scholarly journals Fourth-ventricle leptin infusions dose-dependently activate hypothalamic signal transducer and activator of transcription 3

2016 ◽  
Vol 311 (6) ◽  
pp. E939-E948 ◽  
Author(s):  
Ruth B. S. Harris ◽  
Bhavna N. Desai
Keyword(s):  
Weight Loss ◽  
Energy Balance ◽  
Food Intake ◽  
Fourth Ventricle ◽  
Low Dose ◽  
High Dose ◽  
Rapid Weight Loss ◽  
Leptin Signaling ◽  
Leptin Receptors ◽  
Arcuate Nuclei

Previous studies have shown that very low-dose infusions of leptin into the third or the fourth ventricle alone have little effect on energy balance, but simultaneous low-dose infusions cause rapid weight loss and increased phosphorylation of STAT3 (p-STAT3) in hypothalamic sites that express leptin receptors. Other studies show that injecting high doses of leptin into the fourth ventricle inhibits food intake and weight gain. Therefore, we tested whether fourth-ventricle leptin infusions that cause weight loss are associated with increased leptin signaling in the hypothalamus. In a dose response study 14-day infusions of increasing doses of leptin showed significant hypophagia, weight loss, and increased hypothalamic p-STAT3 in rats receiving at least 0.9 μg leptin/day. In a second study 0.6 μg leptin/day transiently inhibited food intake and reduced carcass fat, but had no significant effect on energy expenditure. In a final study, we identified the localization of STAT3 activation in the hypothalamus of rats receiving 0, 0.3, or 1.2 μg leptin/day. The high dose of leptin, which caused weight loss in the first experiment, increased p-STAT3 in the ventromedial, dorsomedial, and arcuate nuclei of the hypothalamus. The low dose that increased brown fat UCP1 but did not affect body composition in the first experiment had little effect on hypothalamic p-STAT3. We propose that hindbrain leptin increases the precision of control of energy balance by lowering the threshold for leptin signaling in the forebrain. Further studies are needed to directly test this hypothesis.

scholarly journals Low-dose leptin infusion in the fourth ventricle of rats enhances the response to third-ventricle leptin injection

2017 ◽  
Vol 313 (2) ◽  
pp. E134-E147 ◽  
Author(s):  
Ruth B. S. Harris
Keyword(s):  
Weight Loss ◽  
Food Intake ◽  
Fourth Ventricle ◽  
Low Dose ◽  
Respiratory Exchange Ratio ◽  
Third Ventricle ◽  
Separate Experiment ◽  
Rapid Weight Loss ◽  
Leptin Receptors ◽  
The Third

We previously reported that low-dose leptin infusions into the third or fourth ventricle that do not affect energy balance when given independently cause rapid weight loss when given simultaneously. Therefore, we tested whether hindbrain leptin enhances the response to forebrain leptin or whether forebrain leptin enhances the response to hindbrain leptin. Rats received fourth-ventricle infusions of saline or 0.01, 0.1, 0.3, or 0.6 μg leptin/day for 13 days. On days 9 and 13, 0.1 μg leptin was injected into the third ventricle. The injection inhibited food intake for 36 h in saline-infused rats but for 60 h in those infused with 0.6 μg leptin/day. Leptin injection increased intrascapular brown fat temperature in leptin-infused, but not saline-infused, rats. In a separate experiment, rats received third-ventricle infusions of saline or 0.005, 0.01, 0.05, or 0.1 μg leptin/day and fourth-ventricle injections of 1.0 μg leptin on days 9 and 13. Leptin injection inhibited food intake, respiratory exchange ratio, and 14-h food intake in rats infused with saline or the two lowest doses of leptin. There was no effect with higher-dose leptin infusions because food intake, body fat, and lean mass were already inhibited. These data suggest that activation of leptin receptors in the hindbrain enhances the response to third-ventricle leptin, whereas activation of forebrain leptin receptors does not enhance the response to fourth-ventricle leptin, consistent with our previous finding that weight loss in rats treated with fourth-ventricle leptin is associated with indirect activation of hypothalamic STAT3.

