scholarly journals Dynorphin Knockout Reduces Fat Mass and Increases Weight Loss during Fasting in Mice

2007 ◽  
Vol 21 (7) ◽  
pp. 1722-1735 ◽  
Author(s):  
Amanda Sainsbury ◽  
Shu Lin ◽  
Keely McNamara ◽  
Katy Slack ◽  
Ronaldo Enriquez ◽  
...  
Keyword(s):  
Weight Loss ◽  
Energy Homeostasis ◽  
Arcuate Nucleus ◽  
Ventromedial Hypothalamus ◽  
Nutrient Absorption ◽  
Endogenous Opioids ◽  
Acid Oxidation ◽  
Hypothalamic Arcuate Nucleus ◽  
White Fat

Abstract Endogenous opioids, particularly dynorphins, have been implicated in regulation of energy balance, but it is not known how they mediate this in vivo. We investigated energy homeostasis in dynorphin knockout mice (Dyn−/− mice) and probed the interactions between dynorphins and the neuropeptide Y (NPY) system. Dyn−/− mice were no different from wild types with regards to body weight and basal and fasting-induced food intake, but fecal output was increased, suggesting decreased nutrient absorption, and they had significantly less white fat and lost more weight during a 24-h fast. The neuroendocrine and thermal responses to fasting were at least as pronounced in Dyn−/− as in wild types, and there was no stimulatory effect of dynorphin knockout on 24-h energy expenditure (kilocalories of heat produced) or physical activity. However, Dyn−/− mice showed increased circulating concentrations of 3,4-dihydroxyphenlacetic acid and 3,4-dihydroxyphenylglycol, suggesting increased activity of the sympathetic nervous system. The respiratory exchange ratio of male but not female Dyn−/− mice was reduced, demonstrating increased fat oxidation. Interestingly, expression of the orexigenic acting NPY in the hypothalamic arcuate nucleus was reduced in Dyn−/− mice. However, fasting-induced increases in pre-prodynorphin expression in the arcuate nucleus, the paraventricular nucleus, and the ventromedial hypothalamus but not the lateral hypothalamus were abolished by deletion of Y1 but not Y2 receptors. Therefore, ablation of dynorphins results in increases in fatty acid oxidation in male mice, reductions in adiposity, and increased weight loss during fasting, possibly via increases in sympathetic activity, decreases in intestinal nutrient absorption, and interactions with the NPYergic system.

scholarly journals Multinodal regulation of the arcuate/paraventricular nucleus circuit by leptin

2010 ◽  
Vol 108 (1) ◽  
pp. 355-360 ◽  
Author(s):  
Masoud Ghamari-Langroudi ◽  
Dollada Srisai ◽  
Roger D. Cone
Keyword(s):  
Paraventricular Nucleus ◽  
Energy Homeostasis ◽  
Arcuate Nucleus ◽  
Ventromedial Hypothalamus ◽  
Postsynaptic Membrane ◽  
Firing Frequency ◽  
Dependent Manner ◽  
Primary Control ◽  
Regulation Of Activity

Melanocortin-4 receptor (MC4R) is critical for energy homeostasis, and the paraventricular nucleus of the hypothalamus (PVN) is a key site of MC4R action. Most studies suggest that leptin regulates PVN neurons indirectly, by binding to receptors in the arcuate nucleus or ventromedial hypothalamus and regulating release of products like α-melanocyte-stimulating hormone (α-MSH), neuropeptide Y (NPY), glutamate, and GABA from first-order neurons onto the MC4R PVN cells. Here, we investigate mechanisms underlying regulation of activity of these neurons under various metabolic states by using hypothalamic slices from a transgenic MC4R-GFP mouse to record directly from MC4R neurons. First, we show that in vivo leptin levels regulate the tonic firing rate of second-order MC4R PVN neurons, with fasting increasing firing frequency in a leptin-dependent manner. We also show that, although leptin inhibits these neurons directly at the postsynaptic membrane, α-MSH and NPY potently stimulate and inhibit the cells, respectively. Thus, in contrast with the conventional model of leptin action, the primary control of MC4R PVN neurons is unlikely to be mediated by leptin action on arcuate NPY/agouti-related protein and proopiomelanocortin neurons. We also show that the activity of MC4R PVN neurons is controlled by the constitutive activity of the MC4R and that expression of the receptor mRNA and α-MSH sensitivity are both stimulated by leptin. Thus, leptin acts multinodally on arcuate nucleus/PVN circuits to regulate energy homeostasis, with prominent mechanisms involving direct control of both membrane conductances and gene expression in the MC4R PVN neuron.

