A spontaneous leptin receptor point mutation causes obesity and differentially affects leptin signaling in hypothalamic nuclei resulting in metabolic dysfunctions distinct from db/db mice

The brain hypothalamus coordinates extra-hypothalamic regions to maintain energy homeostasis through the regulation of food intake and energy expenditure. A number of anorexigenic and orexigenic molecules in the hypothalamic nuclei participate in the control of energy homeostasis. Leptin and pro-opiomelanocortin (POMC)-derived α-melanocyte-stimulating hormone are key anorectic molecules, and the leptin receptor and POMC gene are both expressed in the hypothalamic arcuate nucleus. Although it has been considered that melanocortin signaling is localized downstream to leptin signaling, data have accumulated to support the concept of a leptin-independent melanocortin signaling system. We focus on and review the melanocortin signaling system that functions dependently or independently of leptin signaling in the regulation of energy homeostasis.

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Endospanin 1 Determines the Balance of Leptin-Regulated Hypothalamic Functions

Neuroendocrinology ◽

10.1159/000494557 ◽

2018 ◽

Vol 108 (2) ◽

pp. 132-141

Author(s):

Clara Roujeau ◽

Ralf Jockers ◽

Julie Dam

Keyword(s):

Signaling Pathways ◽

Intracellular Trafficking ◽

Leptin Receptor ◽

Leptin Resistance ◽

Human Obesity ◽

Leptin Signaling ◽

Diet Induced Obesity ◽

Important Regulator ◽

Neuronal Plasma Membrane ◽

Underlying Mechanisms

Endospanin 1 (Endo1), a protein encoded in humans by the same gene than the leptin receptor (ObR), and increased by diet-induced obesity, is an important regulator of ObR trafficking and cell surface exposure, determining leptin signaling strength. Defective intracellular trafficking of the leptin receptor to the neuronal plasma membrane has been proposed as a mechanism underlying the development of leptin resistance observed in human obesity. More recently, Endo1 has emerged as a mediator of “selective leptin resistance.” The underlying mechanisms of the latter are not completely understood, but the possibility of differential activation of leptin signaling pathways was suggested among others. In this respect, the expression level of Endo1 is crucial for the appropriate balance between different leptin signaling pathways and leptin functions in the hypothalamus and is likely participating in selective leptin resistance for the control of energy and glucose homeostasis.

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Leptin receptor expression in the dorsomedial hypothalamus stimulates breathing during NREM sleep in db/db mice

SLEEP ◽

10.1093/sleep/zsab046 ◽

2021 ◽

Author(s):

Huy Pho ◽

Slava Berger ◽

Carla Freire ◽

Lenise J Kim ◽

Mi-Kyung Shin ◽

...

Keyword(s):

Airway Obstruction ◽

Leptin Receptor ◽

Upper Airway ◽

Nrem Sleep ◽

Upper Airway Obstruction ◽

Co2 Production ◽

Dorsomedial Hypothalamus ◽

Leptin Signaling ◽

Arterial Blood ◽

Obesity Hypoventilation

Abstract Study Objectives Obesity leads to obstructive sleep apnea (OSA), which is recurrent upper airway obstruction during sleep, and obesity hypoventilation syndrome (OHS), hypoventilation during sleep resulting in daytime hypercapnia. Impaired leptin signaling in the brain was implicated in both conditions, but mechanisms are unknown. We have previously shown that leptin stimulates breathing and treats OSA and OHS in leptin- deficient ob/ob mice and leptin-resistant diet-induced obese mice and that leptin’s respiratory effects may occur in the dorsomedial hypothalamus (DMH). We hypothesized that leptin receptor LepR b–deficient db/db mice have obesity hypoventilation and that restoration of leptin signaling in the DMH will increase ventilation during sleep in these animals. Methods We measured arterial blood gas in unanesthetized awake db/db mice. We subsequently infected these animals with Ad-LepR b or control Ad-mCherry virus into the DMH and measured ventilation during sleep as well as CO2 production after intracerebroventricular (ICV) infusions of phosphate-buffered saline or leptin. Results Awake db/db mice had elevated CO2 levels in the arterial blood. Ad-LepR b infection resulted in LepR b expression in the DMH neurons in a similar fashion to wildtype mice. In LepR b-DMH db/db mice, ICV leptin shortened REM sleep and increased inspiratory flow, tidal volume and minute ventilation during NREM sleep without any effect on the quality of NREM sleep or CO2 production. Leptin had no effect on upper airway obstruction in these animals. Conclusion Leptin stimulates breathing and treats obesity hypoventilation acting on LepR b-positive neurons in the DMH.

