scholarly journals Hypothalamic–Pituitary and Adipose Tissue Responses to the Effect of Resistin in Sheep: The Integration of Leptin and Resistin Signaling Involving a Suppressor of Cytokine Signaling 3 and the Long Form of the Leptin Receptor

Nutrients ◽  
2019 ◽  
Vol 11 (9) ◽  
pp. 2180 ◽  
Author(s):  
Dorota Anna Zieba ◽  
Weronika Biernat ◽  
Malgorzata Szczesna ◽  
Katarzyna Kirsz ◽  
Tomasz Misztal
Keyword(s):  
Leptin Receptor ◽  
Brain Regions ◽  
Leptin Resistance ◽  
Cytokine Signaling ◽  
High Dose ◽  
Suppressor Of Cytokine Signaling ◽  
Tissue Responses ◽  
Long Form ◽  
Hypothalamic Arcuate Nucleus ◽  
Central Leptin Resistance

We hypothesized that resistin is engaged in the development of leptin central insensitivity/resistance in sheep, which is a unique animal model to explore reversible leptin resistance. Thirty Polish Longwool ewes, which were ovariectomized with estrogen replacement, were used. Treatments consisted of the intravenous injection of control (saline) or recombinant bovine resistin (rbresistin): control (Control; n = 10), a low dose of rbresistin (R1; 1.0 μg/kg body weight (BW); n = 10), and a high dose of rbresistin (R2; 10.0 μg/kg BW; n = 10). The studies were performed during short-day (SD) and long-day (LD) photoperiods. Leptin and resistin concentrations were determined. Expression levels of a suppressor of cytokine signaling (SOCS)-3 and the long form of the leptin receptor (LeptRb) were determined in selected brain regions, including in the anterior pituitary (AP), hypothalamic arcuate nucleus (ARC), preoptic area (POA), and ventro- and dorsomedial nuclei (VMH/DMH). The results indicate that resistin induced a consistent decrease in LeptRb (except in POA) and an increase in SOCS-3 expression during the LD photoperiod in all selected brain regions. In conclusion, the results demonstrate that the action of resistin appears to be strongly associated with photoperiod-driven changes in the leptin signaling pathway, which may underlie the phenomenon of central leptin resistance.

scholarly journals Region-Specific Leptin Resistance within the Hypothalamus of Diet-Induced Obese Mice

Endocrinology ◽  
2004 ◽  
Vol 145 (11) ◽  
pp. 4880-4889 ◽  
Author(s):  
Heike Münzberg ◽  
Jeffrey S. Flier ◽  
Christian Bjørbæk
Keyword(s):  
High Fat Diet ◽  
Leptin Receptor ◽  
Elevated Serum ◽  
Brain Regions ◽  
Leptin Resistance ◽  
Hypothalamic Nucleus ◽  
Cytokine Signaling ◽  
Mrna Levels ◽  
High Fat ◽  
Suppressor Of Cytokine Signaling

Abstract Leptin resistance in diet-induced obese (DIO) mice is characterized by elevated serum leptin and a decreased response to exogenous leptin and is caused by unknown defects in the central nervous system. Leptin normally acts on several brain nuclei, but a detailed description of leptin resistance within individual brain regions has not been reported. We first mapped leptin-responsive cells in brains from DIO mice using phospho-signal transducer and activator of transcription (P-STAT3) immunohistochemistry. After 16 wk of high-fat-diet feeding, leptin-activated P-STAT3 staining within the arcuate nucleus (ARC) was dramatically decreased. In contrast, other hypothalamic and extrahypothalamic nuclei remained leptin sensitive. Reduced leptin-induced P-STAT3 in the ARC could also be detected after 4 wk and as early as 6 d of a high-fat diet. To examine potential mechanisms for leptin-resistant STAT3 activation in the ARC of DIO mice, we measured mRNA levels of candidate signaling molecules in the leptin receptor-STAT3 pathway. We found that the level of suppressor of cytokine signaling 3 (SOCS-3), an inhibitor of leptin signaling, is specifically increased in the ARC of DIO mice. The study suggests that the ARC is selectively leptin resistant in DIO mice and that this may be caused by elevated suppressor of cytokine signaling 3 in this hypothalamic nucleus. Defects in leptin action in the ARC may play a role in the pathogenesis of leptin-resistant obesity.

