Peripheral oxytocin suppresses food intake and causes weight loss in diet-induced obese rats

Growing evidence suggests that oxytocin plays an important role in the regulation of energy balance and that central oxytocin administration induces weight loss in diet-induced obese (DIO) animals. To gain a better understanding of how oxytocin mediates these effects, we examined feeding and neuronal responses to oxytocin in animals rendered obese following exposure to either a high-fat (HFD) or low-fat diet (LFD). Our findings demonstrate that peripheral administration of oxytocin dose-dependently reduces food intake and body weight to a similar extent in rats maintained on either diet. Moreover, the effect of oxytocin to induce weight loss remained intact in leptin receptor-deficient Koletsky ( fa k/ fa k) rats relative to their lean littermates. To determine whether systemically administered oxytocin activates hindbrain areas that regulate meal size, we measured neuronal c-Fos induction in the nucleus of the solitary tract (NTS) and area postrema (AP). We observed a robust neuronal response to oxytocin in these hindbrain areas that was unexpectedly increased in rats rendered obese on a HFD relative to lean, LFD-fed controls. Finally, we report that repeated daily peripheral administration of oxytocin in DIO animals elicited a sustained reduction of food intake and body weight while preventing the reduction of energy expenditure characteristic of weight-reduced animals. These findings extend recent evidence suggesting that oxytocin circumvents leptin resistance and induces weight-loss in DIO animals through a mechanism involving activation of neurons in the NTS and AP, key hindbrain areas for processing satiety-related inputs.

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

10.20944/preprints202102.0243.v1 ◽

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.

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Level of satiety: in vitro energy metabolism in brain during hypophagic and hyperphagic body weight recovery

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.1989.257.6.r1322 ◽

1989 ◽

Vol 257 (6) ◽

pp. R1322-R1327 ◽

Cited By ~ 2

Author(s):

T. R. Kasser ◽

R. B. Harris ◽

R. J. Martin

Keyword(s):

Weight Loss ◽

Body Weight ◽

Fatty Acid ◽

Food Intake ◽

Fatty Acid Oxidation ◽

Glucose Oxidation ◽

Area Postrema ◽

Tube Feeding ◽

Acid Oxidation

Rates of in vitro glucose and fatty acid oxidation were examined in four brain sites during hypophagic and hyperphagic recovery of normal body weight. Rats were fed 40, 100, or 160% of normal intake, via gastric intubation, for 3 wk. Another group of rats was starved until body weight loss was equivalent to weight loss in 40%-fed rats. Groups of rats were killed at the conclusion of tube feeding or fasting and at specific periods during recovery of body weight. Brain sites examined were the ventrolateral hypothalamus (VLH), ventromedial hypothalamus (VMH), a caudal brain stem site encompassing the area postrema-nucleus of the solitary tract (AP-NTS), and cortex. During recovery, rats previously fed 160% of normal intake (anorectic) maintained low rates of VLH fatty acid oxidation and were hypophagic until most excess fat was depleted. Conversely, rats previously fed 40% of normal intake (hungry) maintained high rates of VLH fatty acid oxidation and were hyperphagic until most deficient fat was repleted. Rats previously starved maintained high rates of VLH fatty acid oxidation during hyperphagic recovery, although levels of VLH fatty acid oxidation and food intake were initially low on refeeding. Rates of glucose oxidation in the brain sites examined did not relate well to energy balance status and the needed adjustments in food intake. The results indicated that the level of glucose oxidation in the VLH and AP-NTS responded to the level of energy immediately coming into the system (food intake).(ABSTRACT TRUNCATED AT 250 WORDS)

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Protein tyrosine phosphatase-1B contributes to LPS-induced leptin resistance in male rats

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00094.2014 ◽

2015 ◽

Vol 308 (1) ◽

pp. E40-E50 ◽

Cited By ~ 9

Author(s):

Beatriz de Carvalho Borges ◽

Rodrigo C. Rorato ◽

Ernane Torres Uchoa ◽

Paula B. Marangon ◽

Carol F. Elias ◽

...

