Ablation of tanycytes of the arcuate nucleus and median eminence increases visceral adiposity and decreases insulin sensitivity in male mice

AbstractTanycytes are radial glial cells located in the mediobasal hypothalamus. Recent studies have proposed that tanycytes play an important role in hypothalamic control of energy homeostasis, although this has not been directly tested. Here, we report the phenotype of mice in which tanycytes of the arcuate nucleus and median eminence were conditionally ablated. Although the CSF-hypothalamic barrier was rendered more permeable, the blood-hypothalamic barrier was not altered. The metabolic effects of tanycyte ablation were likewise moderate. However, we consistently observed a significant increase in visceral fat distribution accompanying insulin insensitivity, but only in male mice, and without an effect on either body weight or food intake. A high-fat diet accelerated overall body weight gain in tanycyte-ablated mice, but the development of visceral adiposity and insulin insensitivity was attenuated. These results clarify the extent to which tanycytes regulate energy metabolism, and indicate a role for tanycytes in controlling body adiposity.

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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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Bimatoprost promotes satiety and attenuates body weight in rats fed standard or obesity-promoting diets.

10.21203/rs.3.rs-24991/v1 ◽

2020 ◽

Author(s):

Clayton Spada ◽

Chau Vu ◽

Iona Raymond ◽

Warren Tong ◽

Chia-Lin Chuang ◽

...

Keyword(s):

Body Weight ◽

Weight Gain ◽

Gastric Emptying ◽

Food Intake ◽

Visceral Fat ◽

Body Weight Gain ◽

Metabolic Effects ◽

Sprague Dawley ◽

Hormone Levels ◽

Gut Hormone

Abstract Background Bimatoprost negatively regulates adipogenesis in vitro and likely participates in a negative feedback loop on anandamide-induced adipogenesis. Here, we investigate the broader metabolic effects of bimatoprost action in vivo in rats under both normal state and obesity-inducing conditions. Methods Male Sprague Dawley rats were a fed standard chow (SC) diet in conjunction with dermally applied bimatoprost treatment for a period of 9–10 weeks. Body weight gain, energy expenditure, food intake, and hormones associated with satiety were measured. Gastric emptying was also separately evaluated. In obesity-promoting diet studies, rats were fed a cafeteria diet (CAF) and gross weight, fat accumulation in SQ, visceral fat and liver was evaluated together with standard serum chemistry. Results Chronic bimatoprost administration attenuated weight gain in rats fed either standard or obesity-promoting diets over a 9–10 weeks. Bimatoprost increased satiety as measured by decreased food intake, gastric emptying and circulating gut hormone levels. Additionally, SQ and visceral fat mass was distinctly affected by treatment. Bimatoprost increased satiety as measured by decreased food intake, gastric emptying and circulating gut hormone levels. Conclusions These findings suggest that bimatoprost (and possibly prostamide F2α) regulates energy homeostasis through actions on dietary intake. These actions likely counteract the metabolic actions of anandamide through the endocannabinoid system potentially revealing a new pathway that could be exploited for therapeutic development.

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Adiponectin is required to mediate rimonabant-induced improvement of insulin sensitivity but not body weight loss in diet-induced obese mice

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.90824.2008 ◽

2009 ◽

Vol 296 (4) ◽

pp. R929-R935 ◽

Cited By ~ 29

Author(s):

Stéphanie Migrenne ◽

Amélie Lacombe ◽

Anne-Laure Lefèvre ◽

Marie-Pierre Pruniaux ◽

Etienne Guillot ◽

...

Keyword(s):

Body Weight ◽

Adipose Tissue ◽

Insulin Sensitivity ◽

Energy Homeostasis ◽

Hepatic Glucose Production ◽

Body Weight Loss ◽

Metabolic Effects ◽

Wild Type ◽

High Fat ◽

Wild Type Littermate

The increase in adiponectin levels in obese patients with untreated dyslipidemia and its mRNA expression in adipose tissue of obese animals are one of the most interesting consequences of rimonabant treatment. Thus, part of rimonabant's metabolic effects could be related to an enhancement of adiponectin secretion and its consequence on the modulation of insulin action, as well as energy homeostasis. The present study investigated the effects of rimonabant in adiponectin knockout mice (Ad−/−) exposed to diet-induced obesity conditions. Six-week-old Ad−/− male mice and their wild-type littermate controls (Ad+/+) were fed a high-fat diet for 7 mo. During the last month, animals were administered daily either with vehicle or rimonabant by mouth (10 mg/kg). High-fat feeding induced weight gain by about 130% in both wild-type and Ad−/− mice. Obesity was associated with hyperinsulinemia and insulin resistance. Treatment with rimonabant led to a significant and similar decrease in body weight in both Ad+/+ and Ad−/− mice compared with vehicle-treated animals. In addition, rimonabant significantly improved insulin sensitivity in Ad+/+ mice compared with Ad+/+ vehicle-treated mice by decreasing hepatic glucose production and increasing glucose utilization index in both visceral and subcutaneous adipose tissue. In contrast, rimonabant failed to improve insulin sensitivity in Ad−/− mice, despite the loss in body weight. Rimonabant's effect on body weight appeared independent of the adiponectin pathway, whereas adiponectin seems required to mediate rimonabant-induced improvement of insulin sensitivity in rodents.