scholarly journals Hypothyroidism Compromises Hypothalamic Leptin Signaling in Mice

2013 ◽  
Vol 27 (4) ◽  
pp. 586-597 ◽  
Author(s):  
Claudia Groba ◽  
Steffen Mayerl ◽  
Alies A. van Mullem ◽  
Theo J. Visser ◽  
Veerle M. Darras ◽  
...  
Keyword(s):  
Arcuate Nucleus ◽  
Leptin Receptor ◽  
Cytokine Signaling ◽  
Suppressor Of Cytokine Signaling ◽  
Double Knockout ◽  
Hypothalamic Arcuate Nucleus ◽  
The Central Nervous System ◽  
Leptin Expression ◽  
The Impact

Abstract The impact of thyroid hormone (TH) on metabolism and energy expenditure is well established, but the role of TH in regulating nutritional sensing, particularly in the central nervous system, is only poorly defined. Here, we studied the consequences of hypothyroidism on leptin production as well as leptin sensing in congenital hypothyroid TRH receptor 1 knockout (Trhr1 ko) mice and euthyroid control animals. Hypothyroid mice exhibited decreased circulating leptin levels due to a decrease in fat mass and reduced leptin expression in white adipose tissue. In neurons of the hypothalamic arcuate nucleus, hypothyroid mice showed increased leptin receptor Ob-R expression and decreased suppressor of cytokine signaling 3 transcript levels. In order to monitor putative changes in central leptin sensing, we generated hypothyroid and leptin-deficient animals by crossing hypothyroid Trhr1 ko mice with the leptin-deficient ob/ob mice. Hypothyroid Trhr1/ob double knockout mice showed a blunted response to leptin treatment with respect to body weight and food intake and exhibited a decreased activation of phospho-signal transducer and activator of transcription 3 as well as a up-regulation of suppressor of cytokine signaling 3 upon leptin treatment, particularly in the arcuate nucleus. These data indicate alterations in the intracellular processing of the leptin signal under hypothyroid conditions and thereby unravel a novel mode of action by which TH affects energy metabolism.

scholarly journals Neuronal suppressor of cytokine signaling-3 deficiency enhances hypothalamic leptin-dependent phosphatidylinositol 3-kinase signaling

2011 ◽  
Vol 300 (5) ◽  
pp. R1185-R1193 ◽  
Author(s):  
Anantha S. Metlakunta ◽  
Maitrayee Sahu ◽  
Hideo Yasukawa ◽  
Sandeep S. Dhillon ◽  
Denise D. Belsham ◽  
...  
Keyword(s):  
Neuronal Cell ◽  
Pi3k Pathway ◽  
Leptin Resistance ◽  
Cytokine Signaling ◽  
Phosphatidylinositol 3 Kinase ◽  
Suppressor Of Cytokine Signaling ◽  
Leptin Sensitivity ◽  
Pi3k Activity ◽  
Central Leptin Resistance ◽  
Phosphatidylinositol 3

Suppressor of cytokine signaling-3 (SOCS3) is thought to be involved in the development of central leptin resistance and obesity by inhibiting STAT3 pathway. Because phosphatidylinositol 3-kinase (PI3K) pathway plays an important role in transducing leptin action in the hypothalamus, we examined whether SOCS3 exerted an inhibition on this pathway. We first determined whether leptin sensitivity in the hypothalamic PI3K pathway was increased in brain-specific Socs3-deficient (NesKO) mice. In NesKO mice, hypothalamic insulin receptor substrate-1 (IRS1)-associated PI3K activity was significantly increased at 30 min and remained elevated up to 2 h after leptin intraperitoneal injection, but in wild-type (WT) littermates, the significant increase was only at 30 min. Hypothalamic p-STAT3 levels were increased up to 5 h in NesKO as opposed to 2 h in WT mice. In food-restricted WT mice with reduced body weight, leptin increased hypothalamic PI3K activity only at 30 min, and p-STAT3 levels at 30–120 min postinjection. These results suggest increased leptin sensitivity in both PI3K and STAT3 pathways in the hypothalamus of NesKO mice, which was not due to a lean phenotype. In the next experiment with a clonal hypothalamic neuronal cell line expressing proopiomelanocortin, we observed that whereas leptin significantly increased IRS1-associated PI3K activity and p-JAK2 levels in cells transfected with control vector, it failed to do so in SOCS3-overexpressed cells. Altogether, these results imply a SOCS3 inhibition of the PI3K pathway of leptin signaling in the hypothalamus, which may be one of the mechanisms behind the development of central leptin resistance and obesity.

