Regulation of body mass and adiposity in the field vole, Microtus agrestis: a model of leptin resistance

Adult mammals are typically highly resistant to perturbations in their energy balance. In obese humans, however, this control appears to be lost. Apart from a few exceptional cases, this loss of control occurs despite appropriate levels of circulating leptin – suggesting that elevated adiposity may be a consequence of failure to respond to the leptin signal: leptin resistance. When cold-acclimated male field voles (Microtus agrestis) are transferred from short (SD, 8 h light) to long (LD, 16 h light) photoperiods, they increase dramatically in body mass and fatness for about 4 weeks. After this period, their mass stabilizes at a new plateau about 25% higher than animals maintained in SD. The increase in adiposity is not caused by significant increases in food intake, but reflects an increase in digestive efficiency. Measures of circulating leptin reveal that the increased adiposity is matched by increased circulating leptin. By infusing voles with exogenous leptin, we have demonstrated that SD voles are leptin sensitive (reducing both body mass and food intake), whereas LD animals are leptin resistant. Voles may therefore be a useful model for understanding the process of leptin resistance. The change in leptin sensitivity in voles was not associated with changes in the levels of gene expression of the orexogenic or anorexogenic neuropeptides, such as neuropeptide Y, agouti-related peptide, POMC and cocaine- and amphetamine-regulated transcript, measured in the hypothalamic arcuate nucleus (ARC). During the phase that body mass was increasing, however, there was a transient increase in the ARC expression of suppressor of cytokine signalling-3 (SOCS3). These data suggest that the changes in the expression of SOCS3 in the ARC may be involved in leptin resistance. However, the mechanism by which these changes may be linked to alterations in digestive efficiency that underpin the changes in adiposity, or how the differences are signalled by changes in photoperiod, remains unclear.

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Altered Expression of SOCS3 in the Hypothalamic Arcuate Nucleus during Seasonal Body Mass Changes in the Field Vole, Microtus agrestis

Journal of Neuroendocrinology ◽

10.1111/j.1365-2826.2006.01507.x ◽

2007 ◽

Vol 19 (2) ◽

pp. 83-94 ◽

Cited By ~ 17

Author(s):

E. Król ◽

A. Tups ◽

Z. A. Archer ◽

A. W. Ross ◽

K. M. Moar ◽

...

Keyword(s):

Body Mass ◽

Arcuate Nucleus ◽

Microtus Agrestis ◽

Field Vole ◽

Altered Expression ◽

Hypothalamic Arcuate Nucleus ◽

Body Mass Changes

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Lateral ventricular ghrelin and fourth ventricular ghrelin induce similar increases in food intake and patterns of hypothalamic gene expression

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00785.2005 ◽

2006 ◽

Vol 290 (6) ◽

pp. R1565-R1569 ◽

Cited By ~ 17

Author(s):

Kimberly P. Kinzig ◽

Karen A. Scott ◽

Jayson Hyun ◽

Sheng Bi ◽

Timothy H. Moran

Keyword(s):

Gene Expression ◽

Food Intake ◽

Fourth Ventricle ◽

Time Course ◽

Arcuate Nucleus ◽

Central Administration ◽

Stimulatory Action ◽

Hypothalamic Arcuate Nucleus ◽

Ghrelin Receptors ◽

The Brain

The gut peptide ghrelin has been shown to stimulate food intake after both peripheral and central administration, and the hypothalamic arcuate nucleus has been proposed to be the major site for mediating this feeding stimulatory action. Ghrelin receptors are widely distributed in the brain, and hindbrain ghrelin administration has been shown to potently stimulate feeding, suggesting that there may be other sites for ghrelin action. In the present study, we have further assessed potential sites for ghrelin action by comparing the ability of lateral and fourth ventricular ghrelin administration to stimulate food intake and alter patterns of hypothalamic gene expression. Ghrelin (0.32, 1, or 3.2 nmol) in the lateral or fourth ventricle significantly increased food intake in the first 4 h after injection, with no ventricle-dependent differences in degree or time course of hyperphagia. One nanomole of ghrelin into either the lateral or fourth ventricle resulted in similar increases in arcuate nucleus neuropeptide Y mRNA expression. Expression levels of agouti-related peptide or proopiomelanocortin mRNA were not affected by ghrelin administration. These data demonstrate that ghrelin can affect food intake and hypothalamic gene expression through interactions at multiple brain sites.