Keyword(s):

Body Weight ◽

Food Intake ◽

Leptin Receptor ◽

Tyrosine Phosphatase ◽

Body Weight Loss ◽

Male Rats ◽

Leptin Resistance ◽

Reduce Food Intake ◽

Low Grade ◽

Lps Treatment

Leptin resistance is induced by the feedback inhibitors tyrosine phosphatase-1B (PTP1B) and decreased Src homology 2 domain-containing tyrosine phosphatase-2 (SHP-2) signaling. To investigate the participation of PTP1B and SHP-2 in LPS-induced leptin resistance, we injected repeated (6-LPS) intraperitoneal LPS doses (100 μg/kg ip) for comparison with a single (1-LPS) treatment and evaluated the expression of SHP-2, PTP1B, p-ERK1/2, and p-STAT3 in the hypothalamus of male Wistar rats. The single LPS treatment increased the expression of p-STAT3 and PTP1B but not SHP-2. The repeated LPS treatment reduced SHP-2, increased PTP1B, and did not change p-STAT3. We observed that the PTP1B expression induced by the endotoxin was highly colocalized with leptin receptor cells in the hypothalamus of LepRb-IRES-Cre-tdTomato reporter mice. The single, but not the repeated, LPS treatment decreased the food intake and body weight. Leptin had no stimulatory effect on the hypophagia, body weight loss, or pSTAT3 expression in 6-LPS rats, indicating leptin unresponsiveness. Notably, the PTP1B inhibitor (3.0 nmol/rat in 5 μl icv) restored the LPS-induced hypophagia in 6-LPS rats and restored the ability of leptin to reduce food intake and body weight as well as to phosphorylate STAT3 in the arcuate, paraventricular, and ventromedial nuclei of the hypothalamus. The present data suggest that an increased PTP1B expression in the hypothalamus underlies the development of leptin resistance during repeated exposure to LPS. Our findings contribute to understanding the mechanisms involved in leptin resistance during low-grade inflammation as seen in obesity.

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Palmitoylated PrRP analog decreases body weight in DIO rats but not in ZDF rats

Journal of Endocrinology ◽

10.1530/joe-15-0519 ◽

2016 ◽

Vol 229 (2) ◽

pp. 85-96 ◽

Cited By ~ 12

Author(s):

Martina Holubová ◽

Jana Zemenová ◽

Barbora Mikulášková ◽

Vladimíra Panajotova ◽

Jiří Stöhr ◽

...

Keyword(s):

Body Weight ◽

Food Intake ◽

Glucose Tolerance ◽

Leptin Receptor ◽

Leptin Resistance ◽

Dependent Manner ◽

Sprague Dawley ◽

Obesity And Diabetes ◽

Diabetes Diet ◽

Zdf Rats

Anorexigenic neuropeptides produced and acting in the brain have the potential to decrease food intake and ameliorate obesity, but are ineffective after peripheral application, owing to a limited ability to cross the blood–brain barrier. We have designed lipidized analogs of prolactin-releasing peptide (PrRP), which is involved in energy balance regulation as demonstrated by obesity phenotypes of bothPrrp-knockout andPrrpreceptor-knockout mice. The aim of this study was to characterize the subchronic effect of a palmitoylated PrRP analog in two rat models of obesity and diabetes: diet-induced obese Sprague–Dawley rats and leptin receptor-deficient Zucker diabetic (ZDF) rats. In the rats with diet-induced obesity (DIO), a two-week intraperitoneal treatment with palmitoylated PrRP lowered food intake by 24% and body weight by 8%. This treatment also improved glucose tolerance and tended to decrease leptin levels and adipose tissue masses in a dose-dependent manner. In contrast, in ZDF rats, the same treatment with palmitoylated PrRP lowered food intake but did not significantly affect body weight or glucose tolerance, probably in consequence of severe leptin resistance due to a nonfunctional leptin receptor. Our data indicate a good efficacy of lipidized PrRP in DIO rats. Thus, the strong anorexigenic, body weight-reducing, and glucose tolerance-improving effects make palmitoylated PrRP an attractive candidate for anti-obesity treatment.

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Role of neonatal hyperleptinaemia on serum adiponectin and suppressor of cytokine signalling-3 expression in young rats

British Journal Of Nutrition ◽

10.1017/s0007114508006521 ◽

2008 ◽

Vol 101 (2) ◽

pp. 250-256 ◽

Cited By ~ 18

Author(s):

Magna Cottini Fonseca Passos ◽

Fabiane Pereira Toste ◽

Sheila Cristina Potente Dutra ◽

Paula Affonso Trotta ◽

Fernanda Pereira Toste ◽

...

