Roux-en-Y Gastric Bypass and Caloric Restriction but Not Gut Hormone-Based Treatments Profoundly Impact the Hypothalamic Transcriptome in Obese Rats

Background: The hypothalamus is an important brain region for the regulation of energy balance. Roux-en-Y gastric bypass (RYGB) surgery and gut hormone-based treatments are known to reduce body weight, but their effects on hypothalamic gene expression and signaling pathways are poorly studied. Methods: Diet-induced obese male Wistar rats were randomized into the following groups: RYGB, sham operation, sham + body weight-matched (BWM) to the RYGB group, osmotic minipump delivering PYY3-36 (0.1 mg/kg/day), liraglutide s.c. (0.4 mg/kg/day), PYY3-36 + liraglutide, and saline. All groups (except BWM) were kept on a free choice of high- and low-fat diets. Four weeks after interventions, hypothalami were collected for RNA sequencing. Results: While rats in the RYGB, BWM, and PYY3-36 + liraglutide groups had comparable reductions in body weight, only RYGB and BWM treatment had a major impact on hypothalamic gene expression. In these groups, hypothalamic leptin receptor expression as well as the JAK–STAT, PI3K-Akt, and AMPK signaling pathways were upregulated. No significant changes could be detected in PYY3-36 + liraglutide-, liraglutide-, and PYY-treated groups. Conclusions: Despite causing similar body weight changes compared to RYGB and BWM, PYY3-36 + liraglutide treatment does not impact hypothalamic gene expression. Whether this striking difference is favorable or unfavorable to metabolic health in the long term requires further investigation.

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Acute food deprivation and chronic food restriction differentially affect hypothalamic NPY mRNA expression

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00734.2002 ◽

2003 ◽

Vol 285 (5) ◽

pp. R1030-R1036 ◽

Cited By ~ 142

Author(s):

Sheng Bi ◽

Benjamin M. Robinson ◽

Timothy H. Moran

Keyword(s):

Gene Expression ◽

Body Weight ◽

Food Deprivation ◽

Food Restriction ◽

Leptin Receptor ◽

Receptor Gene ◽

Body Weight Loss ◽

Receptor Expression ◽

Mrna Levels ◽

Chronic Food Restriction

Although acute food deprivation and chronic food restriction both result in body weight loss, they produce different metabolic states. To evaluate how these two treatments affect hypothalamic peptide systems involved in energy homeostasis, we compared patterns of hypothalamic neuropeptide Y (NPY), agouti-related protein (AgRP), proopiomelanocotin (POMC), and leptin receptor gene expression in acutely food-deprived and chronically food-restricted rats. Both acute food deprivation and chronic food restriction reduced body weight and circulating leptin levels and resulted in increased arcuate NPY and decreased arcuate POMC gene expression. Arcuate AgRP mRNA levels were only elevated in acutely deprived rats. NPY gene expression was increased in the compact subregion of the dorsomedial hypothalamus (DMH) in response to chronic food restriction, but not in response to acute food deprivation. Leptin receptor expression was not affected by either treatment. Double in situ hybridization histochemistry revealed that, in contrast to the situation in the arcuate nucleus, NPY and leptin receptor mRNA-expressing neurons were not colocalized in the DMH. Together, these data suggest that arcuate and DMH NPY gene expression are differentially regulated. DMH NPY-expressing neurons do not appear to be under the direct control of leptin signaling.

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Circulating hormones and hypothalamic energy balance: regulatory gene expression in the Lou/C and Wistar rats

Journal of Endocrinology ◽

10.1677/joe.1.06576 ◽

2006 ◽

Vol 190 (3) ◽

pp. 571-579 ◽

Cited By ~ 11

Author(s):

Sharon E Mitchell ◽

Ruben Nogueiras ◽

Kellie Rance ◽

D Vernon Rayner ◽

Sharon Wood ◽

...

Keyword(s):