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Region-Specific Reduction in Leptin-Induced Phosphorylation of Signal Transducer and Activator of Transcription-3 (STAT3) in the Rat Hypothalamus Is Associated with Leptin Resistance during Pregnancy

Endocrinology ◽

10.1210/en.2004-0338 ◽

2004 ◽

Vol 145 (8) ◽

pp. 3704-3711 ◽

Cited By ~ 98

Author(s):

S. R. Ladyman ◽

D. R. Grattan

Keyword(s):

Food Intake ◽

Arcuate Nucleus ◽

Ventromedial Hypothalamus ◽

Leptin Resistance ◽

Signal Transducer ◽

Pregnant Rats ◽

Hypothalamic Nuclei ◽

Stat3 Phosphorylation ◽

Vehicle Treatment ◽

Plasma Leptin

Abstract Leptin concentrations increase during pregnancy, but this does not prevent the pregnancy-induced increase in food intake, suggesting a state of leptin resistance. This study investigated the response to intracerebroventricular leptin administration in pregnant rats. After fasting, nonpregnant, d-7 and d-14 pregnant rats received leptin (4 μg) or vehicle, then food intake was measured. Serial blood samples were collected in another group of rats to determine plasma leptin concentrations. Further groups of d-14 pregnant and nonpregnant rats were killed after leptin or vehicle treatment, and brains were collected. Hypothalamic nuclei were microdissected, and levels of signal transducer and activator of transcription (STAT)3 phosphorylation were measured using Western blot analysis. Fasting decreased leptin concentrations in both pregnant and nonpregnant rats. Leptin treatment significantly reduced food intake in nonpregnant and d-7 pregnant rats but not in d-14 pregnant rats. In addition, there was no postfasting hyperphagic response in the pregnant rats. In the pregnant rats, leptin-induced STAT3 phosphorylation was suppressed in the arcuate nucleus and, to a lesser extent, in the ventromedial hypothalamus (VMH), compared with nonpregnant rats. Unstimulated STAT3 levels were also decreased in the VMH during pregnancy. Leptin-induced phosphorylation of STAT3 in the dorsomedial and lateral hypothalamus was not different between pregnant and nonpregnant rats. These data indicate that pregnant rats become resistant to the satiety action of leptin. Furthermore, leptin-induced activation of the STAT3 is impaired during pregnancy, specifically in the arcuate nucleus and VMH. These data support the hypothesis that pregnancy is a state of hypothalamic leptin resistance.

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Three weeks of postweaning exercise in DIO rats produces prolonged increases in central leptin sensitivity and signaling

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.90859.2008 ◽

2009 ◽

Vol 296 (3) ◽

pp. R537-R548 ◽

Cited By ~ 65

Author(s):

Christa M. Patterson ◽

Sebastien G. Bouret ◽

Ambrose A. Dunn-Meynell ◽

Barry E. Levin

Keyword(s):

