Role of hypoleptinemia during cold adaptation in Brandt's voles (Lasiopodomys brandtii)

2009 ◽  
Vol 297 (5) ◽  
pp. R1293-R1301 ◽  
Author(s):  
Gang-Bin Tang ◽  
Jian-Guo Cui ◽  
De-Hua Wang
Keyword(s):  
Food Intake ◽  
Cold Adaptation ◽  
Leptin Receptor ◽  
Uncoupling Protein ◽  
Cytokine Signaling ◽  
Mrna Levels ◽  
Serum Leptin ◽  
Brown Adipose ◽  
Lasiopodomys Brandtii

Brandt's voles Lasiopodomys brandtii exhibit large increases in nonshivering thermogenesis to cope with chronic cold exposure, resulting in compensatory hyperphagia and fat mobilization. These physiological events are accompanied by a remarkable reduction in serum leptin levels. However, the role of hypoleptinemia in cold adaptation in this species is still unknown. In the present study, we tested the hypothesis that hypoleptinemia contributes to increases in food intake and brown adipose tissue (BAT) thermogenesis by modifying hypothalamic neuropeptides in cold-exposed Brandt's voles. Adult male voles were transferred to 5°C for 28 days. Accompanied by a decrease in serum leptin levels, hypothalamic agouti-related protein (AgRP) mRNA levels were significantly increased, but there were no changes in the long form of leptin receptor (Ob-Rb), suppressor of cytokine signaling 3 (SOCS3), neuropeptide Y (NPY) mRNA, proopiomelanocortin (POMC), and cocaine- and amphetamine-regulated peptide (CART) mRNA levels in the hypothalamus. When cold-exposed voles were returned to warm (23°C) for 28 days, body mass, food intake, serum leptin, and AgRP mRNA were restored to control levels. Leptin administration in cold-exposed voles decreased food intake as well as hypothalamic AgRP mRNA levels. There were no significant effects of leptin administration on hypothalamic Ob-Rb, SOCS3, NPY, POMC, CART mRNA, and uncoupling protein 1 levels under cold conditions. These results suggest that hypoleptinemia partially contributes to cold-induced hyperphagia, which might involve the elevation of hypothalamic AgRP gene expression.

beta 3-Adrenergic-mediated suppression of leptin gene expression in rats

1997 ◽  
Vol 272 (6) ◽  
pp. E1031-E1036 ◽  
Author(s):  
H. Li ◽  
M. Matheny ◽  
P. J. Scarpace
Keyword(s):  
Gene Expression ◽  
Adipose Tissue ◽  
Food Intake ◽  
Uncoupling Protein ◽  
Mrna Levels ◽  
Interscapular Brown Adipose Tissue ◽  
Brown Adipose ◽  
Cgp 12177 ◽  
Rat Strain

To investigate the role of beta 3-adrenergic receptors in the suppression of leptin gene expression, we fasted F-344 rats to decrease leptin mRNA levels, refed the rats to stimulate leptin mRNA production, and examined the ability of the beta 3-adrenergic agonist CGP-12177 to prevent the rise in leptin mRNA levels. In the initial 2 h after CGP-12177 (0.75 mg/kg), there were significant reductions in both food consumption and leptin mRNA levels in epididymal, perirenal, and interscapular white adipose tissue. We were unable to detect leptin mRNA in interscapular brown adipose tissue (IBAT), whereas there was a significant increase in uncoupling protein mRNA levels in IBAT after CGP-12177. The suppression of leptin mRNA and food intake by CGP-12177 was confirmed in a second experiment using another rat strain, the F-344 x BN. Furthermore, refeeding after a period of fasting increased leptin mRNA, which was prevented by CGP-12177. These data indicate a role for beta 3-adrenergic-mediated regulation of leptin gene expression in nonmutant rodents and are consistent with other reports suggesting that beta 3-adrenergic agonists suppress food intake.

scholarly journals Food Intake and Core Body Temperature of Pups and Adults in a db Mouse Line Deficient in the Long Form of the Leptin Receptor without Misty Mutation

2018 ◽  
Vol 2018 ◽  
pp. 1-9 ◽  
Author(s):  
Wijang Pralampita Pulong ◽  
Miharu Ushikai ◽  
Emi Arimura ◽  
Masaharu Abe ◽  
Hiroaki Kawaguchi ◽  
...  
Keyword(s):  
Food Intake ◽  
Body Temperature ◽  
Leptin Receptor ◽  
Uncoupling Protein ◽  
Core Body Temperature ◽  
Mrna Levels ◽  
Mouse Line ◽  
Brown Adipose ◽  
Long Form ◽  
Core Body