Gene Expression ◽

Body Weight ◽

Energy Balance ◽

Wistar Rats ◽

Leptin Receptor ◽

Regulatory Gene ◽

Receptor Expression ◽

Ghrelin Receptor ◽

Mrna Induction ◽

Plasma Leptin

To ascertain the mechanisms underlying low caloric intake and low body weight in the Lou/C rat, the circulating hormone levels and gene expression of hypothalamic peptides and receptors important in energy balance and the induction of suppressor of cytokine signalling 3 (SOCS3) gene expression in response to leptin challenge were compared with Wistar rats. Plasma leptin levels were lower in the Lou/C rat, as were levels of rat corticosterone, TSH and T4 but not T3. Ghrelin levels were higher in the Lou/C rat. Total leptin receptor (Ob-R) and the long form of the leptin receptor (Ob-Rb) gene expression were lower in the arcuate (ARC) and ventromedial nuclei (VMN) in Lou/C rat. Ghrelin receptor expression in the ARC and VMN was lower in Lou/C than in Wistar rats. However, agouti gene-related peptide (AgRP) and neuropeptide Y (NPY) gene expression were higher in the Lou/C rat. There was no difference in the level of cocaine- and amphetamine-regulated transcript gene expression in the ARC, but both were higher in the paraventricular nuclei of the Lou/C breed. There was no difference in Ob-R gene expression in, or [125I]leptin binding to, the choroid plexus. SOCS3 mRNA induction in response to leptin was lower in the Lou/C rat. This study reveals that the comparatively low plasma leptin, TSH and T4 levels, and high ghrelin levels together with high levels of AgRP and NPY gene expression seen in the Lou/C rat are indicative of a strong drive to eat and decreased energy expenditure, which are in direct opposition to the comparatively low body weight and adiposity of this rat strain.

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Maternal low-protein diet programmes offspring growth in association with alterations in yolk leptin deposition and gene expression in yolk-sac membrane, hypothalamus and muscle of developing Langshan chicken embryos

British Journal Of Nutrition ◽

10.1017/s0007114509276434 ◽

2009 ◽

Vol 102 (6) ◽

pp. 848-857 ◽

Cited By ~ 25

Author(s):

Kaiqing Rao ◽

Jingjing Xie ◽

Xiaojing Yang ◽

Lei Chen ◽

Roland Grossmann ◽

...

Keyword(s):

Gene Expression ◽

Body Weight ◽

Leptin Receptor ◽

Pectoralis Major Muscle ◽

Yolk Sac ◽

Pectoralis Major ◽

The Body ◽

Low Protein ◽

Igf I ◽

Offspring Growth

The present study was aimed to investigate the mechanism underlying the influence of maternal low-protein (LP) diet on offspring growth in the chicken. One hundred and twenty Chinese inbred Langshan breeder hens were allocated randomly into two groups fed diets containing low (10 %, LP) or normal (15 %) crude protein levels. Low dietary protein did not affect the body weight of hens, but significantly decreased the laying rate and egg weight. The yolk leptin content was significantly lower in eggs laid by LP hens, while no differences were detected for yolk contents of corticosterone, tri-iodothyronine (T3) or thyroxine. Despite significantly lower hatch weight, the LP offspring demonstrated obviously higher serum T3 concentration, which is in accordance with the faster post-hatch growth rate achieving significantly heavier body weight and pectoralis major muscle weight 4 weeks post-hatching. Expression of 20-hydroxysteroid dehydrogenase (20-HSD) mRNA in the yolk-sac membrane was significantly down-regulated at embryonic day 14, whereas that of transthyretin and leptin receptor (LepR) was not altered. Moreover, hypothalamic expression of 20-HSD, glucocorticoid receptors, thyrotropin-releasing hormone and LepR mRNA was significantly up-regulated in the LP group compared with their control counterparts. In the pectoralis major muscle, significantly higher expression of insulin-like growth factor (IGF)-I and IGF-I receptor mRNA was observed in LP embryos. The present study provides evidence that maternal LP diet programmes post-hatch growth of the offspring. The associated alterations in yolk leptin deposition as well as in yolk-sac membrane, fetal hypothalamus and muscle gene expression may be involved in mediating such programming effect in the chicken.

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Leptin receptor-deficient obese Zucker rats reduce their food intake in response to hypobaric hypoxia

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00289.2005 ◽

2006 ◽

Vol 290 (3) ◽

pp. E591-E597 ◽

Cited By ~ 29

Author(s):

Nadine Simler ◽

Alexandra Grosfeld ◽

André Peinnequin ◽

Michèle Guerre-Millo ◽

André-Xavier Bigard

Keyword(s):