scholarly journals SAT-607 The Vagus Nerve and the Hypothalamus Mediate Different Aspects of the Anorectic Effects of PYY3-36

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Aldara Martin Alonso ◽  
Simon C Cork ◽  
Yue Ma ◽  
Myrtha Arnold ◽  
Herbert Herzog ◽  
...  
Keyword(s):  
Weight Loss ◽  
Food Intake ◽  
Vagus Nerve ◽  
Low Dose ◽  
Peptide Yy ◽  
Sensory Nerve ◽  
Positive Control ◽  
Vagal Afferents ◽  
High Dose ◽  
Gut Hormone

Abstract Background: Drugs that safely promote weight loss are required to treat the obesity crisis. The gut hormone peptide YY 3-36 (PYY3-36) is secreted post-prandially to suppress appetite via the Y2 receptor (Y2R). However, it is unclear whether PYY3-36 acts directly on the Y2R in the hypothalamic arcuate nucleus (ARC) or the afferent vagus nerve to inhibit food intake. Understanding the pathways by which PYY3-36 mediates its anorectic effects may facilitate the therapeutic targeting of this system. Methods: Y2R knockdown in the ARC (ARC-Y2R-KD) was achieved by stereotactic injection of Cre-expressing adeno-associated virus (AAV-Cre) in Y2R-flox C57Bl/6 mice. Y2R KD in the vagus was achieved by bilateral microinjection of AAV-Cre into the nodose ganglia (NG), where the cell bodies of vagal afferents reside. An alternative germline model of sensory nerve Y2R knockdown was generated using Nav1.8-Cre mice crossed with the Y2R-flox strain (Nav1.8-Y2R-KD). Feeding behaviour over 10 days in metabolic cages and the effects of endogenously released (after oral gavage of a nutrient bolus) or exogenously-administered PYY3-36 were investigated. Results: NG-Y2R-KD animals had 60% reduction in NG Y2R mRNA but remained responsive to cholecystokinin, a positive control of vagal functionality. This is the first example of receptor specific adult vagal deafferentation in mice. The Nav1.8-Y2R-KD model achieved 30% receptor KD. Feeding patterns in the ARC-Y2R-KD and NG-Y2R-KD groups were highly different from their controls, with smaller, faster meals in the KD groups. The anorectic effects (at the next meal) of endogenous PYY3-36 were attenuated in NG-Y2R-KD. Low dose exogenous PYY3-36 at 5 µg/kg significantly reduced 2h post injection food intake (FI) in the control groups (n=8; P=0.045) but this was abrogated in the NG-Y2R-KD group. This pattern was mirrored in the Nav1.8-Y2R-KD model: low dose PYY3-36 significantly reduced FI 1h post-IP compared to vehicle in controls (-0.19±0.05 g; P =0.036; n=8) but not in the Nav1.8-Y2R-KD (-0.004±0.111 g; n=3). Peripherally-administered PYY3-36 at a high dose (30 µg/kg) decreased FI in all groups, including ARC-Y2R-KD. Summary: These results suggest that endogenous PYY3-36 modulates meal patterning. The vagus nerve mediates physiological PYY3-36 signalling but alternative pathways, not exclusively via the ARC, may be more important in mediating its pharmacological effects. This is relevant for the design of more effective weight loss agents.

scholarly journals Leptin receptor-expressing neurons in ventromedial nucleus of the hypothalamus contribute to weight loss caused by fourth ventricle leptin infusions

2019 ◽  
Vol 317 (4) ◽  
pp. E586-E596 ◽  
Author(s):  
Marissa Seamon ◽  
WonMo Ahn ◽  
Ai-Jun Li ◽  
Sue Ritter ◽  
Ruth B. S. Harris
Keyword(s):  
Weight Loss ◽  
Weight Gain ◽  
Energy Balance ◽  
Fourth Ventricle ◽  
Leptin Receptor ◽  
Receptor Activation ◽  
Positive Energy ◽  
Ventromedial Nucleus ◽  
Leptin Receptors ◽  
Brown Adipose

