MC4R agonism promotes durable weight loss in patients with leptin receptor deficiency

2018 ◽  
Author(s):  
Clément K ◽  
Biebermann H ◽  
Farooqi IS ◽  
Van der Ploeg L ◽  
Wolters B ◽  
...  
Keyword(s):  
Weight Loss ◽  
Leptin Receptor

scholarly journals Intranasal Leptin Reduces Appetite and Induces Weight Loss in Rats with Diet-Induced Obesity (DIO)

Endocrinology ◽  
2012 ◽  
Vol 153 (1) ◽  
pp. 143-153 ◽  
Author(s):  
Carla Schulz ◽  
Kerstin Paulus ◽  
Olaf Jöhren ◽  
Hendrik Lehnert
Keyword(s):  
Weight Loss ◽  
Leptin Receptor ◽  
Serum Insulin ◽  
Standard Diet ◽  
Altered Expression ◽  
Diet Induced Obesity ◽  
Before And After ◽  
Altered Expression Pattern ◽  
Male Wistar Rats ◽  
Treatment Of Obesity

Resistance to brain-mediated effects of leptin is a characteristic feature of obesity, resulting from alterations in leptin receptor signaling in hypothalamic neurons and/or transport across the blood-brain-barrier. We have shown previously, that the latter can be circumvented by intranasal (i.n.) application of leptin in lean rats. This prompted us to test i.n. leptin in animals with diet-induced obesity (DIO) as a basis for future human administration. DIO was induced in male Wistar rats by feeding a cafeteria diet for 25 or 32 wk, respectively. Consecutively, these DIO animals (seven to eight per treatment) and standard diet rats (lean) (14–15 per treatment, matched for age and diet duration) were treated with 0.1, 0.2 mg/kg leptin, or control solution i.n. daily for 4 wk before onset of dark period. Energy intake and body weight were measured daily; blood glucose, serum insulin, and leptin were measured before and after treatment. Expression of hypothalamic neuropeptides was assessed by quantitative real-time PCR. We demonstrate, for the first time, that i.n. leptin reduces appetite and induces weight loss in DIO to the same extent as in lean rats. Our findings are supported accordingly by an altered expression pattern of anorexigenic and orexigenic neuropeptides in the hypothalamus, e.g. proopiomelanocortin, cocaine and amphetamine-related transcript, neuropeptide Y, agouti-related protein. It now appears clear that i.n. leptin is effectively acting in obese animals in the same fashion as in their lean counterparts. These findings now clearly warrant studies in humans and may open new perspectives in the treatment of obesity.

scholarly journals Intact Leptin Receptor Signalling is not Required for the Sustained Weight Loss and Appetite Suppression Induced by Roux-en-Y Gastric Bypass Surgery

2021 ◽  
Author(s):  
Mohammed K. Hankir ◽  
Laura Rotzinger ◽  
Arno Nordbeck ◽  
Caroline Corteville ◽  
Annett Hoffmann ◽  
...  
Keyword(s):  
Weight Loss ◽  
Gastric Bypass ◽  
Body Weight ◽  
Food Intake ◽  
Glucose Tolerance ◽  
Leptin Receptor ◽  
Oral Glucose ◽  
Oral Glucose Tolerance ◽  
Sustained Weight Loss ◽  
Obese Rats

Leptin is the archetypal adipokine that promotes a negative whole-body energy balance largely through its action on brain leptin receptors. As such, the sustained weight loss and food intake suppression induced by Roux-en-Y gastric bypass (RYGB) surgery have been attributed to enhancement of endogenous leptin action. We formally revisited this idea in Zucker Fatty fa/fa rats, an established genetic model of leptin receptor deficiency, and carefully compared their body weight, food intake and oral glucose tolerance after RYGB with that of sham-operated fa/fa (obese) and sham-operated fa/+ (lean) rats. We found that RYGB rats sustainably lost body weight, which converged with that of lean rats and was 25.5 % lower than that of obese rats by the end of the 4 week study period. Correspondingly, daily food intake of RYGB rats was similar to that of lean rats from the second postoperative week, while it was always at least 33.9 % lower than that of obese rats. Further, oral glucose tolerance of RYGB rats was normalized at the forth postoperative week. These findings assert that leptin is not an essential mediator of the sustained weight loss and food intake suppression as well as the improved glycemic control induced by RYGB, and instead point to additional circulating and/or neural factors.