scholarly journals Growth hormone receptor (GHR)-expressing neurons in the hypothalamic arcuate nucleus regulate glucose metabolism and energy homeostasis

2020 ◽  
Author(s):  
Juliana Bezerra Medeiros de Lima ◽  
Lucas Kniess Debarba ◽  
Manal Khan ◽  
Chidera Ubah ◽  
Olesya Didyuk ◽  
...  
Keyword(s):  
Growth Hormone ◽  
Glucose Metabolism ◽  
Energy Homeostasis ◽  
Arcuate Nucleus ◽  
Brain Regions ◽  
Designer Drugs ◽  
Whole Body ◽  
Mouse Line ◽  
Hypothalamic Arcuate Nucleus

AbstractGrowth hormone (GH) receptor (GHR), expressed in different brain regions, is known to participate in the regulation of whole-body energy homeostasis and glucose metabolism. However, GH activation of these GHR-expressing neurons is less studied. We have generated a novel GHR-driven Cre recombinase transgenic mouse line (GHRcre) in combination with the floxed tdTomato reporter mouse line we tracked and activated GHR-expressing neurons in different regions of the brain. We focused on neurons of the hypothalamic arcuate nucleus (ARC) where GHR was shown to elicit a negative feedback loop that regulates GH production. We found that ARCGHR+ neurons are co-localized with AgRP, GHRH, and somatostatin neurons, which were activated by GH stimulation. Using designer receptors exclusively activated by designer drugs (DREADDs) to control GHRARC neuronal activity, we revealed that activation of GHRARC neurons was sufficient in regulating distinct aspects of energy balance and glucose metabolism. Overall, our study provides a novel mouse model to study in vivo regulation and physiological function of GHR-expressing neurons in various brain regions. Furthermore, we identified for the first time specific neuronal population that responds to GH and directly linked it to metabolic responses in vivo.

Diet-derived nutrients mediate the inhibition of hypothalamic NPY neurons in the arcuate nucleus of mice during refeeding

2009 ◽  
Vol 297 (1) ◽  
pp. R100-R110 ◽  
Author(s):  
Csilla Becskei ◽  
Thomas A. Lutz ◽  
Thomas Riediger
Keyword(s):  
Neuropeptide Y ◽  
Arcuate Nucleus ◽  
Peptide Yy ◽  
Small Reduction ◽  
Hypothalamic Arcuate Nucleus ◽  
Ad Libitum ◽  
Fos Expression

Fasting activates orexigenic neuropeptide Y neurons in the hypothalamic arcuate nucleus (ARC) of mice, which is reversed by 2 h refeeding with standard chow. Here, we investigated the contribution of diet-derived macronutrients and anorectic hormones to the reversal of the fasting-induced ARC activation during 2 h refeeding. Refeeding of 12-h-fasted mice with a cellulose-based, noncaloric mash induced only a small reduction in c-Fos expression. Refeeding with diets, containing carbohydrates, protein, or fat alone reversed it similar to chow; however, this effect depended on the amount of intake. The fasting-induced ARC activation was unchanged by subcutaneously injected amylin, CCK (both 20 μg/kg), insulin (0.2 U/kg and 0.05 U/kg) or leptin (2.6 mg/kg). Insulin and leptin had no effect on c-Fos expression in neuropeptide Y or proopiomelanocortin-containing ARC neurons. Interestingly, CCK but not amylin reduced the ghrelin-induced c-Fos expression in the ARC in ad libitum-fed mice, suggesting that CCK may inhibit orexigenic ARC neurons when acting together with other feeding-related signals. We conclude that all three macronutrients and also non-nutritive, ingestion-dependent signals contribute to an inhibition of orexigenic ARC neurons after refeeding. Similar to the previously demonstrated inhibitory in vivo action of peptide YY, CCK may be a postprandial mediator of ARC inhibition.