Leptin administration into the hindbrain, and specifically the nucleus of the solitary tract, increases phosphorylated signal transducer and activator of transcription 3 (pSTAT3), a marker of leptin receptor activation, in hypothalamic nuclei known to express leptin receptors. The ventromedial nucleus of the hypothalamus (VMH) shows the greatest response, with a threefold increase in pSTAT3. This experiment tested the importance of VMH leptin receptor-expressing neurons in mediating weight loss caused by fourth ventricle (4V) leptin infusion. Male Sprague-Dawley rats received bilateral VMH 75-nL injections of 260 ng/μL of leptin-conjugated saporin (Lep-Sap) or blank-saporin (Blk-Sap). After 23 days they were fitted with 4V infusion cannulas and 1 wk later adapted to housing in a calorimeter before they were infused with 0.9 μg leptin/day for 14 days. There was no effect of VMH Lep-Sap on weight gain or glucose clearance before leptin infusion. Leptin inhibited food intake and respiratory exchange ratio in Blk-Sap but not Lep-Sap rats. Leptin had no effect on energy expenditure or brown adipose tissue temperature of either group. Inguinal and epididymal fat were significantly reduced in leptin-treated Blk-Sap rats, but the response was greatly attenuated in Lep-Sap rats. VMH pSTAT3 was increased in leptin-treated Blk-Sap but not Lep-Sap rats. These results support the concept that leptin-induced weight loss results from an integrated response across different brain areas. They also support previous reports that VMH leptin receptors do not play a significant role in maintaining energy balance in basal conditions but limit weight gain during positive energy balance.

scholarly journals Blockade of the cerebral aqueduct in rats provides evidence of antagonistic leptin responses in the forebrain and hindbrain

2014 ◽  
Vol 306 (4) ◽  
pp. E414-E423 ◽  
Author(s):  
Michael I. Vaill ◽  
Bhavna N. Desai ◽  
Ruth B. S. Harris
Keyword(s):  
Weight Loss ◽  
Food Intake ◽  
Body Fat ◽  
Fourth Ventricle ◽  
Third Ventricle ◽  
Cerebral Aqueduct ◽  
Sprague Dawley ◽  
Leptin Receptors ◽  
The Third ◽  
Inhibit Food Intake

Previously, we reported that low-dose leptin infusions into the fourth ventricle produced a small but significant increase in body fat. These data contrast with reports that injections of higher doses of leptin into the fourth ventricle inhibit food intake and weight gain. In this study, we tested whether exogenous leptin in the fourth ventricle opposed or contributed to weight loss caused by third ventricle leptin infusion by blocking diffusion of CSF from the third to the fourth ventricle. Male Sprague-Dawley rats received third ventricle infusions of PBS or 0.3 μg leptin/24 h from miniosmotic pumps. After 4 days, rats received a 3-μl cerebral aqueduct injection of saline or of thermogelling nanoparticles (hydrogel) that solidified at body temperature. Third ventricle leptin infusion inhibited food intake and caused weight loss. Blocking the aqueduct exaggerated the effect of leptin on food intake and weight loss but had no effect on the weight of PBS-infused rats. Leptin reduced both body fat and lean body mass but did not change energy expenditure. Blocking the aqueduct decreased expenditure of rats infused with PBS or leptin. Infusion of leptin into the third ventricle increased phosphorylated STAT3 in the VMHDM of the hypothalamus and the medial NTS in the hindbrain. Blocking the aqueduct did not change hypothalamic p-STAT3 but decreased p-STAT3 in the medial NTS. These results support previous observations that low-level activation of hindbrain leptin receptors has the potential to blunt the catabolic effects of leptin in the third ventricle.