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Single-cell analysis reveals cellular heterogeneity and molecular determinants of hypothalamic leptin-receptor cells

10.1101/2020.07.23.217729 ◽

2020 ◽

Author(s):

N. Kakava-Georgiadou ◽

J.F. Severens ◽

A.M. Jørgensen ◽

K.M. Garner ◽

M.C.M Luijendijk ◽

...

Keyword(s):

Single Cell ◽

Leptin Receptor ◽

Single Cell Analysis ◽

Cell Types ◽

Cellular Heterogeneity ◽

Molecular Signature ◽

Neuronal Populations ◽

Hypothalamic Nuclei ◽

Satiety Hormone ◽

Multiple Cell

AbstractHypothalamic nuclei which regulate homeostatic functions express leptin receptor (LepR), the primary target of the satiety hormone leptin. Single-cell RNA sequencing (scRNA-seq) has facilitated the discovery of a variety of hypothalamic cell types. However, low abundance of LepR transcripts prevented further characterization of LepR cells. Therefore, we perform scRNA-seq on isolated LepR cells and identify eight neuronal clusters, including three uncharacterized Trh-expressing populations as well as 17 non-neuronal populations including tanycytes, oligodendrocytes and endothelial cells. Food restriction had a major impact on Agrp neurons and changed the expression of obesity-associated genes. Multiple cell clusters were enriched for GWAS signals of obesity. We further explored changes in the gene regulatory landscape of LepR cell types. We thus reveal the molecular signature of distinct populations with diverse neurochemical profiles, which will aid efforts to illuminate the multi-functional nature of leptin’s action in the hypothalamus.

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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

International Journal of Molecular Sciences ◽

10.3390/ijms21124238 ◽

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.

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Leptin Deficiency and Its Effects on Tibial and Vertebral Bone Mechanical Properties in Mature Genetically Lean and Obese JCR:LA-Corpulent Rats

Journal of Obesity ◽

10.1155/2012/650193 ◽

2012 ◽

Vol 2012 ◽

pp. 1-7 ◽

Cited By ~ 2

Author(s):

Raylene A. Reimer ◽

Jeremy M. LaMothe ◽

Ronald F. Zernicke

Keyword(s):

Mechanical Properties ◽

Leptin Receptor ◽

Lumbar Vertebrae ◽

Insulin Resistance Syndrome ◽

Proportional Limit ◽

Leptin Signaling ◽

Bone Mechanical Properties ◽

Geometrical Properties ◽

Leptin Deficiency ◽

Obese Rats

Leptin signaling deficient rodents have emerged as models of obesity/insulin resistance syndrome. Altered leptin signaling, however, can affect axial and appendicular bone geometrical properties differently, and, thus, we hypothesized that leptin-deficiency would differentially influence mechanical properties of vertebrae and tibiae compared to lean rats. Mature (9 mo) leptin receptor deficient obese (cp/cp;n=8) and lean (+/?;n=7) male JCR:LA-corpulent rats were used to test that hypothesis. Tibiae and the sixth lumbar vertebrae(L6)were scanned with micro-CT and were broken in three point-bending (tibiae) or axial loading(L6). Supporting the hypothesis, vertebrae and tibiae were differentially affected by leptin signaling deficiency. Tibiae, but not vertebrae, were significantly shorter in obese rats and achieved a significantly greater load (>18%), displacement (>15%), and stress (>18%) at the proportional limit, relative to the lean rats. Conversely,L6in obese rats had significantly reduced displacement (>25%) and strain (>32%) at proportional limit, relative to the lean rats. Those combined results suggest that the etiology and duration of obesity may be important determinants of bone mechanical properties, and axial and appendicular bones may be affected differently.