Keyword(s):

Insulin Resistance ◽

Body Weight ◽

Food Intake ◽

Leptin Receptor ◽

Serum Insulin ◽

Leptin Resistance ◽

Serum Adiponectin ◽

Lower Serum ◽

Serum Adiponectin Concentration

Previously we had shown that neonatal leptin treatment programmes for both hyperleptinaemia and hyperinsulinaemia, which lead to leptin resistance and low expression of the hypothalamic leptin receptor (OB-Rb) of rats aged 150 d. Here we investigated in young post-weaned rats (age 30 d) if leptin treatment during lactation induces leptin and insulin resistance and if those changes are accompanied by changes in the suppressor of cytokine signalling-3 (SOCS-3) expression and serum adiponectin concentration. After delivery, the pups were divided into two groups: (1) a leptin group (Lep) that were injected with leptin daily (8 μg/100 g body weight subcutaneously) for the first 10 d of lactation; (2) a control (C) group, receiving saline. After weaning (day 21), body weight was monitored until the animals were age 30 d. They were tested for food intake in response to either leptin (0·5 mg/kg body weight intraperitoneally) (CL, LepL) or saline (CSal, LepSal) when they were aged 30 d. The CL group showed lower food intake, but no response was observed in the LepL group, suggesting leptin resistance. The Lep group had hyperleptinaemia (five-fold), hyperinsulinaemia (+42·5 %) and lower levels of serum adiponectin ( − 43·2 %). The hypothalamic expression of OB-Rb was lower ( − 22 %) and SOCS-3 was higher (+52·8 %) in the Lep group. We conclude that neonatal leptin treatment programmes for leptin resistance as soon as 30 d and suggests that SOCS-3 appears to be of particular importance in this event. In the Lep group, the lower serum adiponectin levels were accompanied by higher serum insulin, indicating a probable insulin resistance.

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Neonatal leptin treatment programmes leptin hypothalamic resistance and intermediary metabolic parameters in adult rat

British Journal Of Nutrition ◽

10.1079/bjn20061726 ◽

2006 ◽

Vol 95 (4) ◽

pp. 830-837 ◽

Cited By ~ 68

Author(s):

Fabiane Pereira Toste ◽

Egberto Gaspar de Moura ◽

Patrícia Cristina Lisboa ◽

Aline Teixeira Fagundes ◽

Elaine de Oliveira ◽

...

Keyword(s):

Body Weight ◽

Food Intake ◽

Leptin Receptor ◽

The Body ◽

Leptin Resistance ◽

Control Group ◽

Adult Rats ◽

Leptin Receptors ◽

Adult Rat ◽

Anorectic Effect

We previously showed that neonatal leptin treatment programmes higher body weight and food intake in adult rats. Here we investigate whether leptin treatment during lactation affects the anorectic effect of leptin on adult rats and their hypothalamic leptin receptors (OB-Rb) and whether those changes could have consequences on intermediary metabolism. When the offspring were born, pups were divided into two groups: the Lep group, injected daily with leptin (8μg/100g body weight, subcutaneously) for the first 10d of lactation, and the control group, injected daily with saline. After weaning (day 21), body weight and food intake were monitored until the rats were 150d old. Food intake was higher in the Lep group (approximately 14%, p<0·05) from day 133 onwards, and body weight was higher (approximately 10%, p<0·05) from day 69 onwards, compared with the control group. At 150d of age, the rats were tested for food intake in response to either leptin (05mg/kg body weight intraperitoneally; groups CL and LepL) or saline (groups CSal and LepSal). The CL group showed a decrease in food intake, but no response was observed in the LepL group, suggesting leptin resistance. The Lep group demonstrated a decrease in OB-Rb expression (−40% p<0·05), hyperleptinaemia (+78%, p<0·05), hyperinsulinaemia (+100%, p<0·02), hypertriacylglycerolaemia (+17%, p<0·05) and a higher protein content in the body (+16%, p<0·05) without changes in fat mass and glycaemia. We conclude that neonatal leptin treatment programmes both hyperleptinaemia and hyperinsulinaemia in adulthood, which leads to leptin resistance by reducing the expression of the hypothalamic leptin receptor.