scholarly journals Global transcriptome analysis of rat hypothalamic arcuate nucleus demonstrates reversal of hypothalamic gliosis following surgically and diet induced weight loss

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Pernille Barkholt ◽  
Kristoffer T. G. Rigbolt ◽  
Mechthilde Falkenhahn ◽  
Thomas Hübschle ◽  
Uwe Schwahn ◽  
...  
Keyword(s):  
Gene Expression ◽  
Weight Loss ◽  
Molecular Mechanisms ◽  
Arcuate Nucleus ◽  
Gene Expression Signature ◽  
Global Gene Expression ◽  
Metabolic Effects ◽  
Expression Of Genes ◽  
Hypothalamic Arcuate Nucleus ◽  
Laser Capture

Abstract The central mechanisms underlying the marked beneficial metabolic effects of bariatric surgery are unclear. Here, we characterized global gene expression in the hypothalamic arcuate nucleus (Arc) in diet-induced obese (DIO) rats following Roux-en-Y gastric bypass (RYGB). 60 days post-RYGB, the Arc was isolated by laser-capture microdissection and global gene expression was assessed by RNA sequencing. RYGB lowered body weight and adiposity as compared to sham-operated DIO rats. Discrete transcriptome changes were observed in the Arc following RYGB, including differential expression of genes associated with inflammation and neuropeptide signaling. RYGB reduced gene expression of glial cell markers, including Gfap, Aif1 and Timp1, confirmed by a lower number of GFAP immunopositive astrocyte profiles in the Arc. Sham-operated weight-matched rats demonstrated a similar glial gene expression signature, suggesting that RYGB and dietary restriction have common effects on hypothalamic gliosis. Considering that RYGB surgery also led to increased orexigenic and decreased anorexigenic gene expression, this may signify increased hunger-associated signaling at the level of the Arc. Hence, induction of counterregulatory molecular mechanisms downstream from the Arc may play an important role in RYGB-induced weight loss.

scholarly journals Nicotine excites hypothalamic arcuate anorexigenic proopiomelanocortin neurons and orexigenic neuropeptide Y neurons: similarities and differences

2011 ◽  
Vol 106 (3) ◽  
pp. 1191-1202 ◽  
Author(s):  
Hao Huang ◽  
Youfen Xu ◽  
Anthony N. van den Pol
Keyword(s):  
Weight Loss ◽  
Neuropeptide Y ◽  
Arcuate Nucleus ◽  
Input Resistance ◽  
Cell Types ◽  
Underlying Mechanism ◽  
Synaptic Activity ◽  
Cognitive Arousal ◽  
Hypothalamic Arcuate Nucleus ◽  
Prevalence Of Obesity

Two of the biggest health problems facing us today are addiction to nicotine and the increased prevalence of obesity. Interestingly, nicotine attenuates obesity, but the underlying mechanism is not clear. Here we address the hypothesis that if weight-reducing actions of nicotine are mediated by anorexigenic proopiomelanocortin (POMC) neurons of the hypothalamic arcuate nucleus, nicotine should excite these cells. Nicotine at concentrations similar to those found in smokers, 100–1,000 nM, excited POMC cells by mechanisms based on increased spike frequency, depolarization of membrane potential, and opening of ion channels. This was mediated by activation of both α7 and α4β2 nicotinic receptors; by itself, this nicotine-mediated excitation could explain weight loss caused by nicotine. However, in control experiments nicotine also excited the orexigenic arcuate nucleus neuropeptide Y (NPY) cells. Nicotine exerted similar actions on POMC and NPY cells, with a slightly greater depolarizing action on POMC cells. Immunocytochemistry revealed cholinergic axons terminating on both cell types. Nicotine actions were direct in both cell types, with nicotine depolarizing the membrane potentials and reducing input resistance. We found no differences in the relative desensitization to nicotine between POMC and NPY neurons. Nicotine inhibited excitatory synaptic activity recorded in NPY, but not POMC, cells. Nicotine also excited hypocretin/orexin neurons that enhance cognitive arousal, but the responses were smaller than in NPY or POMC cells. Together, these results indicate that nicotine has a number of similar actions, but also a few different actions, on POMC and NPY neurons that could contribute to the weight loss associated with smoking.