Food Intake ◽

Receptor Binding ◽

Arcuate Nucleus ◽

Leptin Receptor ◽

High Energy ◽

Decrease Food Intake ◽

Diet Induced Obesity ◽

Leptin Sensitivity

In rats selectively bred to develop diet-induced obesity (DIO) 3 wk of postweaning exercise reduces weight and adipose regain for 10 wk after exercise cessation, despite intake of 31% fat high-energy (HE) diet. To test the hypothesis that this effect is due to increased central leptin sensitivity, 4-wk-old DIO rats were fed the HE diet and left sedentary (Sed), exercised for 3 wk, and then remained sedentary for 10 additional weeks (Ex/Sed) or continued exercise for a full 13 wk (Ex). After 3 wk, leptin (5 mg/kg ip) induced a 36% decrease in 24-h food intake in Ex rats, while Sed rats had no change in 24-h intake. Ex rats also had 23% more leptin-induced phospho-STAT3 (pSTAT3)-expressing neurons in the arcuate nucleus (ARC) and 95% and 68% higher 125I-labeled leptin receptor binding in the ventromedial and dorsomedial nuclei than did Sed rats, respectively. At 7 wk after onset, leptin decreased 24-h intake by 20% in Ex and 24% in Ex/Sed rats without altering Sed intake. After a total of 13 wk, compared with Sed rats, Ex and Ex/Sed rats had 58% and 38% less fat, respectively, but leptin failed to decrease food intake in any group. Nevertheless, Ex, but not Ex/Sed rats, still had 32% more ARC leptin-induced pSTAT3-expressing neurons than Sed rats. These data suggest that brief postweaning exercise in DIO rats that are inherently leptin resistant causes a sustained resistance to obesity on HE diet, which is, in part, due to increased central leptin sensitivity.

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Changes in mRNA expression of arcuate nucleus appetite-regulating peptides during lactation in rats

Journal of Molecular Endocrinology ◽

10.1530/jme-13-0015 ◽

2013 ◽

Vol 52 (2) ◽

pp. 97-109 ◽

Cited By ~ 10

Author(s):

Yoshihiro Suzuki ◽

Keiko Nakahara ◽

Keisuke Maruyama ◽

Rieko Okame ◽

Takuya Ensho ◽

...

Keyword(s):

Food Intake ◽

Mrna Expression ◽

Arcuate Nucleus ◽

Peptide Yy ◽

Weaning Food ◽

Hypothalamic Arcuate Nucleus ◽

Pregnancy And Lactation ◽

Acyl Ghrelin ◽

Plasma Leptin ◽

Agouti Related Protein

The contribution of hypothalamic appetite-regulating peptides to further hyperphagia accompanying the course of lactation in rats was investigated by using PCR array and real-time PCR. Furthermore, changes in the mRNA expression for appetite-regulating peptides in the hypothalamic arcuate nucleus (ARC) were analyzed at all stages of pregnancy and lactation, and also after weaning. Food intake was significantly higher during pregnancy, lactation, and after weaning than during non-lactation periods. During lactation, ARC expression of mRNAs for agouti-related protein (AgRP) and peptide YY was increased, whereas that of mRNAs for proopiomelanocortin (POMC) and cholecystokinin (CCK) was decreased, in comparison with non-lactation periods. The increase in AgRP mRNA expression during lactation was especially marked. The plasma level of leptin was significantly decreased during the course of lactation, whereas that of acyl-ghrelin was unchanged. In addition, food intake was negatively correlated with the plasma leptin level during lactation. This study has clarified synchronous changes in the expression of many appetite-regulating peptides in ARC of rats during lactation. Our results suggest that hyperphagia during lactation in rats is caused by decreases in POMC and CCK expression and increases in AgRP expression in ARC, the latter being most notable. Together with the decrease in the blood leptin level, such changes in mRNA expression may explain the further hyperphagia accompanying the course of lactation.

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Increased Hypothalamic Protein Tyrosine Phosphatase 1B Contributes to Leptin Resistance with Age

Endocrinology ◽

10.1210/en.2006-0672 ◽

2007 ◽

Vol 148 (1) ◽

pp. 433-440 ◽

Cited By ~ 85

Author(s):

Christopher D. Morrison ◽

Christy L. White ◽

Zhong Wang ◽

Seung-Yub Lee ◽

David S. Lawrence ◽

...

Keyword(s):