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Sleep-wake regulation is altered in leptin-resistant (db/db) genetically obese and diabetic mice

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00026.2008 ◽

2008 ◽

Vol 295 (6) ◽

pp. R2059-R2066 ◽

Cited By ~ 79

Author(s):

A. D. Laposky ◽

M. A. Bradley ◽

D. L. Williams ◽

J. Bass ◽

F. W. Turek

Keyword(s):

Energy Metabolism ◽

Eye Movement ◽

Energy Homeostasis ◽

Leptin Receptor ◽

Sleep Time ◽

Rapid Eye Movement ◽

Sleep Regulation ◽

Compensatory Response ◽

Leptin Signaling ◽

Obesity And Diabetes

Recent epidemiological and clinical studies indicate that the control of sleep-wake states may be an important factor in the regulation of energy metabolism. Leptin is a peripherally synthesized hormone that has critical signaling properties in the brain for the control of long-term energy homeostasis. In this study, we examined the hypothesis that leptin signaling exerts a role in sleep-wake regulation and that leptin may represent an important mechanistic link in the coordination of sleep-wake states and metabolism. Sleep-wake patterns were recorded in a genetic mouse model of obesity and diabetes, the db/db mouse, which harbors a mutation in a particular isoform of the leptin receptor (long form, LRb). We found that db/db mice exhibit a variety of alterations in sleep regulation, including an increase in overall sleep time, a dramatic increase in sleep fragmentation, attenuated diurnal rhythmicity in rapid eye movement sleep and non-rapid eye movement EEG delta power (a measure of sleep homeostatic drive), and a decrease in the compensatory response to acute (i.e., 6 h) sleep deprivation. The db/db mice also generated low amounts of locomotor activity and a reduction in the diurnal rhythm of activity. These results indicate that impaired leptin signaling has deleterious effects on the regulation of sleep amount, sleep architecture, and temporal consolidation of these arousal states. In summary, leptin may represent an important molecular component in the integration of sleep, circadian rhythms, and energy metabolism.

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Amylin and Leptin Signaling Converge on Leptin Receptor Neurons of the Nucleus of the Solitary Tract and the Lateral Parabrachial Nucleus in the Murine Brain

Gastroenterology ◽

10.1016/s0016-5085(11)61312-7 ◽

2011 ◽

Vol 140 (5) ◽

pp. S-324

Author(s):

Michael Rajala ◽

Christa Patterson ◽

Martin Myers

Keyword(s):

Leptin Receptor ◽

Parabrachial Nucleus ◽

Solitary Tract ◽

Leptin Signaling ◽

Lateral Parabrachial Nucleus ◽

Receptor Neurons ◽

Murine Brain

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

Journal of Animal Science ◽

10.1093/jas/skz258.727 ◽

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.

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Obesity-prone rats have normal blood-brain barrier transport but defective central leptin signaling before obesity onset

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00393.2003 ◽

2004 ◽

Vol 286 (1) ◽

pp. R143-R150 ◽

Cited By ~ 163

Author(s):

Barry E. Levin ◽

Ambrose A. Dunn-Meynell ◽

William A. Banks

Keyword(s):

Blood Brain Barrier ◽

Leptin Receptor ◽

Nucleus Tractus Solitarius ◽

High Energy ◽

Brain Barrier ◽

Leptin Signaling ◽

Caloric Density ◽

Diet Induced Obesity ◽

Blood Brain ◽

Arcuate Nuclei

Rats selectively bred to develop diet-induced obesity (DIO) were compared with those bred to be diet resistant (DR) on a 31% fat high-energy diet with regard to their central leptin signaling and blood-brain barrier (BBB) transport. Peripheral leptin injection (15 mg/kg ip) into lean 4- to 5-wk-old rats produced 54% less anorexia in DIO than DR rats. DIO rats also had 21, 63, and 64% less leptin-induced immunoreactive phosphorylated signal transducer and activator of transcription 3 (pSTAT3) expression in the hypothalamic arcuate, ventromedial, and dorsomedial nuclei, respectively. However, hindbrain leptin-induced nucleus tractus solitarius pSTAT3 and generalized sympathetic (24-h urine norepinephrine) activation were comparable. Reduced central leptin signaling was not due to defective BBB transport since transport did not differ between lean 4- to 5-wk-old DIO and DR rats. Conversely, DIO leptin BBB transport was reduced when they became obese at 23 wk of age on low-fat chow or after 6 wk on high-energy diet. In addition, leptin receptor mRNA expression was 23% lower in the arcuate nuclei of 4- to 5-wk-old DIO compared with DR rats. Thus a preexisting reduction in hypothalamic but not brain stem leptin signaling might contribute to the development of DIO when dietary fat and caloric density are increased. Defects in leptin transport appear to be an acquired defect associated with the development of obesity and possibly age.

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