Combined Deletion of Y1, Y2, and Y4 Receptors Prevents Hypothalamic Neuropeptide Y Overexpression-Induced Hyperinsulinemia despite Persistence of Hyperphagia and Obesity

Neuropeptide Y (NPY) is a key regulator of energy homeostasis and is implicated in the development of obesity and type 2 diabetes. Whereas it is known that hypothalamic administration of exogenous NPY peptides leads to increased body weight gain, hyperphagia, and many hormonal and metabolic changes characteristic of an obesity syndrome, the Y receptor(s) mediating these effects is disputed and unclear. To investigate the role of different Y receptors in the NPY-induced obesity syndrome, we used recombinant adeno-associated viral vector to overexpress NPY in mice deficient of selective single or multiple Y receptors (including Y1, Y2, and Y4). Results from this study demonstrated that long-term hypothalamic overexpression of NPY lead to marked hyperphagia, hypogonadism, body weight gain, enhanced adipose tissue accumulation, hyperinsulinemia, and other hormonal changes characteristic of an obesity syndrome. NPY-induced hyperphagia, hypogonadism, and obesity syndrome persisted in all genotypes studied (Y1−/−, Y2−/−, Y2Y4−/−, and Y1Y2Y4−/− mice). However, triple deletion of Y1, Y2, and Y4 receptors prevented NPY-induced hyperinsulinemia. These findings suggest that Y1, Y2, and Y4 receptors under this condition are not crucially involved in NPY’s hyperphagic, hypogonadal, and obesogenic effects, but they are responsible for the central regulation of circulating insulin levels by NPY.

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Early leptin blockade predisposes fat-fed rats to overweight and modifies hypothalamic microRNAs

Journal of Endocrinology ◽

10.1530/joe-12-0561 ◽

2013 ◽

Vol 218 (1) ◽

pp. 35-47 ◽

Cited By ~ 37

Author(s):

Charlotte Benoit ◽

Hassina Ould-Hamouda ◽

Delphine Crepin ◽

Arieh Gertler ◽

Laurence Amar ◽

...

Keyword(s):

Insulin Resistance ◽

Body Weight ◽

Weight Gain ◽

Expression Pattern ◽

Expression Profile ◽

Mirna Expression ◽

Energy Homeostasis ◽

Body Weight Gain ◽

Mirna Expression Pattern

Perinatal leptin impairment has long-term consequences on energy homeostasis leading to body weight gain. The underlying mechanisms are still not clearly established. We aimed to analyze the long-term effects of early leptin blockade. In this study, newborn rats received daily injection of a pegylated rat leptin antagonist (pRLA) or saline from day 2 (d2) to d13 and then body weight gain, insulin/leptin sensitivity, and expression profile of microRNAs (miRNAs) at the hypothalamic level were determined at d28, d90, or d153 (following 1 month of high-fat diet (HFD) challenge). We show that pRLA treatment predisposes rats to overweight and promotes leptin/insulin resistance in both hypothalamus and liver at adulthood. pRLA treatment also modifies the hypothalamic miRNA expression profile at d28 leading to the upregulation of 34 miRNAs and the downregulation of four miRNAs. For quantitative RT-PCR confirmation, we show the upregulation of rno-miR-10a at d28 and rno-miR-200a, rno-miR-409-5p, and rno-miR-125a-3p following HFD challenge. Finally, pRLA treatment modifies the expression of genes involved in energy homeostasis control such as UCPs and AdipoRs. In pRLA rat muscle,Ucp2/3andAdipor1/r2are upregulated at d90. In liver, pRLA treatment upregulatesAdipor1/r2following HFD challenge. These genes are known to be involved in insulin resistance and type 2 diabetes. In conclusion, we demonstrate that the impairment of leptin action in early life promotes insulin/leptin resistance and modifies the hypothalamic miRNA expression pattern in adulthood, and finally, this study highlights the potential link between hypothalamic miRNA expression pattern and insulin/leptin responsiveness.