Different involvement of leptin signaling in food intake (FI) and body temperature (BT) in pups and adults has been suggested. However, the leptin receptor (Lepr) long-form-deficient (db) mouse line has not been fully examined in pups. In the most available db mouse line, wild-type (WT) mice have a mutation in the dedicator of cytokinesis 7 gene, named misty, which was recently revealed to be involved in neuronal development. Therefore, we established a line of db mice without the misty mutation using natural mating. Adult (8 weeks of age) homozygous db/db mice displayed significantly higher core body weight (BW) and FI and significantly lower core BT than WT mice. However, postnatal (2 weeks of age) db/db mice displayed similar BW and milk intake and significantly lower core BT than WT mice. Correspondingly, adult and postnatal db/db mice exhibited altered mRNA levels of hypothalamic orexigenic and anorexigenic peptide in adults but not in pups. Additionally, db/db mice displayed significantly lower mRNA levels of brown adipose tissue uncoupling protein 1 at both ages. In conclusion, the db mouse line without the misty mutation clearly showed the different involvements of the Lepr long form in FI and BT in pups and adults.

scholarly journals Leptin Sensitivity in the Developing Rat Hypothalamus

Endocrinology ◽  
2007 ◽  
Vol 148 (12) ◽  
pp. 6073-6082 ◽  
Author(s):  
A.-S. Carlo ◽  
M. Pyrski ◽  
C. Loudes ◽  
A. Faivre-Baumann ◽  
J. Epelbaum ◽  
...  
Keyword(s):  
Food Intake ◽  
Neuropeptide Y ◽  
Leptin Receptor ◽  
Primary Cultures ◽  
Cytokine Signaling ◽  
Neuronal Cultures ◽  
Mrna Levels ◽  
Leptin Signaling ◽  
Leptin Sensitivity

In adults, the adipocyte-derived hormone, leptin, regulates food intake and body weight principally via the hypothalamic arcuate nucleus (ARC). During early postnatal development, leptin functions to promote the outgrowth of neuronal projections from the ARC, whereas a selective insensitivity to the effects of leptin on food intake appears to exist. To investigate the mechanisms underlying the inability of leptin to regulate food intake during early development, leptin signaling was analyzed both in vitro using primary cultures of rat embryonic ARC neurones and in vivo by challenging early postnatal rats with leptin. In neuronal cultures, despite the presence of key components of the leptin signaling pathway, no detectable activation of either signal transducer and activator of transcription 3 or the MAPK pathways by leptin was detected. However, leptin down-regulated mRNA levels of proopiomelanocortin and neuropeptide Y and decreased somatostatin secretion. Leptin challenge in vivo at postnatal d (P) 7, P14, P21, and P28 revealed that, in contrast to adult and P28 rats, mRNA levels of neuropeptide Y, proopiomelanocortin, agouti-related peptide and cocaine- and amphetamine-regulated transcript were largely unaffected at P7, P14, and P21. Furthermore, leptin stimulation increased the suppressor of cytokine signaling-3 mRNA levels at P14, P21, and P28 in several hypothalamic nuclei but not at P7, indicating that selective leptin insensitivity in the hypothalamus is coupled to developmental shifts in leptin receptor signaling. Thus, the present study defines the onset of leptin sensitivity in the regulation of energy homeostasis in the developing hypothalamus.

scholarly journals Leptin Receptor Signaling in Sim1-Expressing Neurons Regulates Body Temperature and Adaptive Thermogenesis

Endocrinology ◽  
2019 ◽  
Vol 160 (4) ◽  
pp. 863-879 ◽  
Author(s):  
Isin Cakir ◽  
Myriam Diaz-Martinez ◽  
Pauline Lining Pan ◽  
E Brian Welch ◽  
Sachin Patel ◽  
...  
Keyword(s):  
Body Temperature ◽  
Energy Expenditure ◽  
Molecular Mechanisms ◽  
Leptin Receptor ◽  
Uncoupling Protein ◽  
Gene Copy ◽  
Adaptive Thermogenesis ◽  
Brown Adipose ◽  
Core Body

