Activation of prodynorphin neurons in the dorsomedial hypothalamus inhibits food intake and promotes positive valence

AbstractThe regulation of food intake is one of the major research areas in the study of metabolic syndromes such as obesity. Gene targeting studies have clarified the roles of hypothalamic neurons in feeding behaviour. However, our understanding of neural function under physiological conditions is still limited. Immediate early genes, such as activity-regulated cytoskeleton-associated protein (Arc/Arg3.1), are useful markers of neuronal activity. Here, we investigated the role of Arc/Arg3.1 gene-expressing neurons in the hypothalamus after refeeding using the targeted recombination in active populations method. We identified refeeding-responsive prodynorphin/cholecystokinin neurons in the dorsomedial hypothalamus that project to the paraventricular hypothalamic nucleus. Chemogenetic activation of these neurons decreased food intake and promoted positive valence. Our findings provide insight into the role of newly identified hedonic neurons in the process of feeding-induced satiety.

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Coinjection of CCK and leptin reduces food intake via increased CART/TRH and reduced AMPK phosphorylation in the hypothalamus

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00664.2013 ◽

2014 ◽

Vol 306 (11) ◽

pp. E1284-E1291 ◽

Cited By ~ 25

Author(s):

Sayaka Akieda-Asai ◽

Paul-Emile Poleni ◽

Yukari Date

Keyword(s):

Energy Balance ◽

Food Intake ◽

Interactive Effect ◽

Reduce Food Intake ◽

Mrna Levels ◽

Neural Pathway ◽

Ampk Phosphorylation ◽

Amp Activated Protein Kinase ◽

Insight Into

CCK and leptin are anorectic hormones produced in the small intestine and white adipose tissue, respectively. Investigating how these hormones act together as an integrated anorectic signal is important for elucidating the mechanisms by which energy balance is maintained. We found here that coadministration of subthreshold CCK and leptin, which individually have no effect on feeding, dramatically reduced food intake in rats. Phosphorylation of AMP-activated protein kinase (AMPK) in the hypothalamus significantly decreased after coinjection of CCK and leptin. In addition, coadministration of these hormones significantly increased mRNA levels of anorectic cocaine- and amphetamine-regulated transcript (CART) and thyrotropin-releasing hormone (TRH) in the hypothalamus. The interactive effect of CCK and leptin on food intake was abolished by intracerebroventricular preadministration of the AMPK activator AICAR or anti-CART/anti-TRH antibodies. These findings indicate that coinjection of CCK and leptin reduces food intake via reduced AMPK phosphorylation and increased CART/TRH in the hypothalamus. Furthermore, by using midbrain-transected rats, we investigated the role of the neural pathway from the hindbrain to the hypothalamus in the interaction of CCK and leptin to reduce food intake. Food intake reduction induced by coinjection of CCK and leptin was blocked in midbrain-transected rats. Therefore, the neural pathway from hindbrain to hypothalamus plays an important role in transmitting the anorectic signals provided by coinjection of CCK and leptin. Our findings give further insight into the mechanisms of feeding and energy balance.

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Oxytocinergic cells of the posterior hypothalamic paraventricular nucleus participate in the food entrained clock

Scientific Reports ◽

10.1038/s41598-021-99266-0 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Mario Caba ◽

Enrique Meza ◽

Carolina Escobar ◽

Angeles Jiménez ◽

Mario Daniel Caba-Flores ◽

...

Keyword(s):

Food Intake ◽

Hypothalamic Nucleus ◽

Restricted Feeding ◽

Adult Rats ◽

Peripheral Oscillators ◽

Food Anticipatory Activity ◽

Ad Libitum ◽

Anticipatory Activity ◽

Oxytocinergic Cells

AbstractThe mechanisms underlying food anticipatory activity are still poorly understood. Here we explored the role of oxytocin (OT) and the protein c-Fos in the supraoptic nucleus (SON), medial (PVNm) and posterior (PVNp) regions of the paraventricular hypothalamic nucleus. Adult rats were assigned to one of four groups: scheduled restricted feeding (RF), ad libitum (AL), fasting after restricted feeding (RF-F), to explore the possible persistence of oscillations, or ad libitum fasted (AL-F). In the SON and in the PVNm, OT cells were c-Fos positive after food intake; in contrast, OT cells in the PVNp showed c-Fos activation in anticipation to food access, which persisted in RF-F subjects. We conclude that OT and non-OT cells of the SON and PVNm may play a role as recipients of the entraining signal provided by food intake, whereas those of the PVNp which contain motor preautonomic cells that project to peripheral organs, may be involved in the hormonal and metabolic anticipatory changes in preparation for food presentation and thus, may be part of a link between central and peripheral oscillators. In addition, due to their persistent activation they may participate in the neuronal network for the clock mechanism that leads to food entrainment.