Food Intake ◽

Protein Tyrosine Phosphatase ◽

Middle Age ◽

Tyrosine Phosphatase ◽

Leptin Resistance ◽

Protein Tyrosine Phosphatase 1B ◽

Sprague Dawley ◽

Protein Tyrosine ◽

Leptin Sensitivity ◽

Old Rats

Animals at advanced ages exhibit a reduction in central leptin sensitivity. However, changes in growth, metabolism, and obesity risk occur much earlier in life, particularly during the transition from youth to middle age. To determine when initial decreases in central leptin sensitivity occur, leptin-dependent suppression of food intake was tested in 8-, 12-, and 20-wk-old male, chow-fed Sprague Dawley rats. Intracerebroventricular leptin injection (3 μg) suppressed 24-h food intake in 8- and 12-wk-old rats (P < 0.05) but not 20-wk-old rats. To identify potential cellular mediators of this resistance, we focused on protein tyrosine phosphatase 1B (PTP1B), a recently described inhibitor of leptin signaling. PTP1B protein levels, as determined by Western blot, were significantly higher in mediobasal hypothalamic punches collected from 20-wk-old rats, compared with 8-wk-old rats (P < 0.05). When 20-wk-old rats were fasted for 24 h, levels of hypothalamic PTP1B decreased (P < 0.05), coincident with a restoration of leptin sensitivity. To directly test whether inhibition of PTP1B restores leptin sensitivity, 20-wk-old chow-fed rats were pretreated with a pharmacological PTP1B inhibitor 1 h before leptin, and 24-h food intake was recorded. As expected, leptin alone produced a small but nonsignificant reduction in food intake. However, pretreatment with the PTP1B inhibitor resulted in a marked improvement in leptin-dependent suppression of food intake (P < 0.05). These data are consistent with the hypothesis that increases in PTP1B contribute to hypothalamic leptin resistance as rats transition into middle age.

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Involvement of the Acyl-CoA binding domain containing 7 in the control of food intake and energy expenditure in mice

eLife ◽

10.7554/elife.11742 ◽

2016 ◽

Vol 5 ◽

Cited By ~ 12

Author(s):

Damien Lanfray ◽

Alexandre Caron ◽

Marie-Claude Roy ◽

Mathieu Laplante ◽

Fabrice Morin ◽

...

Keyword(s):

Food Intake ◽

Energy Expenditure ◽

Arcuate Nucleus ◽

Binding Domain ◽

Nucleotide Polymorphism ◽

Melanocortin System ◽

Single Nucleotide ◽

Hypothalamic Arcuate Nucleus ◽

Paralog Gene ◽

G Protein Coupled

Acyl-CoA binding domain-containing 7 (Acbd7) is a paralog gene of the diazepam-binding inhibitor/Acyl-CoA binding protein in which single nucleotide polymorphism has recently been associated with obesity in humans. In this report, we provide converging evidence indicating that a splice variant isoform of the Acbd7 mRNA is expressed and translated by some POMC and GABAergic-neurons in the hypothalamic arcuate nucleus (ARC). We have demonstrated that the ARC ACBD7 isoform was produced and processed into a bioactive peptide referred to as nonadecaneuropeptide (NDN) in response to catabolic signals. We have characterized NDN as a potent anorexigenic signal acting through an uncharacterized endozepine G protein-coupled receptor and subsequently via the melanocortin system. Our results suggest that ACBD7-producing neurons participate in the hypothalamic leptin signalling pathway. Taken together, these data suggest that ACBD7-producing neurons are involved in the hypothalamic control exerted on food intake and energy expenditure by the leptin-melanocortin pathway.

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Selective Inactivation of Socs3 in SF1 Neurons Improves Glucose Homeostasis without Affecting Body Weight

Endocrinology ◽

10.1210/en.2008-0805 ◽

2008 ◽

Vol 149 (11) ◽

pp. 5654-5661 ◽

Cited By ~ 59

Author(s):

Ren Zhang ◽

Harveen Dhillon ◽

Huali Yin ◽

Akihiko Yoshimura ◽

Bradford B. Lowell ◽

...

Keyword(s):