Leptin Receptor Lys656Asn Polymorphism Is Associated with Decreased Leptin Response and Weight Loss Secondary to a Lifestyle Modification in Obese Patients

2006 ◽  
Vol 37 (7) ◽  
pp. 854-859 ◽  
Author(s):  
Daniel de Luis Roman ◽  
Rocio Aller de la Fuente ◽  
Manuel Gonzalez Sagrado ◽  
Olatz Izaola ◽  
Rosa Conde Vicente
Keyword(s):  
Weight Loss ◽  
Leptin Receptor ◽  
Lifestyle Modification ◽  
Obese Patients

MC4R agonism promotes durable weight loss in patients with leptin receptor deficiency

2018 ◽  
Vol 24 (5) ◽  
pp. 551-555 ◽  
Author(s):  
Karine Clément ◽  
Heike Biebermann ◽  
I. Sadaf Farooqi ◽  
Lex Van der Ploeg ◽  
Barbara Wolters ◽  
...  
Keyword(s):  
Weight Loss ◽  
Leptin Receptor

Changes in Oxidized Low-Density Lipoprotein Rather Than in Paraoxonase1 are Associated with Changes in the Leptin/Leptin Receptor Ratio in Obese Children During Weight-Loss Therapy

2018 ◽  
Vol 127 (05) ◽  
pp. 267-275 ◽  
Author(s):  
Joanna Gajewska ◽  
Magdalena Chełchowska ◽  
Jadwiga Ambroszkiewicz ◽  
Agnieszka Riahi ◽  
Halina Weker ◽  
...  
Keyword(s):  
Weight Loss ◽  
Leptin Receptor ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Low Density ◽  
Z Score ◽  
Oxidized Low Density Lipoprotein ◽  
Obese Children ◽  
Score Change ◽  
R Ratio

Abstract Background Oxidative stress and impaired production of adipokines in childhood obesity contribute to the development of obesity-related disorders. We assessed whether weight loss after lifestyle intervention alters biomarkers of oxidant/antioxidant status, and whether these alterations are associated with changes in anthropometric parameters and adipokines in obese children. Materials and Methods We determined oxidized low-density lipoprotein (ox-LDL), anti ox-LDL, paraoxonase1 (PON1), leptin, soluble leptin receptor (sOB-R), total adiponectin, high molecular weight adiponectin concentrations and body composition (by dual-energy X-ray absorptiometry) in 60 prepubertal obese children (Body Mass Index, BMI Z-score>2) before and after a 3-month intervention. The control group consisted of 44 non-obese children (BMI Z-score<−1+1>). Results Ox-LDL, ox-LDL/LDL, and anti ox-LDL concentrations as well as leptin to sOb-R ratio were reduced (p<0.001; p=0.018; p<0.001; p<0.001, respectively) in obese children with weight loss (BMI Z-score change≤−0.5) after a 3-month therapy. These parameters were stable in the obese group without weight loss (BMI Z-score change>−0.5). Changes in ox-LDL and PON1 levels in all obese children correlated positively with changes in the leptin to sOB-R ratio (r=0.400, p=0.002; r=0.304, p=0.028, respectively). After adjustment for changes in BMI Z-score in the multivariate regression model, the association between the changes in ox-LDL levels and changes in the leptin/sOb-R ratio remained statistically significant (β=0.184, p=0.014). Conclusions We found out that a 3-month lifestyle intervention associated with weight loss improves the oxidant/antioxidant balance and promotes anti-atherogenic changes in prepubertal obese children in a way dependent on the alterations in the leptin to sOB-R ratio.

scholarly journals Xiaoyaosan Decoction Regulates Changes in Neuropeptide Y and Leptin Receptor in the Rat Arcuate Nucleus after Chronic Immobilization Stress

2012 ◽  
Vol 2012 ◽  
pp. 1-16 ◽  
Author(s):  
Shao-Xian Wang ◽  
Jia-Xu Chen ◽  
Guang-Xin Yue ◽  
Ming-Hua Bai ◽  
Mei-Jing Kou ◽  
...  
Keyword(s):  
Weight Loss ◽  
Food Intake ◽  
Neuropeptide Y ◽  
Chronic Stress ◽  
Arcuate Nucleus ◽  
Leptin Receptor ◽  
Bodyweight Loss ◽  
Stress Group ◽  
Regulatory Effects ◽  
Neuroendocrine Mechanism

The arcuate nucleus (ARC) in the basal of hypothalamus plays an important role in appetite regulation and energy balance. We sought to investigate the central neuroendocrine mechanism of appetite decrease and weight loss under chronic stress by observing the regulatory effects of Xiaoyaosan decoction in the expression of leptin receptor (ob-R) and neuropeptide Y (NPY) in the ARC. Our results showed that bodyweight and food intake of rats in the 21-day stress group increased slower than those of the normal group. Higher contents of Leptin andob-Rwere noted in the 21-day stress group compared with control rats, while NPY expression was not statistically different. Xiaoyaosan powder can significantly downregulate the contents of leptin andob-Rin the hypothalamus of stressed rats. These findings suggest that increase ofob-Rexpression in the ARC is possibly one key central neuroendocrine change for the somatic discomfort. Weight loss and decreased food intake in rats caused by the binding of leptin toob-Rin hypothalamus do not appear to utilize the NPY pathway. This study also suggests thatob-Rin the ARC may act as the target of Xiaoyaosan in regulating the symptoms such as appetite decrease and bodyweight loss under chronic stress.