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High Intakes of [6S]-5-Methyltetrahydrofolic Acid Compared with Folic Acid during Pregnancy Programs Central and Peripheral Mechanisms Favouring Increased Food Intake and Body Weight of Mature Female Offspring

Nutrients ◽

10.3390/nu13051477 ◽

2021 ◽

Vol 13 (5) ◽

pp. 1477

Author(s):

Emanuela Pannia ◽

Rola Hammoud ◽

Ruslan Kubant ◽

Jong Yup Sa ◽

Rebecca Simonian ◽

...

Keyword(s):

Body Weight ◽

Folic Acid ◽

Food Intake ◽

Leptin Receptor ◽

Liver Weight ◽

Female Offspring ◽

Mature Female ◽

Cytokine Signaling ◽

Light Cycle ◽

Energy Regulation

Supplementation with [6S]-5-methyltetrahydrofolic acid (MTHF) is recommended as an alternative to folic acid (FA) in prenatal supplements. This study compared equimolar gestational FA and MTHF diets on energy regulation of female offspring. Wistar rats were fed an AIN-93G diet with recommended (2 mg/kg diet) or 5-fold (5X) intakes of MTHF or FA. At weaning, female offspring were fed a 45% fat diet until 19 weeks. The 5X-MTHF offspring had higher body weight (>15%), food intake (8%), light-cycle energy expenditure, and lower activity compared to 5X-FA offspring (p < 0.05). Both the 5X offspring had higher plasma levels of the anorectic hormone leptin at birth (60%) and at 19 weeks (40%), and lower liver weight and total liver lipids compared to the 1X offspring (p < 0.05). Hypothalamic mRNA expression of leptin receptor (ObRb) was lower, and of suppressor of cytokine signaling-3 (Socs3) was higher in the 5X-MTHF offspring (p < 0.05), suggesting central leptin dysregulation. In contrast, the 5X-FA offspring had higher expression of genes encoding for dopamine and GABA- neurotransmitter receptors (p < 0.01), consistent with their phenotype and reduced food intake. When fed folate diets at the requirement level, no differences were found due to form in the offspring. We conclude that MTHF compared to FA consumed at high levels in the gestational diets program central and peripheral mechanisms to favour increased weight gain in the offspring. These pre-clinical findings caution against high gestational intakes of folates of either form and encourage clinical trials examining their long-term health effects when consumed during pregnancy.

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GPR40 reduces food intake and body weight through GLP-1

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00435.2016 ◽

2017 ◽

Vol 313 (1) ◽

pp. E37-E47 ◽

Cited By ~ 16

Author(s):

Judith N. Gorski ◽

Michele J. Pachanski ◽

Joel Mane ◽

Christopher W. Plummer ◽

Sarah Souza ◽

...

Keyword(s):

Weight Loss ◽

Body Weight ◽

Food Intake ◽

Partial Agonist ◽

Glucose Lowering ◽

Partial Agonists ◽

Lower Glucose ◽

Glucagon Like Peptide 1 ◽

Glucose Stimulated Insulin Secretion ◽

G Protein Coupled

G protein-coupled receptor 40 (GPR40) partial agonists lower glucose through the potentiation of glucose-stimulated insulin secretion, which is believed to provide significant glucose lowering without the weight gain or hypoglycemic risk associated with exogenous insulin or glucose-independent insulin secretagogues. The class of small-molecule GPR40 modulators, known as AgoPAMs (agonist also capable of acting as positive allosteric modulators), differentiate from partial agonists, binding to a distinct site and functioning as full agonists to stimulate the secretion of both insulin and glucagon-like peptide-1 (GLP-1). Here we show that GPR40 AgoPAMs significantly increase active GLP-1 levels and reduce acute and chronic food intake and body weight in diet-induced obese (DIO) mice. These effects of AgoPAM treatment on food intake are novel and required both GPR40 and GLP-1 receptor signaling pathways, as demonstrated in GPR40 and GLP-1 receptor-null mice. Furthermore, weight loss associated with GPR40 AgoPAMs was accompanied by a significant reduction in gastric motility in these DIO mice. Chronic treatment with a GPR40 AgoPAM, in combination with a dipeptidyl peptidase IV inhibitor, synergistically decreased food intake and body weight in the mouse. The effect of GPR40 AgoPAMs on GLP-1 secretion was recapitulated in lean, healthy rhesus macaque demonstrating that the putative mechanism mediating weight loss translates to higher species. Together, our data indicate effects of AgoPAMs that go beyond glucose lowering previously observed with GPR40 partial agonist treatment with additional potential for weight loss.

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