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Oxytocinergic Cells of the Posterior Hypothalamic Paraventricular Nucleus Participate in the Food Entrained Clock

10.21203/rs.3.rs-622616/v1 ◽

2021 ◽

Author(s):

Mario Caba ◽

Enrique Meza ◽

Carolina Escobar ◽

Angeles Jiménez ◽

Mario Daniel Caba-Flores ◽

...

Keyword(s):

Food Intake ◽

Hypothalamic Nucleus ◽

Restricted Feeding ◽

Adult Rats ◽

Peripheral Oscillators ◽

Food Anticipatory Activity ◽

Ad Libitum ◽

Anticipatory Activity ◽

Oxytocinergic Cells

Abstract The mechanisms underlying food anticipatory activity is still not well understood. Here we explored the role of oxytocin (OT) and the protein c-Fos in the supraoptic nucleus (SON) and in the medial (PVNm) and posterior (PVNp) regions of the paraventricular hypothalamic nucleus. Adult rats were assigned to one of four groups: scheduled restricted feeding (RF), Ad libitum (AL), fasting after restricted feeding (RF-F), to explore the possible persistence of oscillations, or Ad libitum fasted (AL-F). In the SON and in the PVNm, OT cells were c-Fos positive after food intake; contrasting, OT cells in the PVNp showed c-Fos activation in anticipation to food access, which persisted in RF-F subjects. We conclude that OT cells of the SON and PVNm may play a role as recipients of the entraining signal provided by food intake, whereas those of the PVNp which contain motor preautonomic cells that project to peripheral organs, may be involved in the hormonal and metabolic anticipatory changes in preparation for food presentation and thus, may be part of a link between central and peripheral oscillators. In addition, due to their persistent activation they may participate in the neuronal network for the clock mechanism that leads to food entrainment.

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Central Nesfatin-1 Reduces Dark-Phase Food Intake and Gastric Emptying in Rats: Differential Role of Corticotropin-Releasing Factor2 Receptor

Endocrinology ◽

10.1210/en.2009-0578 ◽

2009 ◽

Vol 150 (11) ◽

pp. 4911-4919 ◽

Cited By ~ 159

Author(s):

Andreas Stengel ◽

Miriam Goebel ◽

Lixin Wang ◽

Jean Rivier ◽

Peter Kobelt ◽

...

Keyword(s):

Gastric Emptying ◽

Food Intake ◽

Nucleus Tractus Solitarius ◽

Hypothalamic Nucleus ◽

Reduce Food Intake ◽

Dark Phase ◽

Crf2 Receptor ◽

Brain Ventricle ◽

Dose Dependent

Nesfatin-1, derived from nucleobindin2, is expressed in the hypothalamus and reported in one study to reduce food intake (FI) in rats. To characterize the central anorexigenic action of nesfatin-1 and whether gastric emptying (GE) is altered, we injected nesfatin-1 into the lateral brain ventricle (intracerebroventricular, icv) or fourth ventricle (4v) in chronically cannulated rats or into the cisterna magna (intracisternal, ic) under short anesthesia and compared with ip injection. Nesfatin-1 (0.05 μg/rat, icv) decreased 2–3 h and 3–6 h dark-phase FI by 87 and 45%, respectively, whereas ip administration (2 μg/rat) had no effect. The corticotropin-releasing factor (CRF)1/CRF2 antagonist astressin-B or the CRF2 antagonist astressin2-B abolished icv nesfatin-1’s anorexigenic action, whereas an astressin2-B analog, devoid of CRF-receptor binding affinity, did not. Nesfatin-1 icv induced a dose-dependent reduction of GE by 26 and 43% that was not modified by icv astressin2-B. Nesfatin-1 into the 4v (0.05 μg/rat) or ic (0.5 μg/rat) decreased cumulative dark-phase FI by 29 and 60% at 1 h and by 41 and 37% between 3 and 5 h, respectively. This effect was neither altered by ic astressin2-B nor associated with changes in GE. Cholecystokinin (ip) induced Fos expression in 43% of nesfatin-1 neurons in the paraventricular hypothalamic nucleus and 24% of those in the nucleus tractus solitarius. These data indicate that nesfatin-1 acts centrally to reduce dark phase FI through CRF2-receptor-dependent pathways after forebrain injection and CRF2-receptor-independent pathways after hindbrain injection. Activation of nesfatin-1 neurons by cholecystokinin at sites regulating food intake may suggest a role in gut peptide satiation effect.