scholarly journals Changes in Expression of the Genes for the Leptin Signaling in Hypothalamic-Pituitary Selected Areas and Endocrine Responses to Long-Term Manipulation in Body Weight and Resistin in Ewes

2020 ◽  
Vol 21 (12) ◽  
pp. 4238
Author(s):  
Dorota Anna Zieba ◽  
Weronika Biernat ◽  
Malgorzata Szczesna ◽  
Katarzyna Kirsz ◽  
Justyna Barć ◽  
...  
Keyword(s):  
Body Weight ◽  
Leptin Receptor ◽  
Fat Body ◽  
Density Lipoprotein ◽  
Reproductive Hormones ◽  
Leptin Resistance ◽  
Nonesterified Fatty Acid ◽  
Cytokine Signaling ◽  
Leptin Signaling

Both long-term undernutrition and overnutrition disturb metabolic balance, which is mediated partially by the action of two adipokines, leptin and resistin (RSTN). In this study, we manipulated the diet of ewes to produce either a thin (lean) or fat (fat) body condition and investigated how RSTN affects endocrine and metabolic status under different leptin concentrations. Twenty ewes were distributed into four groups (n = 5): the lean and fat groups were administered with saline (Lean and Fat), while the Lean-R (Lean-Resistin treated) and Fat-R (Fat-Resistin treated) groups received recombinant bovine resistin. Plasma was assayed for LH, FSH, PRL, RSTN, leptin, GH, glucose, insulin, total cholesterol, nonesterified fatty acid (NEFA), high-density lipoprotein (HDL)-cholesterol, low-density lipoprotein (LDL)-cholesterol and triglycerides. Expression levels of a suppressor of cytokine signaling (SOCS-3) and the long form of the leptin receptor (LRb) were determined in selected brain regions, such as the anterior pituitary, hypothalamic arcuate nucleus, preoptic area and ventro- and dorsomedial nuclei. The results indicate long-term alterations in body weight affect RSTN-mediated effects on metabolic and reproductive hormones concentrations and the expression of leptin signaling components: LRb and SOCS-3. This may be an adaptive mechanism to long-term changes in adiposity during the state of long-day leptin resistance.

scholarly journals Functional Role of Suppressor of Cytokine Signaling 3 Upregulation in Hypothalamic Leptin Resistance and Long-Term Energy Homeostasis

Diabetes ◽  
2010 ◽  
Vol 59 (4) ◽  
pp. 894-906 ◽  
Author(s):  
A. S. Reed ◽  
E. K. Unger ◽  
L. E. Olofsson ◽  
M. L. Piper ◽  
M. G. Myers ◽  
...  
Keyword(s):  
Functional Role ◽  
Energy Homeostasis ◽  
Leptin Resistance ◽  
Cytokine Signaling ◽  
Suppressor Of Cytokine Signaling ◽  
Term Energy

scholarly journals Neuropeptide W: An Anorectic Peptide Regulated by Leptin and Metabolic State

Endocrinology ◽  
2010 ◽  
Vol 151 (5) ◽  
pp. 2200-2210 ◽  
Author(s):  
Yukari Date ◽  
Muhtashan S. Mondal ◽  
Haruaki Kageyama ◽  
Masoud Ghamari-Langroudi ◽  
Fumiko Takenoya ◽  
...  
Keyword(s):  
Leptin Receptor ◽  
Fluorescent Protein ◽  
Extracellular Recording ◽  
Hypothalamic Nucleus ◽  
Cytokine Signaling ◽  
Melanocortin 4 Receptor ◽  
Hypothalamic Nuclei ◽  
Hypothalamic Arcuate Nucleus ◽  
Receptor Signaling Pathway ◽  
Green Fluorescent