scholarly journals Low-dose infusions of leptin into the nucleus of the solitary tract increase sensitivity to third ventricle leptin

2019 ◽  
Vol 316 (5) ◽  
pp. E719-E728 ◽  
Author(s):  
Ruth B. S. Harris
Keyword(s):  
Food Intake ◽  
Fourth Ventricle ◽  
Low Dose ◽  
Third Ventricle ◽  
Solitary Tract ◽  
Neural Pathway ◽  
Leptin Receptors ◽  
Reduced Body ◽  
Neural Connection ◽  
Cumulative Intake

Previous studies suggest that weight loss occurs when leptin receptors in both the forebrain and hindbrain are activated. Experiments described here tested whether this integration is mediated through a neural connection or by leptin diffusion through the subarachanoid space. If the hypothalamus and hindbrain communicated through a neural pathway, then a very low dose of leptin infused directly into the nucleus of the solitary tract (NTS) would enhance the response to third ventricle (3V) leptin but would have no effect if infused into the fourth ventricle (4V). A 12-day infusion of 10 ng/24 h into the 4V or the NTS reduced body fat. Leptin at 5 ng/24 h into the 4V or NTS had no effect on food intake or body composition, but infusion of 5 ng of leptin/24 h into the NTS combined with a 3V injection of 0.1 μg of leptin inhibited food intake between 6 and 12 h after injection. Cumulative intake was inhibited for up to 36 h. 3V leptin had no effect on food intake of rats receiving the 4V leptin infusion. Similar results were found using infusions of 5 ng leptin/24 h and a 3V injection of 0.025 μg leptin. These data suggest that activation of leptin receptors in the NTS lowers the threshold for response to leptin in the forebrain through a neural network.

Exacerbated febrile responses to LPS, but not turpentine, in TNF double receptor-knockout mice

1997 ◽  
Vol 272 (2) ◽  
pp. R563-R569 ◽  
Author(s):  
L. R. Leon ◽  
W. Kozak ◽  
J. Peschon ◽  
M. J. Kluger
Keyword(s):  
Body Weight ◽  
Food Intake ◽  
Motor Activity ◽  
Knockout Mice ◽  
Low Dose ◽  
Late Phase ◽  
High Dose ◽  
Wild Type ◽  
Inflammatory Stimuli ◽  
Necrosis Factor

We examined the effects of injections of systemic [lipopolysaccharide (LPS), 2.5 mg/kg or 50 pg/kg ip] or local (turpentine, 100 microl sc) inflammatory stimuli on fever, motor activity, body weight, and food intake in tumor necrosis factor (TNF) double receptor (TNFR)-knockout mice. A high dose of LPS resulted in exacerbated fevers in TNFR-knockout mice compared with wild-type mice for the early phase of fever (3-15 h); the late phase of fever (16-24 h) and fevers to a low dose of LPS were similar in both groups. Motor activity, body weight, and food intake were similarly reduced in both groups of mice after LPS administration. In response to turpentine, TNFR-knockout and wild-type mice developed virtually identical responses to all variables monitored. These results suggest that 1) TNF modulates fevers to LPS dose dependently, 2) TNF does not modulate fevers to a subcutaneous injection of turpentine, and 3) knockout mice may develop cytokine redundancy in the regulation of the acute phase response to intraperitoneally injected LPS or subcutaneously injected turpentine.

scholarly journals Metabolic adaptations during negative energy balance and their potential impact on appetite and food intake

2019 ◽  
Vol 78 (3) ◽  
pp. 279-289 ◽  
Author(s):  
Nuno Casanova ◽  
Kristine Beaulieu ◽  
Graham Finlayson ◽  
Mark Hopkins
Keyword(s):  
Weight Loss ◽  
Energy Balance ◽  
Food Intake ◽  
Negative Energy ◽  
Fat Free Mass ◽  
Negative Energy Balance ◽  
Energy Deficit ◽  
Behavioural Responses ◽  
Compensatory Responses ◽  
Metabolic Adaptations