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Effects of long-term ingestion of aspartame on hypothalamic neuropeptide Y, plasma leptin and body weight gain and composition

Physiology & Behavior ◽

10.1016/s0031-9384(01)00654-0 ◽

2002 ◽

Vol 75 (1-2) ◽

pp. 41-47 ◽

Cited By ~ 19

Author(s):

Bernard Beck ◽

Arlette Burlet ◽

Jean-Pierre Max ◽

Alain Stricker-Krongrad

Keyword(s):

Body Weight ◽

Weight Gain ◽

Neuropeptide Y ◽

Body Weight Gain ◽

Plasma Leptin

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Neither Agouti-Related Protein nor Neuropeptide Y Is Critically Required for the Regulation of Energy Homeostasis in Mice

Molecular and Cellular Biology ◽

10.1128/mcb.22.14.5027-5035.2002 ◽

2002 ◽

Vol 22 (14) ◽

pp. 5027-5035 ◽

Cited By ~ 296

Author(s):

Su Qian ◽

Howard Chen ◽

Drew Weingarth ◽

Myrna E. Trumbauer ◽

Dawn E. Novi ◽

...

Keyword(s):

Body Weight ◽

Neuropeptide Y ◽

Energy Homeostasis ◽

Arcuate Nucleus ◽

Body Weight Gain ◽

Physiological Role ◽

Related Protein ◽

Double Knockout ◽

Orexigenic Peptide ◽

Agouti Related Protein

ABSTRACT Agouti-related protein (AgRP), a neuropeptide abundantly expressed in the arcuate nucleus of the hypothalamus, potently stimulates feeding and body weight gain in rodents. AgRP is believed to exert its effects through the blockade of signaling by α-melanocyte-stimulating hormone at central nervous system (CNS) melanocortin-3 receptor (Mc3r) and Mc4r. We generated AgRP-deficient (Agrp−/− ) mice to examine the physiological role of AgRP. Agrp−/− mice are viable and exhibit normal locomotor activity, growth rates, body composition, and food intake. Additionally, Agrp−/− mice display normal responses to starvation, diet-induced obesity, and the administration of exogenous leptin or neuropeptide Y (NPY). In situ hybridization failed to detect altered CNS expression levels for proopiomelanocortin, Mc3r, Mc4r, or NPY mRNAs in Agrp−/− mice. As AgRP and the orexigenic peptide NPY are coexpressed in neurons of the arcuate nucleus, we generated AgRP and NPY double-knockout (Agrp−/− ;Npy−/− ) mice to determine whether NPY or AgRP plays a compensatory role in Agrp−/− or NPY-deficient (Npy−/− ) mice, respectively. Similarly to mice deficient in either AgRP or NPY, Agrp−/− ;Npy−/− mice suffer no obvious feeding or body weight deficits and maintain a normal response to starvation. Our results demonstrate that neither AgRP nor NPY is a critically required orexigenic factor, suggesting that other pathways capable of regulating energy homeostasis can compensate for the loss of both AgRP and NPY.

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Neonatal nutritional programming impairs adiponectin effects on energy homeostasis in adult life of male rats

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00358.2017 ◽

2018 ◽

Vol 315 (1) ◽

pp. E29-E37 ◽

Cited By ~ 3

Author(s):

Mariana Peduti Halah ◽

Paula Beatriz Marangon ◽

Jose Antunes-Rodrigues ◽

Lucila L. K. Elias

Keyword(s):

Body Weight ◽

Adipose Tissue ◽

Weight Gain ◽

Food Intake ◽

White Adipose Tissue ◽

Energy Homeostasis ◽

Body Weight Gain ◽

Adult Life ◽

Male Rats ◽

Nutritional Programming

Neonatal nutritional changes induce long-lasting effects on energy homeostasis. Adiponectin influences food intake and body weight. The aim of this study was to investigate the effects of neonatal nutritional programming on the central stimulation of adiponectin. Male Wistar rats were divided on postnatal (PN) day 3 in litters of 3 (small litter, SL), 10 (normal litter, NL), or 16 pups/dam (large litter, LL). We assessed body weight gain for 60 days, adiponectin concentration, and white adipose tissue weight. We examined the response of SL, NL, and LL rats on body weight gain, food intake, oxygen consumption (V̇o2), respiratory exchange ratio (RER), calorimetry, locomotor activity, phosphorylated-AMP-activated protein kinase (AMPK) expression in the hypothalamus, and uncoupling protein (UCP)-1 in the brown adipose tissue after central stimulus with adiponectin. After weaning, SL rats maintained higher body weight gain despite similar food intake compared with NL rats. LL rats showed lower body weight at weaning, with a catch up afterward and higher food intake. Both LL and SL groups had decreased plasma concentrations of adiponectin at PN60. SL rats had increased white adipose tissue. Central injection of adiponectin decreased body weight and food intake and increased V̇o2, RER, calorimetry, p-AMPK and UCP- 1 expression in NL rats, but it had no effect on SL and LL rats, compared with the respective vehicle groups. In conclusion, neonatal under- and overfeeding induced an increase in body weight gain in juvenile and early adult life. Unresponsiveness to central effects of adiponectin contributes to the imbalance of the energy homeostasis in adult life induced by neonatal nutritional programming.