scholarly journals Manipulation of dietary amino acids prevents and reverses obesity in mice through multiple mechanisms that modulate energy homeostasis

2020 ◽  
Author(s):  
Ada Admin ◽  
Chiara Ruocco ◽  
Maurizio Ragni ◽  
Fabio Rossi ◽  
Pierluigi Carullo ◽  
...  
Keyword(s):  
Amino Acids ◽  
Energy Metabolism ◽  
Energy Homeostasis ◽  
Molecular Mechanisms ◽  
Uncoupling Protein ◽  
Essential Amino Acids ◽  
Brown Fat ◽  
Acid Oxidation ◽  
White Fat

Reduced activation of energy metabolism increases adiposity in humans and other mammals. Thus, exploring dietary and molecular mechanisms able to improve energy metabolism is of paramount medical importance, as such mechanisms can be leveraged as a therapy for obesity and related disorders. Here, <a>we show that a designer protein-deprived diet enriched in free essential amino acids can i) promote the brown fat thermogenic program and fatty acid oxidation, ii) stimulate uncoupling protein 1 (UCP1)-independent respiration in subcutaneous white fat, iii) change the gut microbiota composition, and iv) prevent and reverse obesity and dysregulated glucose homeostasis in multiple mouse models, prolonging the healthy lifespan. </a>These effects are independent of unbalanced amino acid ratio, energy consumption, and intestinal calorie absorption. A brown fat-specific activation of the mechanistic target of rapamycin complex 1 seems involved in the diet-induced beneficial effects, as also strengthened by <i>in vitro</i> experiments. Hence, our results suggest that brown and white fat may be targets of specific amino acids to control UCP1-dependent and -independent thermogenesis, thereby contributing to the improvement of metabolic health.

scholarly journals A role for glial fibrillary acidic protein (GFAP)-expressing cells in the regulation of gonadotropin-releasing hormone (GnRH) but not arcuate kisspeptin neuron output

2021 ◽  
Author(s):  
Charlotte Vanacker ◽  
R. Anthony DeFazio ◽  
Charlene M. Sykes ◽  
Suzanne M. Moenter
Keyword(s):  
Arcuate Nucleus ◽  
Designer Drugs ◽  
Neuron Activity ◽  
Gnrh Neurons ◽  
Hypothalamic Arcuate Nucleus ◽  
Lh Release ◽  
Main Regulator ◽  
Kndy Neurons

AbstractGnRH neurons are the final central neural output regulating fertility. Kisspeptin neurons in the hypothalamic arcuate nucleus (KNDy neurons) are considered the main regulator of GnRH output. GnRH and KNDy neurons are surrounded by astrocytes, which can modulate neuronal activity and communicate over distances. Prostaglandin E2 (PGE2), synthesized primarily by astrocytes, increases GnRH neuron activity and downstream pituitary release of luteinizing hormone (LH). We hypothesized GFAP-expressing astrocytes play a role regulating GnRH and/or KNDy neuron activity and LH release. We used adenoassociated viruses to target designer receptor exclusively activated by designer drugs (DREADDs) to GFAP-expressing cells to activate Gq or Gi-mediated signaling. Activating Gq signaling in the preoptic area, near GnRH neurons, but not in the arcuate, increases LH release in vivo and GnRH firing in vitro via a mechanism in part dependent upon PGE2. These data suggest astrocytes can activate GnRH/LH release in a manner independent of KNDy neurons.

scholarly journals Galanin and Galanin-Like Peptide Differentially Modulate Neuronal Activities in Rat Arcuate Nucleus Neurons

2006 ◽  
Vol 95 (5) ◽  
pp. 3228-3234 ◽  
Author(s):  
Yan Dong ◽  
Joanna P. Tyszkiewicz ◽  
Tung M. Fong
Keyword(s):  
G Protein ◽  
Differential Effect ◽  
Energy Homeostasis ◽  
Arcuate Nucleus ◽  
Reproductive Function ◽  
Resting Membrane Potential ◽  
Protein Activity ◽  
Neurophysiological Mechanism ◽  
Spike Firing