This review examines the metabolic adaptations that occur in response to negative energy balance and their potential putative or functional impact on appetite and food intake. Sustained negative energy balance will result in weight loss, with body composition changes similar for different dietary interventions if total energy and protein intake are equated. During periods of underfeeding, compensatory metabolic and behavioural responses occur that attenuate the prescribed energy deficit. While losses of metabolically active tissue during energy deficit result in reduced energy expenditure, an additional down-regulation in expenditure has been noted that cannot be explained by changes in body tissue (e.g. adaptive thermogenesis). Sustained negative energy balance is also associated with an increase in orexigenic drive and changes in appetite-related peptides during weight loss that may act as cues for increased hunger and food intake. It has also been suggested that losses of fat-free mass (FFM) could also act as an orexigenic signal during weight loss, but more data are needed to support these findings and the signalling pathways linking FFM and energy intake remain unclear. Taken together, these metabolic and behavioural responses to weight loss point to a highly complex and dynamic energy balance system in which perturbations to individual components can cause co-ordinated and inter-related compensatory responses elsewhere. The strength of these compensatory responses is individually subtle, and early identification of this variability may help identify individuals that respond well or poorly to an intervention.

scholarly journals PSXIII-31 Hypothalamic and pituitary responses to resistin in sheep: integration of resistin and leptin signaling involving SOCS-3 and LepRb

2019 ◽  
Vol 97 (Supplement_3) ◽  
pp. 364-364
Author(s):  
Dorota A Zieba ◽  
Weronika Biernat ◽  
Malgorzata Szczesna ◽  
Katarzyna Kirsz ◽  
Tomasz Misztal
Keyword(s):  
Low Dose ◽  
Arcuate Nucleus ◽  
Preoptic Area ◽  
Leptin Resistance ◽  
High Dose ◽  
Leptin Signaling ◽  
Hypothalamic Nuclei ◽  
Natural Photoperiod ◽  
Tissue Sensitivity ◽  
Short Days

Abstract Leptin and resistin play important roles in regulating body weight and glucose metabolism. Herein, we hypothesized that resistin is a factor leading to decreased tissue sensitivity to leptin through effects on SOCS-3 and LeptRb expression. Expression of SOCS-3 and LeptRb were determined using Real-Time PCR in selected brain tissues: arcuate nucleus (ARC), ventro- and dorsomedial nuclei (VMH/DMH), preoptic area (POA) and anterior pituitary (AP). Thirty ewes (10/group), ovariectomized with E2-replacement, were fed ad libitum and housed under natural photoperiod. Intravenous treatments consisted of 1) control, 2) low dose of rbresistin (R1; 1.0 μg/kg BW), and 3) high dose of rbresistin (R2; 10.0 μg/kg BW). During long days (LD), LeptRb transcript in ARC decreased in response to R2 (P < 0.001) compared to Control. Expression of LeptRb in VMH/DMH decreased in response to R1(P < 0.001) and R2 (P < 0.001) during short days (SD) and to R2 (P < 0.001) during LD. Conversely, LeptrB transcript increased (P < 0.001) 8-fold in R1 and 4-fold in R2 (P < 0.05) in POA during SD. LeptrB transcript in the AP increased (P < 0.001) 2.1- and 1.8-fold, respectively, in response to R1 and R2 during LD. Within the ARC, SOCS-3 expression increased (P < 0.001) after R2 in LD. In POA, a 2.3-fold (P < 0.001) increase was noted in R2 only during LD. Moreover, SOCS-3 transcript increased in the AP during both LD (8.5-fold) and SD (5.8-fold) in response to R2 (P < 0.001). Evidence indicates that resistin resulted in a consistent decrease in LeptRb (except POA) and increase in SOCS-3 expression during LD in all hypothalamic nuclei. In AP, resistin increased SOCS-3 during both LD and SD and LeptRb transcript during LD. Taken together, the effects of resistin appear to be strongly associated with photoperiod-driven changes in the leptin signaling pathway, which may underlie the phenomenon of leptin resistance.

