomography , Radiopharmaceuticals/pharmacokinetics , Receptor, Serotonin, 5-HT2A/metabolism , Animals , Brain/metabolism , Fluorine Radioisotopes/pharmacokinetics , Ketanserin/pharmacokinetics , Serotonin Antagonists/pharmacokinetics , Swine , Tissue Distribution , Tritium/pharmacokinetics
16.
J Neurosci Res ; 91(5): 634-41, 2013 May.
Article in English | MEDLINE | ID: mdl-23404493

ABSTRACT

Prefrontal serotonin 2A receptors (5-HT2A Rs) have been linked to the pathogenesis and treatment of schizophrenia. Many antipsychotics fully occupy 5-HT2A R at clinical relevant doses, and activation of 5-HT2A receptors by lysergic acid diethylamide (LSD) and LSD-like drugs induces a schizophrenia-like psychosis in humans. Subchronic phencyclidine (PCP) administration is a well-established model for schizophrenia-like symptoms in rodents. The aim of the present study was to investigate whether subchronic PCP administration changes expression, binding, or functionality of cortical 5-HT2A Rs. As a measure of 5-HT2A R functionality, we used the 5-HT2A R agonist 2,5-dimethoxy-4-iodoamphetamine (DOI)-induced head-twitch response (HTR) and mRNA expression of the immediate-early genes (IEGs) activity-related cytoskeletal associated-protein (Arc), c-fos, and early growth response protein 2 (egr-2) in the frontal cortex. Mice were treated with PCP (10 mg/kg) or saline for 10 days, followed by a 5-day washout period. The PCP pretreatment increased the overall induction of HTR and frontal cortex IEG mRNA expression following a single challenge with DOI. These functional changes were not associated with changes in 5-HT2A R binding. Also, binding of the 5-HT1A R and the 5-HT transporter was unaffected. Finally, basal mRNA level of Arc was increased in the prefrontal cortex after subchronic PCP administration as revealed with in situ hybridization. Together these findings indicate that PCP administration produces changes in the brain that result in an increase in the absolute effect of DOI. Therefore, neurotransmission involving the 5-HT2A R could contribute to the behavioral deficits observed after PCP treatment. © 2013 Wiley Periodicals, Inc.


Subject(s)
Gene Expression Regulation/drug effects , Phencyclidine/pharmacology , Prefrontal Cortex/drug effects , Receptors, Serotonin, 5-HT2/metabolism , Schizophrenia/chemically induced , Schizophrenia/pathology , Signal Transduction/drug effects , AIDS-Related Complex/genetics , AIDS-Related Complex/metabolism , Amphetamines/pharmacology , Analysis of Variance , Animals , Autoradiography , Disease Models, Animal , Gene Expression Regulation/physiology , Genes, Immediate-Early/genetics , Male , Mice , Mice, Inbred C57BL , Phencyclidine/toxicity , Prefrontal Cortex/metabolism , Proto-Oncogene Proteins c-fos/genetics , Proto-Oncogene Proteins c-fos/metabolism , RNA, Messenger/metabolism , Serotonin Receptor Agonists/pharmacology , Time Factors
17.
Exp Neurol ; 237(1): 116-25, 2012 Sep.
Article in English | MEDLINE | ID: mdl-22735491

ABSTRACT

Human apolipoprotein E (apoE) plays an important role in lipid transport and distribution, being involved in neurite growth and neuroprotection in the brain. In humans, the apoE4 isoform is a risk factor for developing Azheimer's disease (AD), while apoE2 seems to provide neuroprotection. However, very little information is available on apoE2 genotype. In the present study, we have characterized behavioral and learning phenotypes in young transgenic mice apoE2, apoE3 and apoE4 of both sexes. We have also determined the levels of brain-derived neurotrophic factor (BDNF) and its receptor TrkB in cortex and hippocampus of male and female mice carrying either genotype. Our results show a worse performance of apoE4 and apoE2 mice in the acquisition of a spatial task compared to apoE3 mice, and a worse retention in apoE2 mice compared to the other two genotypes. On the other hand, an increase in the exploration of an open-field, which is compatible with a hyperactive behavior, was found in apoE2 females, while a decreased activity was observed in apoE4 mice. Increased BDNF levels in the frontal cortex were observed in apoE2 mice compared to apoE3. These results underscore behavioral differences between apoE genotypes in young mice, as well as the existence of interactions between genotype and gender, providing new valuable information on the apoE2 genotype.


Subject(s)
Apolipoproteins E/physiology , Behavior, Animal/physiology , Brain-Derived Neurotrophic Factor/physiology , Phenotype , Age Factors , Animals , Apolipoprotein E2/genetics , Apolipoprotein E3/genetics , Apolipoprotein E4/genetics , Apolipoproteins E/biosynthesis , Apolipoproteins E/genetics , Brain-Derived Neurotrophic Factor/genetics , Female , Frontal Lobe/physiology , Genotype , Hippocampus/physiology , Male , Mice , Mice, Transgenic , Protein Isoforms/biosynthesis , Protein Isoforms/genetics , Protein Isoforms/physiology , Sex Characteristics , Spatial Behavior/physiology
18.
Obesity (Silver Spring) ; 20(10): 2133-41, 2012 Oct.
Article in English | MEDLINE | ID: mdl-22450706

ABSTRACT

Food intake and body weight are regulated by a complex system of neural and hormonal signals, of which the anorexigenic neurotransmitter serotonin (5-hydroxytryptamine or 5-HT) is central. In this study, rat models of obesity and weight loss intervention were compared with regard to several 5-HT markers. Using receptor autoradiography, brain regional-densities of the serotonin transporter (SERT) and the 5-HT(2A) and 5-HT(4) receptors were measured in (i) selectively bred polygenic diet-induced obese (pgDIO) rats, (ii) outbred DIO rats, and (iii) Roux-en-Y gastric bypass (RYGB)-operated rats. pgDIO rats had higher 5-HT(4) and 5-HT(2A) receptor binding and lower SERT binding when compared to polygenic diet-resistant (pgDR) rats. The most pronounced difference between pgDIO and pgDR rats was observed in the nucleus accumbens shell (NAcS), a brain region regulating reward aspects of feeding. No differences were found in the 5-HT markers between DIO rats, chow-fed control rats, and DIO rats experiencing a weight loss. The 5-HT markers were also similar in RYGB and sham-operated rats except for a downregulation of 5-HT(2A) receptors in the NAcS. The higher receptor and lower SERT binding in pgDIO as compared to pgDR rats corresponds to what is reported in overweight humans and suggests that the dysfunctions of the 5-HT system associated with overeating or propensity to become overweight are polygenically determined. Our results support that the obesity-prone rat model has high translational value and suggests that susceptibility to develop obesity is associated with changed 5-HT tone in the brain that may also regulate hedonic aspects of feeding.


Subject(s)
Gastric Bypass , Obesity/metabolism , Receptors, Serotonin/metabolism , Animals , Biomarkers/metabolism , Body Weight , Disease Models, Animal , Eating , Male , Obesity/surgery , Rats , Rats, Sprague-Dawley , Rats, Wistar , Receptor, Serotonin, 5-HT2A/metabolism , Receptors, Serotonin, 5-HT1/metabolism , Up-Regulation , Weight Loss
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