Neuropeptides galanin and galanin-like peptide (GALP) share similar amino acid sequence and presumably interact with the same group of receptors, but they differentially regulate a variety of physiological and pathophysiological processes including metabolism and reproduction. Here we explored the neurophysiological basis of the in vivo differential effect between galanin and GALP by examining galanin and GALP modulation of neuronal activities of neurons in the arcuate nucleus (Arc), a brain region critically involved in energy homeostasis and reproductive function. We demonstrated that galanin and GALP inhibited excitatory and inhibitory postsynaptic currents in a similar way. In contrast, galanin and GALP differentially affected the intrinsic membrane property. In most recorded Arc neurons, galanin perfusion induced significant hyperpolarization of the resting membrane potential, which was not affected by GALP perfusion. In addition, galanin perfusion substantially suppressed the spontaneous spike firing in most Arc neurons, whereas in response to GALP perfusion, about half of the Arc neurons exhibited mild reduction in spontaneous spike firing and the other half showed enhancement. Furthermore, the Arc neurons that had been previously responsive to galanin perfusion no longer responded to galanin if co-applied with GALP, indicating that GALP can physiologically antagonize galanin effect. This differential effect appears to be mediated by G protein within the recorded cell, as the galanin effect on firing rate was abolished when the recorded cell was loaded with GDP-βS, an agent that blocks G protein activity. Taken together, these differential effects of galanin and GALP may provide a neurophysiological mechanism through which galanin and GALP differentially regulate energy balance, reproductive function, and other physiological processes.

scholarly journals Carnitine Palmitoyltransferase-1 (CPT-1) Activity Stimulation by Cerulenin via Sympathetic Nervous System Activation Overrides Cerulenin’s Peripheral Effect

Endocrinology ◽  
2004 ◽  
Vol 145 (7) ◽  
pp. 3197-3204 ◽  
Author(s):  
Yong-Jun Jin ◽  
Song-Zhe Li ◽  
Zheng-Shan Zhao ◽  
Juan Ji An ◽  
Ryang Yeo Kim ◽  
...  
Keyword(s):  
Nervous System ◽  
Sympathetic Nervous System ◽  
Core Temperature ◽  
Arcuate Nucleus ◽  
Late Phase ◽  
Ventromedial Hypothalamus ◽  
Sympathetic Nervous ◽  
Carnitine Palmitoyltransferase 1

Abstract To clarify the paradoxic effects of cerulenin, namely its in vitro inhibitory effects on fat catabolism and its in vivo reduction of fat mass, we studied the in vivo and in vitro effects of cerulenin on carnitine palmitoyltransferase-1 (CPT-1) activity, the rate-limiting enzyme of fatty acid oxidation. A single ip injection of cerulenin significantly reduced body weight and increased core temperature without significantly reducing food intake. In situ hybridization study revealed that a single injection of cerulenin did not affect the expression of orexigenic neuropeptide mRNA. Cerulenin’s effect on CPT-1 activity was biphasic in the liver and muscle: early suppression during the first 1 h and late stimulation in the 3–5 h after ip treatment. In vitro cerulenin treatment reduced CPT-1 activity, which was overcome by cotreating with catecholamine. Intracerebroventricular injection of cerulenin increased CPT-1 activity significantly in soleus muscle, and this effect was sustained for up to 3 h. Pretreatment with α-methyl-p-tyrosine inhibited the cerulenin-induced increase in core temperature and the late-phase stimulating effect of cerulenin on CPT-1 activity. In adrenalectomized mice, cerulenin also increased the activity. In vivo cerulenin treatment enhanced muscle CPT-1 activity in monosodium glutamate-treated arcuate nucleus lesioned mice but not in gold thioglucose-treated ventromedial hypothalamus lesioned mice. These findings suggest that cerulenin-induced late-phase stimulating effects on CPT-1 activity and energy expenditure is mediated by the activation of innervated sympathetic nervous system neurons through the firing of undefined neurons of the ventromedial hypothalamus, rather than the arcuate nucleus.

Sign in / Sign up

Export Citation Format

Share Document