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Variability in Reward Responsivity and Obesity: Evidence from Brain Imaging Studies

10.31232/osf.io/fsqde ◽

2017 ◽

Author(s):

Kyle Stanley Burger

Keyword(s):

Food Intake ◽

Brain Regions ◽

Vulnerability Factors ◽

Imaging Studies ◽

Vulnerability Model ◽

Reward Responsivity ◽

The Brain ◽

Insight Into ◽

Neuroimaging Techniques

Advances in neuroimaging techniques have provided insight into the role of the brain in the regulation of food intake and weight. Growing evidence demonstrate that energy dense, palatable foods elicit similar responses in reward-related brain regions that mimic those of addictive substances. Currently, various models of obesity’s relation to reward from food have been theorized. There is evidence to support a theory of hypo-responsivity of reward regions to food, where individuals consume excess amounts to overcome this reward deficit. There is also data to support a theory of hyper-responsivity of reward regions, where individuals who experience greater reward from food intake are at risk for overeating. However, these seemingly discordant theories are static in nature and do not account for the possible effects of repeated overeating on brain responsivity to food and initial vulnerability factors. Here we review data that support these theories and propose a dynamic vulnerability model of obesity that appears to offer a parsimonious theory that accommodates extant findings.

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Refeeding activates neurons in the dorsomedial hypothalamus to inhibit food intake and promote positive valence

Molecular Metabolism ◽

10.1016/j.molmet.2021.101366 ◽

2021 ◽

pp. 101366

Author(s):

Daigo Imoto ◽

Izumi Yamamoto ◽

Hirokazu Matsunaga ◽

Toya Yonekura ◽

Ming-Liang Lee ◽

...

Keyword(s):

Food Intake ◽

Dorsomedial Hypothalamus ◽

Inhibit Food Intake ◽

Positive Valence

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Habenular kisspeptin modulates fear in the zebrafish

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1314184111 ◽

2014 ◽

Vol 111 (10) ◽

pp. 3841-3846 ◽

Cited By ~ 63

Author(s):

Satoshi Ogawa ◽

Fatima M. Nathan ◽

Ishwar S. Parhar

Keyword(s):

Gonadotropin Releasing Hormone ◽

Hypothalamic Nucleus ◽

Alarm Substance ◽

Solute Carrier Family ◽

Fear Response ◽

Axonal Projections ◽

Solute Carrier ◽

G Protein Coupled ◽

Insight Into

Kisspeptin, a neuropeptide encoded by the KISS1/Kiss1, and its cognate G protein-coupled receptor, GPR54 (kisspeptin receptor, Kiss-R), are critical for the control of reproduction in vertebrates. We have previously identified two kisspeptin genes (kiss1 and kiss2) in the zebrafish, of which kiss1 neurons are located in the habenula, which project to the median raphe. kiss2 neurons are located in the hypothalamic nucleus and send axonal projections to gonadotropin-releasing hormone neurons and regulate reproductive functions. However, the physiological significance of the Kiss1 expressed in the habenula remains unknown. Here we demonstrate the role of habenular Kiss1 in alarm substance (AS)-induced fear response in the zebrafish. We found that AS-evoked fear experience significantly reduces kiss1 and serotonin-related genes (plasmacytoma expressed transcript 1 and solute carrier family 6, member 4) in the zebrafish. Furthermore, Kiss1 administration suppressed the AS-evoked fear response. To further evaluate the role of Kiss1 in fear response, zebrafish Kiss1 peptide was conjugated to saporin (SAP) to selectively inactivate Kiss-R1-expressing neurons. The Kiss1-SAP injection significantly reduced Kiss1 immunoreactivity and c-fos mRNA in the habenula and the raphe compared with control. Furthermore, 3 d after Kiss1-SAP injection, the fish had a significantly reduced AS-evoked fear response. These findings provide an insight into the role of the habenular kisspeptin system in inhibiting fear.

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Ingestive behavior of rats with ibotenic acid lesions of the dorsomedial hypothalamus

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.1987.252.5.r938 ◽

1987 ◽

Vol 252 (5) ◽

pp. R938-R946 ◽

Cited By ~ 2

Author(s):

L. L. Bellinger

Keyword(s):