scholarly journals Leptin-Mediated Hypothalamic Pathway of Cholecystokinin (CCK-8) to Regulate Body Weight in Free-Feeding Rats

Endocrinology ◽  
2007 ◽  
Vol 149 (4) ◽  
pp. 1994-2000 ◽  
Author(s):  
Beatriz Merino ◽  
Victoria Cano ◽  
Rocío Guzmán ◽  
Beatriz Somoza ◽  
Mariano Ruiz-Gayo
Keyword(s):  
Skeletal Muscle ◽  
Body Weight ◽  
Energy Balance ◽  
Negative Impact ◽  
Muscle Metabolism ◽  
Peripheral Circulation ◽  
Leptin Signaling ◽  
Leptin Receptors ◽  
Free Feeding ◽  
Amp Activated Protein Kinase

Regulation of body weight (BW) results from the interplay between different hormonal systems acting at central and peripheral level. This study aims at characterizing the involvement of cholecystokinin (CCK) in BW and energy balance regulation. We have characterized, in free-feeding rats, the effect of CCK-8 on 1) food intake, BW, and adiposity; 2) skeletal muscle metabolism; 3) leptin signaling pathway within the arcuate nucleus of the hypothalamus; and 4) the permeability of brain barriers to leptin. We demonstrate here that CCK-8 acutely decreases BW by a mechanism partially dependent on central leptin pathways, based on the following results: 1) the effect of CCK was less intense in rats lacking functional leptin receptors (Zucker fa/fa), 2) CCK-8 facilitated the uptake of leptin from peripheral circulation to cerebrospinal fluid (CSF), 3) the concentration of leptin in CSF of rats receiving CCK was more elevated in those animals showing higher loss of BW, and 4) CCK activated leptin signaling pathways within the hypothalamus as well as phosphorylation of AMP-activated protein kinase in skeletal muscle. We also suggest that gain of BW may be linked to individual susceptibility to the effect of CCK, because we observed that in animals treated with this hormone, the increase of BW negatively correlated with leptin concentration within the CSF. Our data show that CCK has a negative impact on energy balance and suggest that CCK facilitates the access of leptin to hypothalamic areas, thus allowing leptin to act on hypothalamic targets involved in BW control.

scholarly journals Effects of continuous positive airway pressure on energy balance regulation: a systematic review

2016 ◽  
Vol 48 (6) ◽  
pp. 1640-1657 ◽  
Author(s):  
Ari Shechter
Keyword(s):  
Physical Activity ◽  
Systematic Review ◽  
Weight Loss ◽  
Energy Metabolism ◽  
Continuous Positive Airway Pressure ◽  
Energy Balance ◽  
Food Intake ◽  
Metabolic Rate ◽  
Airway Pressure ◽  
Positive Airway Pressure

Obesity is both a cause and a possible consequence of obstructive sleep apnoea (OSA), as OSA seems to affect parameters involved in energy balance regulation, including food intake, hormonal regulation of hunger/satiety, energy metabolism and physical activity. It is known that weight loss improves OSA, yet it remains unclear why continuous positive airway pressure (CPAP) often results in weight gain.The goal of this systematic review is to explore if and how CPAP affects the behaviour and/or metabolism involved in regulating energy balance.CPAP appears to correct for a hormonal profile characterised by abnormally high leptin and ghrelin levels in OSA, by reducing the circulating levels of each. This is expected to reduce excess food intake. However, reliable measures of food intake are lacking, and not yet sufficient to make conclusions. Although studies are limited and inconsistent, CPAP may alter energy metabolism, with reports of reductions in resting metabolic rate or sleeping metabolic rate. CPAP appears to not have an appreciable effect on altering physical activity levels. More work is needed to characterise how CPAP affects energy balance regulation.It is clear that promoting CPAP in conjunction with other weight loss approaches should be used to encourage optimal outcomes in OSA patients.

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