Neuropeptide W (NPW) is an anorectic peptide produced in the brain. Here, we showed that NPW was present in several hypothalamic nuclei, including the paraventricular hypothalamic nucleus, ventromedial hypothalamic nucleus, lateral hypothalamus, and hypothalamic arcuate nucleus. NPW expression was significantly up-regulated in leptin-deficient ob/ob and leptin receptor-deficient db/db mice. The increase in NPW expression in ob/ob mice was abrogated to control levels after leptin replacement. Leptin induced suppressors of cytokine signaling-3 after phosphorylation of signal transducer and activator of transcription-3 in NPW-expressing neurons. In addition, we demonstrated that NPW reduces feeding via the melanocortin-4-receptor signaling pathway. We also showed that NPW activates proopiomelanocortin and inhibits neuropeptide Y neurons using loose-patch extracellular recording of these neurons identified by promoter-driven green fluorescent protein expression. This study indicates that NPW may play an important role in the regulation of feeding and energy metabolism under the conditions of leptin insufficiency.

scholarly journals Signaling through Tyr985 of Leptin Receptor as an Age/Diet-Dependent Switch in the Regulation of Energy Balance

2009 ◽  
Vol 30 (7) ◽  
pp. 1650-1659 ◽  
Author(s):  
Jia You ◽  
Yue Yu ◽  
Lei Jiang ◽  
Wenxia Li ◽  
Xinxin Yu ◽  
...  
Keyword(s):  
Energy Balance ◽  
Energy Homeostasis ◽  
Leptin Receptor ◽  
Negative Regulator ◽  
Leptin Resistance ◽  
Leptin Signaling ◽  
Diet Induced Obesity ◽  
Long Form ◽  
Elevated Expression ◽  
Multiple Signaling

ABSTRACT Leptin regulates energy homeostasis through central activation of multiple signaling pathways mediated by Ob-Rb, the long form of leptin receptor. Leptin resistance underlies the pathogenic development of obesity, which is closely associated with environmental factors. To further understand the physiological function of leptin signaling mechanisms, we generated a knock-in line of mice (Y985F) expressing a mutant Ob-Rb with a phenylalanine substitution for Tyr985, one of the three intracellular tyrosines that mediate leptin's signaling actions. Surprisingly, whereas young homozygous Y985F animals were slightly leaner, they exhibit adult-onset or diet-induced obesity. Importantly, both age-dependent and diet-induced deterioration of energy balance was paralleled with pronounced leptin resistance, which was largely attributable to attenuation of leptin-responsive hypothalamic STAT3 activation as well as prominently elevated expression of hypothalamic SOCS3, a key negative regulator of leptin signaling. Thus, these results unmask distinct binary roles for Try985-mediated signaling in energy metabolism, acting as an age/diet-dependent regulatory switch to counteract age-associated or diet-induced obesity.

Abstract 25: Angiotensin AT 1A Receptors on Leptin Receptor-Expressing Cells are Required for the Blood Pressure and Metabolic Rate Effects of Leptin

Hypertension ◽  
2013 ◽  
Vol 62 (suppl_1) ◽  
Author(s):  
Justin L Grobe ◽  
Kristin E Claflin
Keyword(s):  
Blood Pressure ◽  
Metabolic Rate ◽  
Body Mass ◽  
Leptin Receptor ◽  
Receptor Gene ◽  
Brain Regions ◽  
Leptin Resistance ◽  
Brown Adipose ◽  
Obesity Hypertension ◽  
The Brain