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Long-Term Effects of Early Postnatal Nutrition on Subsequent Body Weight Gain, Emotionality and Learning Behaviour in Male Rats

Experimental and Clinical Endocrinology & Diabetes ◽

10.1055/s-0029-1210258 ◽

2009 ◽

Vol 82 (04) ◽

pp. 73-77 ◽

Cited By ~ 3

Author(s):

G. Hinz ◽

K. Hecht ◽

W. Rohde ◽

G. Dörner

Keyword(s):

Body Weight ◽

Weight Gain ◽

Body Weight Gain ◽

Male Rats ◽

Learning Behaviour ◽

Long Term Effects

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Long term differentiated phosphorus supply from below to above requirement affects nutrient balance and retention, body weight gain and bone growth in growing-finishing pigs

Livestock Science ◽

10.1016/j.livsci.2018.03.002 ◽

2018 ◽

Vol 211 ◽

pp. 14-20 ◽

Cited By ~ 11

Author(s):

K.U. Sørensen ◽

A.-H. Tauson ◽

H.D. Poulsen

Keyword(s):

Body Weight ◽

Weight Gain ◽

Bone Growth ◽

Body Weight Gain ◽

Nutrient Balance ◽

Finishing Pigs

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Effects of neonatal treatment with Tyr-MIF-1 and naloxone on the long-term body weight gain induced by repeated postnatal stressful stimuli

Peptides ◽

10.1016/s0196-9781(99)00152-7 ◽

1999 ◽

Vol 20 (12) ◽

pp. 1425-1430 ◽

Cited By ~ 3

Author(s):

Antonio d’Amore ◽

Alberto Loizzo

Keyword(s):

Body Weight ◽

Weight Gain ◽

Body Weight Gain ◽

Neonatal Treatment

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Mechanisms Responsible for Adult Onset Decline in Food Intake and Body Weight gain due to Neonatal Neuropeptide Y Administration • 1582

Pediatric Research ◽

10.1203/00006450-199804001-01604 ◽

1998 ◽

Vol 43 ◽

pp. 270-270

Author(s):

Amit Varma ◽

Jing He ◽

Sherin U Devaskar

Keyword(s):

Body Weight ◽

Weight Gain ◽

Food Intake ◽

Neuropeptide Y ◽

Body Weight Gain ◽

Adult Onset

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Stress facilitates body weight gain in genetically predisposed rats on medium-fat diet

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00072.2003 ◽

2003 ◽

Vol 285 (4) ◽

pp. R791-R799 ◽

Cited By ~ 40

Author(s):

Chantal Michel ◽

Barry E. Levin ◽

Ambrose A. Dunn-Meynell

Keyword(s):

Body Weight ◽

Weight Gain ◽

Dentate Gyrus ◽

Energy Homeostasis ◽

Body Weight Gain ◽

High Energy ◽

The Body ◽

Central Nucleus ◽

Sprague Dawley ◽

Dorsomedial Nucleus

To assess the interaction between stress and energy homeostasis, we immobilized male Sprague-Dawley rats prone to diet-induced obesity (DIO) or diet resistance (DR) once for 20 min and then fed them either low-fat (4.5%) chow or a medium-fat (31%), high-energy (HE) diet for 9 days. Stressed, chow-fed DIO rats gained less, while stressed DIO rats on HE diet gained more body weight and had higher feed efficiency and plasma leptin levels than unstressed controls. Neither stress nor diet affected DR body weight gain. While stress-induced plasma corticosterone levels did not differ between phenotypes, DIO rats were initially more active in an open field and had higher hippocampal dentate gyrus and CA1 glucocorticoid receptor (GR) mRNA than DR rats, regardless of prior stress or diet. HE diet intake was associated with raised dentate gyrus and CA1 GR and amygdalar central nucleus (CeA) corticotropin-releasing hormone (CRH) mRNA expression, while stress was associated with reduced hypothalamic dorsomedial nucleus Ob-R mRNA and CeA CRH specifically in DIO rats fed HE diet. Thus a single stress triggers a complex interaction among weight gain phenotype, diet, and stress responsivity, which determines the body weight and adiposity of a given individual.

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