scholarly journals Leptin Acts in the Periphery to Protect Thymocytes from Glucocorticoid-Mediated Apoptosis in the Absence of Weight Loss

Endocrinology ◽  
2008 ◽  
Vol 149 (10) ◽  
pp. 5209-5218 ◽  
Author(s):  
Robert N. Trotter-Mayo ◽  
Margo R. Roberts
Keyword(s):  
Weight Loss ◽  
Low Dose ◽  
Leptin Receptor ◽  
Additional Data ◽  
Wild Type ◽  
Double Positive ◽  
Cell Frequency ◽  
Thymic Atrophy ◽  
Leptin Receptors

Leptin is a member of the IL-6 cytokine family and is primarily produced by adipose tissue. At high enough concentration, leptin engages leptin receptors expressed in the hypothalamus that regulate a variety of functions, including induction of weight loss. Mice deficient in leptin (ob/ob) or leptin receptor (db/db) function exhibit thymic atrophy associated with a reduction in double-positive (DP) thymocytes. However, the mediator of such thymic atrophy remains to be identified, and the extent to which leptin acts in the periphery vs. the hypothalamus to promote thymocyte cellularity is unknown. In the present study, we first demonstrate that thymic cellularity and composition is fully restored in ob/ob mice subjected to adrenalectomy. Second, we observe that ob/ob mice treated with low-dose leptin peripherally but not centrally exhibit increased thymocyte cellularity in the absence of any weight loss or significant reduction in systemic corticosterone levels. Third, we demonstrate that reconstitution of db/db mice with wild-type bone marrow augments thymocyte cellularity and restores DP cell frequency despite elevated corticosterone levels. These and additional data support a mode of action whereby leptin acts in the periphery to reduce the sensitivity of DP thymocytes to glucocorticoid-mediated apoptosis in vivo. Strikingly, our data reveal that leptin’s actions on thymic cellularity in the periphery can be uncoupled from its anorectic actions in the hypothalamus.

scholarly journals Metformin increases hepatic leptin receptor and decreases steatosis in mice

2016 ◽  
Vol 230 (2) ◽  
pp. 227-237 ◽  
Author(s):  
Xuemei Tang ◽  
Jingwen Li ◽  
Wei Xiang ◽  
Ye Cui ◽  
Bin Xie ◽  
...  
Keyword(s):  
Gene Expression ◽  
Weight Loss ◽  
Fatty Acid Synthase ◽  
Leptin Receptor ◽  
Regulatory Element ◽  
Chow Diet ◽  
Insulin Sensitizer ◽  
Nonalcoholic Fatty Liver ◽  
Leptin Receptors ◽  
Leptin Sensitivity

In addition to the ascertained efficacy as antidiabetic drug, metformin is increasingly being used as weight-loss agent in obesity, and as insulin sensitizer in nonalcoholic fatty liver disease (NAFLD). However, the mechanisms underlying these effects are still incompletely understood. Emerging evidence suggest metformin as leptin sensitizer to mediate the weight-loss effect in the brain. In this study, we investigated effects of metformin on expression of leptin receptors in liver and kidney in mice. C57BL/6 mice were fed with chow diet (CD) or high-fat diet (HF) for 5months. Afterward, mice were treated with metformin (50mg/kg or 200mg/kg) for 15days. Metabolic parameters and hepatic gene expression were analyzed at the end of the treatment. We also tested the effects of metformin on plasma-soluble leptin receptor (sOB-R) levels in newly diagnosed type 2 diabetes mellitus (T2DM) patients, and assessed its effect on hepatosteatosis in mice. Results showed that metformin upregulates the expression of leptin receptors (OB-Ra, -Rb, -Rc, and -Rd) in liver but not kidney. The stimulation effect is dose-dependent in both chow and HF mice. Upregulation of OB-Rb, long signaling isoform, needs a relatively higher dose of metformin. This effect was paralleled by increased sOBR levels in mice and T2DM patients, and decreased hepatic triglyceride (TG) content and lipogenic gene expression, including sterol regulatory element-binding protein 1c (SREBP-1c), fatty acid synthase (FAS) and acetyl-CoA carboxylase-1 (ACC-1). Taken together, these data identify hepatic leptin receptor as target gene being upregulated by metformin which may enhance leptin sensitivity in liver to alleviate steatosis.

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.

Weight Loss Increases Soluble Leptin Receptor Levels and the Soluble Receptor Bound Fraction of Leptin

2002 ◽  
Vol 10 (7) ◽  
pp. 597-601 ◽  
Author(s):  
Markus Laimer ◽  
Christoph F. Ebenbichler ◽  
Susanne Kaser ◽  
Anton Sandhofer ◽  
Helmut Weiss ◽  
...  
Keyword(s):  
Weight Loss ◽  
Leptin Receptor ◽  
Soluble Receptor ◽  
Soluble Leptin Receptor
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