Abstract Leptin signals to regulate food intake and energy expenditure under conditions of normative energy homeostasis. The central expression and function of leptin receptor B (LepRb) have been extensively studied during the past two decades; however, the mechanisms by which LepRb signaling dysregulation contributes to the pathophysiology of obesity remains unclear. The paraventricular nucleus of the hypothalamus (PVN) plays a crucial role in regulating energy balance as well as the neuroendocrine axes. The role of LepRb expression in the PVN in regard to the regulation of physiological function of leptin has been controversial. The single-minded homolog 1 gene (Sim1) is densely expressed in the PVN and in parts of the amygdala, making Sim1-Cre mice a useful model for examining molecular mechanisms regulating PVN function. In this study, we characterized the physiological role of LepRb in Sim1-expressing neurons using LepRb-floxed × Sim1-Cre mice. Sim1-specific LepRb-deficient mice were surprisingly hypophagic on regular chow but gained more weight upon exposure to a high-fat diet than did their control littermates. We show that Sim1-specific deletion of a single LepRb gene copy caused decreased surface and core body temperatures as well as decreased energy expenditure in ambient room temperatures in both female and male mice. Furthermore, cold-induced adaptive (nonshivering) thermogenesis is disrupted in homozygous knockout mice. A defective thermoregulatory response was associated with defective cold-induced upregulation of uncoupling protein 1 in brown adipose tissue and reduced serum T4. Our study provides novel functional evidence supporting LepRb signaling in Sim1 neurons in the regulation of body weight, core body temperature, and cold-induced adaptive thermogenesis.

scholarly journals Leptin Signaling in the Hypothalamus during Chronic Central Leptin Infusion

Endocrinology ◽  
2003 ◽  
Vol 144 (9) ◽  
pp. 3789-3798 ◽  
Author(s):  
Rekha Pal ◽  
Abhiram Sahu
Keyword(s):  
Food Intake ◽  
Leptin Receptor ◽  
Binding Activity ◽  
Janus Kinase ◽  
Male Rats ◽  
Leptin Resistance ◽  
Cytokine Signaling ◽  
Mrna Levels ◽  
Leptin Signaling ◽  
Initial Decrease

Abstract Using a rat model of chronic central leptin infusion in which neuropeptide Y neurons develop leptin resistance, we examined whether leptin signal transduction mechanism in the hypothalamus is altered during central leptin infusion. Adult male rats were infused chronically into the lateral cerebroventricle with leptin (160 ng/h) or vehicle via Alzet pumps for 16 d. In the leptin-infused group, the initial decrease in food intake was followed by a recovery to their preleptin levels by d 16, although food intake remained significantly lower than in artificial cerebrospinal fluid controls; and body weight gradually decreased reaching a nadir at d 11 and remained stabilized at lower level thereafter. Phosphorylated leptin receptor and phosphorylated signal transducer and activator of transcription-3 (p-STAT3) remained elevated in association with a sustained elevation in DNA-binding activity of STAT3 in the hypothalamus throughout 16-d period of leptin infusion. However, phosphorylated Janus kinase-2 was increased during the early part of leptin infusion but remained unaltered on d 16. Although hypothalamic suppressors of cytokine signaling-3 (SOCS3) mRNA levels were increased throughout leptin infusion, SOCS3 protein levels were increased only on d 16. This study demonstrates a sustained elevation in hypothalamic leptin receptor signaling through Janus kinase-STAT pathway despite an increased expression of SOCS3 during chronic central leptin infusion. We propose that an alteration in leptin signaling in the hypothalamus through pathways other than STAT3 and/or a defect in downstream of STAT3 signaling may be involved in food intake recovery seen after an initial decrease during chronic central leptin infusion.

Plasticity in food intake, thermogenesis and body mass in the tree shrew (Tupaia belangeri) is affected by food restriction and refeeding

2016 ◽  
Vol 66 (2) ◽  
pp. 201-217 ◽  
Author(s):  
Wen-rong Gao ◽  
Wan-long Zhu ◽  
Fang-yan Ye ◽  
Mu-lin Zuo ◽  
Zheng-kun Wang
Keyword(s):  
Adipose Tissue ◽  
Food Intake ◽  
Brown Adipose Tissue ◽  
Body Mass ◽  
Food Restriction ◽  
Uncoupling Protein ◽  
Tissue Mass ◽  
Serum Leptin ◽  
Brown Adipose ◽  
Ad Libitum

Physiological adjustments are important strategies for small mammals in response to variation in food availability. To determine the physiological mechanisms affected by food restriction and refeeding, tree shrews were restricted to 85% of initial food intake for 4 weeks and refedad libitumfor another 4 weeks. Changes in food intake, body mass, thermogenesis, body composition, mitochondrial cytochromecoxidase activity, uncoupling protein-1 content in brown adipose tissue and serum leptin levels were measured. The results showed that body mass, body fat mass and serum leptin levels significantly decreased in food restricted tree shrews, and increased when the restriction ended, showing a short “compensatory growth” rather than over-weight or obesity compared withad libitumcontrols. Resting metabolic rate, non-shivering thermogenesis, brown adipose tissue mass (mg), and uncoupling protein-1 content decreased significantly in response to food restriction, and returned to the control levels after the animals were refedad libitum, while the brown adipose tissue mass (%) and cytochromecoxidase activity remained stable during food restriction and refeeding. Food intake increased shortly after refeeding, which perhaps contributed to the rapid regaining of body mass. These results suggest thatTupaia belangerican adjust the status of its physiology integratively to cope with the lack of food by means of decreasing body mass, thermogenesis and serum leptin levels. Leptin may act as a starvation signal to predominantly mediate the reduction in body mass and energy expenditure.