Gene Expression ◽

Body Weight ◽

Adipose Tissue ◽

Food Intake ◽

Hypobaric Hypoxia ◽

Leptin Receptor ◽

Zucker Rats ◽

Hypoxia Exposure ◽

Obese Rats ◽

Hypothalamic Neuropeptides

Exposure to hypoxia induces anorexia in humans and rodents, but the role of leptin remains under discussion and that of orexigenic and anorexigenic hypothalamic neuropeptides remains unknown. The present study was designed to address this issue by using obese (Leprfa/Leprfa) Zucker rats, a rat model of genetic leptin receptor deficiency. Homozygous lean (LeprFA/LeprFA) and obese (Leprfa/Leprfa) rats were randomly assigned to two groups, either kept at ambient pressure or exposed to hypobaric hypoxia for 1, 2, or 4 days (barometric pressure, 505 hPa). Food intake and body weight were recorded throughout the experiment. The expression of leptin and vascular endothelial growth factor (VEGF) genes was studied in adipose tissue with real-time quantitative PCR and that of selected orexigenic and anorexigenic neuropeptides was measured in the hypothalamus. Lean and obese rats exhibited a similar hypophagia (38 and 67% of initial values at day 1, respectively, P < 0.01) and initial decrease in body weight during hypoxia exposure. Hypoxia led to increased plasma leptin levels only in obese rats. This resulted from increased leptin gene expression in adipose tissue in response to hypoxia, in association with enhanced VEGF gene expression. Increased hypothalamic neuropeptide Y levels in lean rats 2 days after hypoxia exposure contributed to accounting for the enhanced food consumption. No significant changes occurred in the expression of other hypothalamic neuropeptides involved in the control of food intake. This study demonstrates unequivocally that altitude-induced anorexia cannot be ascribed to anorectic signals triggered by enhanced leptin production or alterations of hypothalamic neuropeptides involved in anabolic or catabolic pathways.

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Liraglutide, a GLP-1 Receptor Agonist, Which Decreases Hypothalamic 5-HT2A Receptor Expression, Reduces Appetite and Body Weight Independently of Serotonin Synthesis in Mice

Journal of Diabetes Research ◽

10.1155/2018/6482958 ◽

2018 ◽

Vol 2018 ◽

pp. 1-6 ◽

Cited By ~ 3

Author(s):

Katsunori Nonogaki ◽

Takao Kaji

Keyword(s):

Gene Expression ◽

Weight Loss ◽

Body Weight ◽

Receptor Agonist ◽

Tryptophan Hydroxylase ◽

Intraperitoneal Administration ◽

Body Weight Loss ◽

Receptor Activation ◽

The Body ◽

Receptor Expression

A recent report suggested that brain-derived serotonin (5-HT) is critical for maintaining weight loss induced by glucagon-like peptide-1 (GLP-1) receptor activation in rats and that 5-HT2A receptors mediate the feeding suppression and weight loss induced by GLP-1 receptor activation. Here, we show that changes in daily food intake and body weight induced by intraperitoneal administration of liraglutide, a GLP-1 receptor agonist, over 4 days did not differ between mice treated with the tryptophan hydroxylase (Tph) inhibitor p-chlorophenylalanine (PCPA) for 3 days and mice without PCPA treatment. Treatment with PCPA did not affect hypothalamic 5-HT2A receptor expression. Despite the anorexic effect of liraglutide disappearing after the first day of treatment, the body weight loss induced by liraglutide persisted for 4 days in mice treated with or without PCPA. Intraperitoneal administration of liraglutide significantly decreased the gene expression of hypothalamic 5-HT2A receptors 1 h after injection. Moreover, the acute anorexic effects of liraglutide were blunted in mice treated with the high-affinity 5-HT2A agonist (4-bromo-3,6-dimethoxybenzocyclobuten-1-yl) methylamine hydrobromide 14 h or 24 h before liraglutide injection. These findings suggest that liraglutide reduces appetite and body weight independently of 5-HT synthesis in mice, whereas GLP-1 receptor activation downregulates the gene expression of hypothalamic 5-HT2A receptors.

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Assessing the Association Between Fennel (Foeniculum vulgare) Extract and Serum Lipid Profile and Leptin Receptor Expression

Basic and Clinical Neuroscience Journal ◽

10.32598/bcn.2021.998.2 ◽

2021 ◽

Author(s):

Forogh Zakernezhad ◽

◽

Mahmood Barati ◽

Nima Sanadgol ◽

Monireh Movahedi ◽

...

Keyword(s):

Body Weight ◽

Lipid Profile ◽

Serum Lipid ◽

Leptin Receptor ◽

Receptor Expression ◽

Receptor Protein ◽

Herbal Extracts ◽

Foeniculum Vulgare ◽

Serum Leptin ◽

Significant Health

Introduction:Obesity is one of the most serious challenges of our era, with significant health consequences and high economic burden for health systems. Therefore, many countries have developed political agendas to cope with this ever-rising challenge. Along with chemical medications that are developed to manage obesity, researchers have focused on some natural ingredients and herbal extracts which are proved to be effective in reducing weight. The current study aimed to investigate the association between Foeniculum vulgar (fennel) extracts and body weight, lipid profile, and leptin. Methods: 35 adult male BALB/c mice were investigated, in sham, fennel 50 mg/kg, fennel 100 mg/kg, and fennel 200 mg/kg (n=7) groups. Mice were administered fennel extracts for fourteen days, while weighted at the beginning and the end of the intervention. Then, their weight, lipid profile, serum leptin, and expression of leptin protein in the hypothalamus were measured. Results: After providing the intervention, leptin receptor protein expression was increased in all groups, while serum leptin didn’t change significantly. Moreover, a significant decrease was observed in the cholesterol in the dose of 100 mg/kg/day, triglycerides in doses of 100 and 200 mg/kg/day, and LDL in doses of 50 and 100 mg/kg/day. Serum HDL was increased significantly in a dose of 100 mg/kg/day. Conclusion: Fennel extract can decrease the lipid profile by changing the expression of the leptin receptor.