Circulating leptin and the local brain renin-angiotensin system (RAS) both contribute to the control of food intake (FI), resting metabolic rate (RMR) and blood pressure (BP), and both have been postulated to contribute to obesity-hypertension. Here we examined the provocative hypothesis that the brain RAS is required for (or mediates) the RMR- and BP-stimulating effects of leptin. To create animals lacking the AT 1A receptor specifically in cells expressing the leptin receptor (“KO”), mice with a flox’ed version of the endogenous angiotensin AT 1A receptor gene (AT 1A flox ) were crossed with mice expressing cre-recombinase via the leptin receptor promoter (ObR-Cre). Body mass, body composition, blood chemistry, glucose tolerance, and FI behaviors were essentially unchanged through 34 weeks of age in mice maintained on standard chow (Teklad 7013). In contrast, anesthetized BP (MAP; control n=9, 91.6 ± 4.1, vs KO n=8, 78.0 ± 3.7 mmHg) and heart rate (351 ± 13, vs 308 ± 11 BPM) were reduced in KO mice (both P<0.05). Further, interscapular brown adipose (BAT SNA, 112 ± 22, vs 22 ± 35 % above baseline at 3 hr) and renal (154 ± 19, vs 53 ± 23 % above baseline at 3 hr) sympathetic nerve activity responses to acute leptin injection (60 μg, i.v.) were completely abolished (both P<0.05). When maintained on a 45% high fat diet (OpenSource D12451 ) to increase endogenous leptin production, KO mice exhibited accelerated body mass (control n=15, -0.1 ± 0.1, vs KO n=4, +1.7 ± 0.5 g/wk) and fat mass (+2.9 ± 0.5, vs +4.9 ± 1.1 g/5 wk) gains (both P<0.05), likely due to normal FI behaviors but a 18% reduction in RMR (control n=16, 0.196 ± 0.011, vs KO n=7, 0.161 ± 0.004 kcal/hr at 30°C, P<0.05). We conclude that expression of angiotensin AT 1A receptors on leptin-sensitive cells is required for the metabolic rate and cardiovascular effects of leptin. Ongoing studies are focused on identifying the brain regions and subsets of leptin receptor-expressing cells in which this RAS-leptin cross-talk occurs, and the directionality and molecular mediators of this interaction. We hypothesize that uncontrolled or pathological activity of the brain RAS may thus help explain the clinically variable effects of leptin, and contribute to the mechanism(s) of selective leptin resistance and obesity-hypertension.

scholarly journals Protection Against High-Fat Diet-Induced Obesity in Helz2-Deficient Male Mice Due to Enhanced Expression of Hepatic Leptin Receptor

Endocrinology ◽  
2014 ◽  
Vol 155 (9) ◽  
pp. 3459-3472 ◽  
Author(s):  
Satoshi Yoshino ◽  
Tetsurou Satoh ◽  
Masanobu Yamada ◽  
Koshi Hashimoto ◽  
Takuya Tomaru ◽  
...  
Keyword(s):  
Gene Expression ◽  
Protein Kinase ◽  
High Fat Diet ◽  
Leptin Receptor ◽  
Leptin Resistance ◽  
High Fat ◽  
Leptin Sensitivity ◽  
Amp Activated Protein Kinase ◽  
Central Leptin Resistance ◽  
Deficient Mice

Abstract Obesity arises from impaired energy balance, which is centrally coordinated by leptin through activation of the long form of leptin receptor (Leprb). Obesity causes central leptin resistance. However, whether enhanced peripheral leptin sensitivity could overcome central leptin resistance remains obscure. A peripheral metabolic organ targeted by leptin is the liver, with low Leprb expression. We here show that mice fed a high-fat diet (HFD) and obese patients with hepatosteatosis exhibit increased expression of hepatic helicase with zinc finger 2, a transcriptional coactivator (Helz2), which functions as a transcriptional coregulator of several nuclear receptors, including peroxisome proliferator-activated receptor γ in vitro. To explore the physiological importance of Helz2, we generated Helz2-deficient mice and analyzed their metabolic phenotypes. Helz2-deficient mice showing hyperleptinemia associated with central leptin resistance were protected against HFD-induced obesity and had significantly up-regulated hepatic Leprb expression. Helz2 deficiency and adenovirus-mediated liver-specific exogenous Leprb overexpression in wild-type mice significantly stimulated hepatic AMP-activated protein kinase on HFD, whereas Helz2-deficient db/db mice lacking functional Leprb did not. Fatty acid-β oxidation was increased in Helz2-deficeint hepatocytes, and Helz2-deficient mice revealed increased oxygen consumption and decreased respiratory quotient in calorimetry analyses. The enhanced hepatic AMP-activated protein kinase energy-sensing pathway in Helz2-deficient mice ameliorated hyperlipidemia, hepatosteatosis, and insulin resistance by reducing lipogenic gene expression and stimulating lipid-burning gene expression in the liver. These findings together demonstrate that Helz2 deficiency ameliorates HFD-induced metabolic abnormalities by stimulating endogenous hepatic Leprb expression, despite central leptin resistance. Hepatic HELZ2 might be a novel target molecule for the treatment of obesity with hepatosteatosis.

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