scholarly journals Leptin Modulates the Response of Brown Adipose Tissue to Negative Energy Balance: Implication of the GH/IGF-I Axis

2021 ◽  
Vol 22 (6) ◽  
pp. 2827
Author(s):  
Vicente Barrios ◽  
Laura M. Frago ◽  
Sandra Canelles ◽  
Santiago Guerra-Cantera ◽  
Eduardo Arilla-Ferreiro ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Energy Balance ◽  
Brown Adipose Tissue ◽  
Uncoupling Protein ◽  
Negative Energy ◽  
Negative Energy Balance ◽  
Cytokine Signaling ◽  
Mrna Levels ◽  
Brown Adipose ◽  
Igf I

The growth hormone (GH)/insulin-like growth factor I (IGF-I) axis is involved in metabolic control. Malnutrition reduces IGF-I and modifies the thermogenic capacity of brown adipose tissue (BAT). Leptin has effects on the GH/IGF-I axis and the function of BAT, but its interaction with IGF-I and the mechanisms involved in the regulation of thermogenesis remains unknown. We studied the GH/IGF-I axis and activation of IGF-I-related signaling and metabolism related to BAT thermogenesis in chronic central leptin infused (L), pair-fed (PF), and control rats. Hypothalamic somatostatin mRNA levels were increased in PF and decreased in L, while pituitary GH mRNA was reduced in PF. Serum GH and IGF-I concentrations were decreased only in PF. In BAT, the association between suppressor of cytokine signaling 3 and the IGF-I receptor was reduced, and phosphorylation of the IGF-I receptor increased in the L group. Phosphorylation of Akt and cyclic AMP response element binding protein and glucose transporter 4 mRNA levels were increased in L and mRNA levels of uncoupling protein-1 (UCP-1) and enzymes involved in lipid anabolism reduced in PF. These results suggest that modifications in UCP-1 in BAT and changes in the GH/IGF-I axis induced by negative energy balance are dependent upon leptin levels.

Effects of leptin infusion during peak lactation on food intake, body composition, litter growth, and maternal neuroendocrine status in female Brandt's voles (Lasiopodomys brandtii)

2011 ◽  
Vol 300 (2) ◽  
pp. R447-R459 ◽  
Author(s):  
Jian-Guo Cui ◽  
Gang-Bin Tang ◽  
De-Hua Wang ◽  
John R. Speakman
Keyword(s):  
Food Intake ◽  
Alternative Hypothesis ◽  
Uncoupling Protein ◽  
Fat Reserves ◽  
Energy Demands ◽  
Brown Adipose ◽  
Total Energy Balance ◽  
Fat Stores ◽  
Pup Growth ◽  
Lasiopodomys Brandtii

During lactation, female small mammals frequently reduce their fat reserves to very low levels. The function of this reduction is unclear, as calculations suggest that the contribution of the withdrawn energy from fat to the total energy balance of lactation is trivial. An alternative hypothesis is that reducing fat leads to a reduction in circulating adipokines, such as leptin, that play a role in stimulating the hyperphagia of lactation. We investigated the role of circulating leptin in lactation by repleting leptin levels using miniosmotic pumps during the last 7 days of lactation in Brandt's voles ( Lasiopodomys brandtii ), a model small wild mammal we have extensively studied in the context of lactation energy demands. Repletion of leptin resulted in a dose-dependent reduction of body mass and food intake in lactating voles. Comparisons to nonreproducing individuals suggests that the reduced leptin in lactation, due to reduced fat stores, may account for ∼16% of the lactational hyperphagia. Reduced leptin in lactation may, in part, cause lactational hyperphagia via stimulatory effects on hypothalamic orexigenic neuropeptides (neuropeptide Y and agouti-related peptide) and inhibition of the anorexigenic neuropeptide (proopiomelanocortin). These effects were reversed by the experimental repletion of leptin. There was no significant effect of leptin treatment on daily energy expenditure, milk production or pup growth, but leptin repletion did result in a reversal of the suppression of uncoupling protein-1 levels in brown adipose tissue, indicating an additional role for reducing body fat and leptin during peak lacation.