Food Intake ◽

Ibotenic Acid ◽

Ingestive Behavior ◽

Hypothalamic Nucleus ◽

Sprague Dawley ◽

Dorsomedial Hypothalamus ◽

Reduced Body ◽

Sprague Dawley Rats ◽

Obesity Index ◽

Food And Water Intake

Rats with electrolytic or kainic acid (KA) lesions of the dorsomedial hypothalamic nucleus area (DMHA-L) are hypophagic, hypodipsic, and have a reduced body weight (BW) compared with controls. In the present study, male Sprague-Dawley rats received bilateral ibotenic acid (IBO) lesions of the DMHA (3 micrograms in 0.3 microliter) or sham (S) operations. During the next 32 days the IBO DMHA-L rats showed reduced (P less than 0.01) food and water intake, BW, and linear growth (P less than 0.03), although having a normal Lee obesity index. After a 24-h fast both groups became hyperphagic (P less than 0.01) with the DMHA-L group eating the most (P less than 0.01) during the 1st h; lost BW was regained at the same rate. In the absence of food, DMHA-L rats took less (P less than 0.01) water (data normalized) than S rats. During 24 h of water deprivation, both groups ate similar amounts of food (data normalized); following deprivation the groups were hyperdipsic. Both groups increased their food intake when given 300 mg/kg of 2-deoxy-D-glucose, which contrasts rats with electrolytic or KA DMHA-L rats. Both groups decreased their food intake when given cholecystokinin (3 micrograms/kg ip), which contrasts rats with electrolytic DMHA-L. The DMHA-L rats were not deficient in plasma glucose, insulin, growth hormone, or plasma Na+ and K+. Histology revealed many, but not all neurons, were destroyed in the DMN after IBO. The data indicate that IBO, electrolytic, or KA lesions of the DMHA produce similar but not identical physiological changes.

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Role of VMH ketone bodies in adjusting caloric intake to increased dietary fat content in DIO and DR rats

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00015.2015 ◽

2015 ◽

Vol 308 (10) ◽

pp. R872-R878 ◽

Cited By ~ 17

Author(s):

Christelle Le Foll ◽

Ambrose A. Dunn-Meynell ◽

Henry M. Miziorko ◽

Barry E. Levin

Keyword(s):

Food Intake ◽

Potential Role ◽

Ketone Bodies ◽

Caloric Intake ◽

High Energy ◽

Leptin Resistance ◽

Hypothalamic Nucleus ◽

Diet Intake ◽

Body Production

The objective of this study was to determine the potential role of astrocyte-derived ketone bodies in regulating the early changes in caloric intake of diet induced-obese (DIO) versus diet-resistant (DR) rats fed a 31.5% fat high-energy (HE) diet. After 3 days on chow or HE diet, DR and DIO rats were assessed for their ventromedial hypothalamic (VMH) ketone bodies levels and neuronal ventromedial hypothalamic nucleus (VMN) sensing using microdialysis coupled to continuous food intake monitoring and calcium imaging in dissociated neurons, respectively. DIO rats ate more than DR rats over 3 days of HE diet intake. On day 3 of HE diet intake, DR rats reduced their caloric intake while DIO rats remained hyperphagic. Local VMH astrocyte ketone bodies production was similar between DR and DIO rats during the first 6 h after dark onset feeding but inhibiting VMH ketone body production in DR rats on day 3 transiently returned their intake of HE diet to the level of DIO rats consuming HE diet. In addition, dissociated VMN neurons from DIO and DR rats were equally sensitive to the largely excitatory effects of β-hydroxybutyrate. Thus while DR rats respond to increased VMH ketone levels by decreasing their intake after 3 days of HE diet, this is not the case of DIO rats. These data suggest that DIO inherent leptin resistance prevents ketone bodies inhibitory action on food intake.

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Chromosomics: Bridging the Gap between Genomes and Chromosomes

Genes ◽

10.3390/genes10080627 ◽

2019 ◽

Vol 10 (8) ◽

pp. 627 ◽

Cited By ~ 21

Author(s):

Janine E. Deakin ◽

Sally Potter ◽

Rachel O’Neill ◽

Aurora Ruiz-Herrera ◽

Marcelo B. Cioffi ◽

...

Keyword(s):

Cell Biology ◽

Sequence Data ◽

Full Potential ◽

Genome Plasticity ◽

Sequencing Technology ◽

Research Areas ◽

And Function ◽

New Generation ◽

Insight Into

The recent advances in DNA sequencing technology are enabling a rapid increase in the number of genomes being sequenced. However, many fundamental questions in genome biology remain unanswered, because sequence data alone is unable to provide insight into how the genome is organised into chromosomes, the position and interaction of those chromosomes in the cell, and how chromosomes and their interactions with each other change in response to environmental stimuli or over time. The intimate relationship between DNA sequence and chromosome structure and function highlights the need to integrate genomic and cytogenetic data to more comprehensively understand the role genome architecture plays in genome plasticity. We propose adoption of the term ‘chromosomics’ as an approach encompassing genome sequencing, cytogenetics and cell biology, and present examples of where chromosomics has already led to novel discoveries, such as the sex-determining gene in eutherian mammals. More importantly, we look to the future and the questions that could be answered as we enter into the chromosomics revolution, such as the role of chromosome rearrangements in speciation and the role more rapidly evolving regions of the genome, like centromeres, play in genome plasticity. However, for chromosomics to reach its full potential, we need to address several challenges, particularly the training of a new generation of cytogeneticists, and the commitment to a closer union among the research areas of genomics, cytogenetics, cell biology and bioinformatics. Overcoming these challenges will lead to ground-breaking discoveries in understanding genome evolution and function.

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