Body Weight ◽

Food Intake ◽

Energy Expenditure ◽

Glucose Homeostasis ◽

Leptin Resistance ◽

High Fat ◽

Leptin Signaling ◽

Leptin Sensitivity ◽

High Fat Diets ◽

Fat Diets

Suppressor of cytokine signaling 3 (Socs3) has been identified as a mediator of central leptin resistance, but the identity of specific neurons in which Socs3 acts to suppress leptin signaling remains elusive. The ventromedial hypothalamus (VMH) was recently shown to be an important site for leptin action because deleting leptin receptor within VMH neurons causes obesity. To examine the role of VMH Socs3 in leptin resistance and energy homeostasis, we generated mice lacking Socs3 specifically in neurons positive for steroidogenic factor 1 (SF1), which is expressed abundantly in the VMH. These mice had increased phosphorylation of signal transducer and activator of transcription-3 in VMH neurons, suggesting improved leptin signaling, and consistently, food intake and weight-reducing effects of exogenous leptin were enhanced. Furthermore, on either chow or high-fat diets, these mice had reduced food intake. Unexpectedly, energy expenditure was reduced as well. Mice lacking Socs3 in SF1 neurons, despite no change in body weight, had improved glucose homeostasis and were partially protected from hyperglycemia and hyperinsulinemia induced by high-fat diets. These results suggest that Socs3 in SF1 neurons negatively regulates leptin signaling and plays important roles in mediating leptin sensitivity, glucose homeostasis, and energy expenditure.

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Abstract P249: ICV Infusion Of AgRP Modulates Feeding Behavior And Energy Expenditure In Mice

Hypertension ◽

10.1161/hyp.76.suppl_1.p249 ◽

2020 ◽

Vol 76 (Suppl_1) ◽

Author(s):

Vanessa Oliveira ◽

Kirthikaa Balapattabi ◽

John J Reho ◽

Sebastiao D Silva ◽

Chetan N Patil ◽

...

Keyword(s):

Food Intake ◽

Energy Expenditure ◽

Feeding Behavior ◽

Body Mass ◽

High Dose ◽

Digestive Efficiency ◽

Genetic Ablation ◽

Total Food Intake ◽

Intracerebroventricular Infusion

A subset of Agouti-related protein (AgRP) neurons within the arcuate nucleus express angiotensin type 1a receptors (AT1A), and genetic ablation of AT1A in these cells disinhibits AgRP gene expression and attenuates energy expenditure (EE) in mice. To further understand the role of AgRP in metabolic control, and to establish relevant dosing schedules in this species, here we tested the effect of intracerebroventricular infusion (icv) of recombinant AgRP on metabolic functions in C57BL/6J male mice. First, we examined the effects of AgRP(82-132) (21 days, 1 or 10 nmol/d, icv) or artificial cerebrospinal fluid (aCSF) using metabolic cages. High dose AgRP reduced body mass (aCSF n=12, +0.8±0.6 vs 1 nmol/d n=14, +0.6±0.6 vs 10 nmol/d n=11, -1.5±0.5 p<0.05 g/21d), without affecting food intake (15.1±1.2 vs 14.1±1.1 vs 16.3±1.1 kcal/d) or digestive efficiency (85.2±0.5 vs 84.5±0.7 vs 85.1±0.6 %), but a significant reduction in energy efficiency (+3.8±2.0 vs +2.7±2.8 vs -5.9±2.2 p<0.05 mg/kcal) indicated increased total EE. Next, we examined the effect of AgRP(82-132) (14 days, 1 nmol/d, icv) using a multiplexed system (Promethion, Sable). AgRP had no effect on body mass (25.1±1.2, n=8 vs 26.7±0.5, n=8), overall body composition (by NMR), heat production (Weir, 24h: 0.485±0.015 vs 0.490±0.022 kcal/h), or respiratory exchange ratio (0.88±0.01 vs 0.89±0.01). AgRP increased total food intake (10.1±0.6, n=8 vs 11.9±0.5, n=8, kcal/d, p=0.03) through a synergistic effect on number of meals and median meal mass. We conclude that AgRP (1-10 nmol/d, 2-3 wk, icv) infusion causes subtle changes in feeding behavior without effect on digestive efficiency. In contrast, EE is paradoxically increased by AgRP when infused at a high dose (10 nmol/d). We postulate that these differences may reflect differential accessibility of the peptide to relevant feeding vs autonomic control regions of the hypothalamus when infused into the cerebral ventricles, and/or compensatory increases in EE secondary to changes in feeding behavior. Future studies to deconvolute the role of AgRP in the control of EE in mice will require site-specific delivery of the peptide to relevant target regions or manipulation of its receptor in those regions. Funding: HL134850, HL084207

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