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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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The PYY/Y2R-Deficient Mouse Responds Normally to High-Fat Diet and Gastric Bypass Surgery

10.20944/preprints201902.0100.v1 ◽

2019 ◽

Author(s):

Brandon Boland ◽

Michael B. Mumphrey ◽

Zheng Hao ◽

Benji Gill ◽

R. Leigh Townsend ◽

...

Keyword(s):

Gastric Bypass ◽

Body Composition ◽

Body Weight ◽

High Fat Diet ◽

Body Weight Loss ◽

Liver Weight ◽

Receptor Subtypes ◽

High Fat ◽

Knockout Mouse Model ◽

Gut Hormone

Background/Goals: The gut hormone PYY secreted from intestinal L-cells has been implicated in the mechanisms of satiation via Y2-receptor (Y2R) signaling in the brain and periphery and is a major candidate for mediating the beneficial effects of bariatric surgery on appetite and body weight. Methods: Here we assessed the role of Y2R signaling in the response to low- and high-fat diets and its role in the effects of Roux-en-Y gastric bypass (RYGB) surgery on body weight, body composition, food intake, energy expenditure and glucose handling, in global Y2R-deficient (Y2RKO) and wildtype mice made obese on high-fat diet. Results: Both male and female Y2RKO mice responded normally to low- and high-fat diet in terms of body weight, body composition, fasting levels of glucose and insulin, as well as glucose and insulin tolerance for up to 30 weeks of age. Contrary to expectations, obese Y2RKO mice also responded similarly to RYGB compared to WT mice for up to 20 weeks after surgery, with initial hypophagia, sustained body weight loss, and significant improvements in fasting insulin, glucose tolerance, HOMA-IR, and liver weight compared to sham-operated mice. Furthermore, non-surgical Y2RKO mice weight-matched to RYGB showed the same improvements in glycemic control as Y2RKO mice with RYGB that were similar to WT mice. Conclusions: PYY signaling through Y2R is not required for the normal appetite-suppressing and body weight-lowering effects of RYGB in this global knockout mouse model. Potential compensatory adaptations of PYY signaling through other receptor subtypes or other gut satiety hormones such as GLP-1 remain to be investigated.

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The PYY/Y2R-Deficient Mouse Responds Normally to High-Fat Diet and Gastric Bypass Surgery

Nutrients ◽

10.3390/nu11030585 ◽

2019 ◽

Vol 11 (3) ◽

pp. 585 ◽

Cited By ~ 6

Author(s):

Brandon Boland ◽

Michael Mumphrey ◽

Zheng Hao ◽

Benji Gill ◽

R. Townsend ◽

...

Keyword(s):

Gastric Bypass ◽

Body Composition ◽

Body Weight ◽

High Fat Diet ◽

Peptide Yy ◽

Body Weight Loss ◽

Receptor Subtypes ◽

High Fat ◽

Knockout Mouse Model ◽

Gut Hormone

Background/Goals: The gut hormone peptide YY (PYY) secreted from intestinal L-cells has been implicated in the mechanisms of satiation via Y2-receptor (Y2R) signaling in the brain and periphery and is a major candidate for mediating the beneficial effects of bariatric surgery on appetite and body weight. Methods: Here we assessed the role of Y2R signaling in the response to low- and high-fat diets and its role in the effects of Roux-en-Y gastric bypass (RYGB) surgery on body weight, body composition, food intake, energy expenditure and glucose handling, in global Y2R-deficient (Y2RKO) and wildtype (WT) mice made obese on high-fat diet. Results: Both male and female Y2RKO mice responded normally to low- and high-fat diet in terms of body weight, body composition, fasting levels of glucose and insulin, as well as glucose and insulin tolerance for up to 30 weeks of age. Contrary to expectations, obese Y2RKO mice also responded similarly to RYGB compared to WT mice for up to 20 weeks after surgery, with initial hypophagia, sustained body weight loss, and significant improvements in fasting insulin, glucose tolerance, insulin resistance (HOMA-IR), and liver weight compared to sham-operated mice. Furthermore, non-surgical Y2RKO mice weight-matched to RYGB showed the same improvements in glycemic control as Y2RKO mice with RYGB that were similar to WT mice. Conclusions: PYY signaling through Y2R is not required for the normal appetite-suppressing and body weight-lowering effects of RYGB in this global knockout mouse model. Potential compensatory adaptations of PYY signaling through other receptor subtypes or other gut satiety hormones such as glucagon-like peptide-1 (GLP-1) remain to be investigated.

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