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Collective and Individual Functions of Leptin Receptor Modulated Neurons Controlling Metabolism and Ingestion

Endocrinology ◽

10.1210/en.2007-1132 ◽

2007 ◽

Vol 149 (4) ◽

pp. 1773-1785 ◽

Cited By ~ 222

Author(s):

Esther van de Wall ◽

Rebecca Leshan ◽

Allison W. Xu ◽

Nina Balthasar ◽

Roberto Coppari ◽

...

Keyword(s):

Body Weight ◽

Energy Homeostasis ◽

Arcuate Nucleus ◽

Leptin Receptor ◽

Receptor Gene ◽

Normal Glucose Tolerance ◽

Adult Mice ◽

Normal Glucose ◽

High Doses ◽

Agouti Gene

Two known types of leptin-responsive neurons reside within the arcuate nucleus: the agouti gene-related peptide (AgRP)/neuropeptide Y (NPY) neuron and the proopiomelanocortin (POMC) neuron. By deleting the leptin receptor gene (Lepr) specifically in AgRP/NPY and/or POMC neurons of mice, we examined the several and combined contributions of these neurons to leptin action. Body weight and adiposity were increased by Lepr deletion from AgRP and POMC neurons individually, and simultaneous deletion in both neurons (A+P LEPR-KO mice) further increased these measures. Young (periweaning) A+P LEPR-KO mice exhibit hyperphagia and decreased energy expenditure, with increased weight gain, oxidative sparing of triglycerides, and increased fat accumulation. Interestingly, however, many of these abnormalities were attenuated in adult animals, and high doses of leptin partially suppress food intake in the A+P LEPR-KO mice. Although mildly hyperinsulinemic, the A+P LEPR-KO mice displayed normal glucose tolerance and fertility. Thus, AgRP/NPY and POMC neurons each play mandatory roles in aspects of leptin-regulated energy homeostasis, high leptin levels in adult mice mitigate the importance of leptin-responsiveness in these neurons for components of energy balance, suggesting the presence of other leptin-regulated pathways that partially compensate for the lack of leptin action on the POMC and AgRP/NPY neurons.

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Long-term effects of ghrelin and ghrelin receptor agonists on energy balance in rats

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00040.2008 ◽

2008 ◽

Vol 295 (1) ◽

pp. E78-E84 ◽

Cited By ~ 45

Author(s):

Sabine Strassburg ◽

Stefan D. Anker ◽

Tamara R. Castaneda ◽

Lukas Burget ◽

Diego Perez-Tilve ◽

...

Keyword(s):

Body Weight ◽

Energy Balance ◽

Food Intake ◽

Energy Expenditure ◽

Therapeutic Potential ◽

Body Weight Gain ◽

Metabolic Effects ◽

Positive Energy ◽

High Dose ◽

Growth Hormone Secretagogue

Ghrelin, an endogenous ligand of the growth hormone secretagogue receptor (GHS-R), is the only circulating agent to powerfully promote a positive energy balance. Such action is mediated predominantly by central nervous system pathways controlling food intake, energy expenditure, and nutrient partitioning. The ghrelin pathway may therefore offer therapeutic potential for the treatment of catabolic states. However, the potency of the endogenous hormone ghrelin is limited due to a short half-life and the fragility of its bioactivity ensuring acylation at serine 3. Therefore, we tested the metabolic effects of two recently generated GHS-R agonists, BIM-28125 and BIM-28131, compared with ghrelin. All agents were administered continuously for 1 mo in doses of 50 and 500 nmol·kg−1·day−1 using implanted subcutaneous minipumps in rats. High-dose treatment with single agonists or ghrelin increased body weight gain by promoting fat mass, whereas BIM-28131 was the only one also increasing lean mass significantly. Food intake increased during treatment with BIM-28131 or ghrelin, whereas no effects on energy expenditure were detected. With the lower dose, only BIM-28131 had a significant effect on body weight. This also held true when the compound was administered by subcutaneous injection three times/day. No symptoms or signs of undesired effects were observed in any of the studies or treated groups. These results characterize BIM-28131 as a promising GHS-R agonist with an attractive action profile for the treatment of catabolic disease states such as cachexia.

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

Endocrinology ◽

10.1210/en.2006-0097 ◽

2006 ◽

Vol 147 (11) ◽

pp. 5094-5101 ◽

Cited By ~ 43

Author(s):

En-Ju D. Lin ◽

Amanda Sainsbury ◽

Nicola J. Lee ◽

Dana Boey ◽

Michelle Couzens ◽

...

Keyword(s):

Body Weight ◽

Weight Gain ◽

Neuropeptide Y ◽

Energy Homeostasis ◽

Viral Vector ◽

Body Weight Gain ◽

Hormonal Changes ◽

Obesity Syndrome ◽

Y Receptors

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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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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