Regulation of beta 3-adrenergic receptor mRNA by sympathetic nerves and glucocorticoids in BAT of Zucker obese rats

1995 ◽  
Vol 269 (3) ◽  
pp. R519-R526 ◽  
Author(s):  
T. Onai ◽  
G. Kilroy ◽  
D. A. York ◽  
G. A. Bray
Keyword(s):  
Adrenergic Receptor ◽  
Uncoupling Protein ◽  
Sympathetic Nerves ◽  
Mrna Levels ◽  
Receptor Mrna ◽  
Brown Adipose ◽  
Obese Rats ◽  
Sympathetic Nervous ◽  
Opposite Response

Impaired brown adipose tissue (BAT) thermogenesis in the genetically obese Zucker fatty (fa/fa) rat is restored to normal by adrenalectomy. We investigated the role of the sympathetic nervous system in modulating the effects of adrenalectomy by studying beta3-adrenergic receptor (AR) and uncoupling protein (UCP) mRNA levels in unilaterally sympathectomized interscapular BAT of lean and obese rats. UCP mRNA levels were increased by adrenalectomy. Sympathetic denervation prevented this adrenalectomy-induced increase in lean rats but not in obese rats. beta 3-AR mRNA was decreased in BAT of obese rats. Adrenalectomy decreased and denervation increased beta 3-AR mRNA in lean rats but the opposite response was observed to both of these manipulations in obese rats. beta 3-AR mRNA and UCP mRNA were negatively correlated in lean rats but positively correlated in obese rats. Norepinephrine increased UCP mRNA levels in denervated BAT of both lean and obese rats and decreased beta 3-AR mRNA in lean rats but not obese rats. These data suggest that the regulation of the beta 3-AR gene in response to sympathetic stimuli and glucocorticoids is abnormal in the obese rat.

Temperature-dependent feeding: lack of role for leptin and defect in brown adipose tissue-ablated obese mice

1998 ◽  
Vol 274 (4) ◽  
pp. R1131-R1135 ◽  
Author(s):  
Anna Melnyk ◽  
Jean Himms-Hagen
Keyword(s):  
Adipose Tissue ◽  
Food Intake ◽  
Brown Adipose Tissue ◽  
Uncoupling Protein ◽  
Brown Adipocytes ◽  
Serum Leptin ◽  
Brown Adipose ◽  
Increase Food Intake ◽  
Diphtheria Toxin A ◽  
A Chain

The objective was to characterize the ability of control and transgenic brown adipose tissue (BAT)-ablated uncoupling protein diphtheria toxin A chain (UCP-DTA) mice to adjust food intake in relation to changes in environmental temperature and to assess the involvement of leptin in this adjustment. We measured serum leptin in mice from a previous study of UCP-DTA mice raised at thermoneutrality (35°C) or at the usual rearing temperature (24°C) from weaning [Melnyk, A., M.-E. Harper, and J. Himms-Hagen. Am. J. Physiol. 272 ( Regulatory Integrative Comp. Physiol. 41): R1088–R1093, 1997] and extended the study by acclimating control and obese UCP-DTA mice at 18 wk of age to cold (14°C) for up to 14 days. Leptin levels did not change in control mice at 14°C; however, food intake increased threefold within 1 day and remained at this level. Serum leptin level was elevated in UCP-DTA mice at 24°C compared with control mice at 24°C; this elevated level decreased within 1 day at 14°C and was not different from the level in control mice by 14 days. Food intake of UCP-DTA mice that were hyperphagic at 24°C did not change during 7 days at 14°C, then increased slowly. Similar low leptin levels were present in control mice raised at 24 or 35°C and in UCP-DTA mice raised at 35°C. Food intake of control mice raised at 24°C was two times that of control mice raised at 35°C. UCP-DTA mice raised at 35°C ate the same low amount as control mice raised at 35°C. UCP-DTA mice at 24°C were hyperphagic relative to control mice at 24°C yet had elevated leptin levels in their serum. Two principal conclusions are drawn. First, adjustment of food intake over a fourfold range by control mice acclimated to temperatures from 35 down to 14°C is independent of changes in serum leptin levels. Second, this adjustment of food intake in relation to temperature is defective in the UCP-DTA mouse; the defect leads to hyperphagia at 24°C and a failure to increase food intake as rapidly as control mice when exposed to 14°C. Because lack of UCP-1-mediated thermogenesis in BAT of knockout mice is known not to induce hyperphagia, we propose that deficiency of UCP-1-expressing brown adipocytes in BAT of UCP-DTA mice results in lack of a satiety factor, secreted by these cells in BAT of control mice in inverse relationship to sympathetic nervous system activity.

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