Synergistic Control of KNDy Neuronal Influence on Energy Balance by Ghrelin and Estradiol

Abstract The gut peptide, ghrelin, mediates negative energy homeostasis and the neuroendocrine control of energy homeostasis by acting through its receptor, growth hormone secretagogue receptor (GHSR). GHSR, expressed in hypothalamic Kisspeptin/Neurokinin B/Dynorphin (KNDy) neurons in the arcuate (ARC), is well known to regulate energy balance. We have previously shown 17-beta-estradiol (E2) robustly increases Ghsr expression in KNDy neurons, enhancing their sensitivity to ghrelin. We hypothesize that E2-induced increase in GHSR expression augments KNDy sensitivity in a fasting state by elevating ghrelin to reduce energy expenditure in females. We developed a Kiss1-specific GHSR knockout to determine the role of GHSR in ARC KNDy neurons and fed them either a low-fat diet (LFD) or a high-fat diet (HFD). Knockout (experimental) females were resistant to HFD in terms of body weight gain, adiposity, and food intake compared to HFD-fed controls. HFD-fed experimental females also exhibited slower glucose clearance compared to HFD-fed controls. Experimental females, regardless of diet, exhibited elevated fasting (5h) glucose. Metabolic rates (V.O2, V.CO2) and energy expenditure (heat) were not different. Respiratory Exchange Ratio (RER) was elevated in LFD-fed females, indicating the utilization of carbohydrates over fat for energy. Further meal pattern analysis revealed a reduction in meal duration in HFD-fed females, but elevated meal frequency, while HFD-fed experimental females exhibited a reduced meal size. In two separate meal pattern experiments, experimental and control females were fasted for 24h and refed or injected with ghrelin (I.P. 1mg/kg) or saline. We observed a striking delay in refeeding behavior in experimental females compared to controls during the refeeding period after fasting. After injection, control females responded to ghrelin with a rapid and sustained increase in food intake which was blunted in experimentals. Collectively, these data suggest that GHSR activation in KNDy neurons modulates metabolism, glucose homeostasis, and feeding behavior, illustrating a novel mechanism for E2 and ghrelin to synergistically control KNDy neuronal output and their subsequent behavioral and physiological outcomes.

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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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Ghrelin in the lateral parabrachial nucleus influences the excitability of glucosensing neurons, increases food intake and body weight

Endocrine Connections ◽

10.1530/ec-20-0285 ◽

2020 ◽

Vol 9 (12) ◽

pp. 1168-1177

Author(s):

Caishun Zhang ◽

Junhua Yuan ◽

Qian Lin ◽

Manwen Li ◽

Liuxin Wang ◽

...

Keyword(s):

Body Weight ◽

Weight Gain ◽

Food Intake ◽

Firing Rate ◽

Body Weight Gain ◽

Parabrachial Nucleus ◽

Growth Hormone Secretagogue Receptor ◽

Growth Hormone Secretagogue ◽

Lateral Parabrachial Nucleus

Ghrelin plays a pivotal role in the regulation of food intake, body weight and energy metabolism. However, these effects of ghrelin in the lateral parabrachial nucleus (LPBN) are unexplored. C57BL/6J mice and GHSR−/− mice were implanted with cannula above the right LPBN and ghrelin was microinjected via the cannula to investigate effect of ghrelin in the LPBN. In vivo electrophysiological technique was used to record LPBN glucose-sensitive neurons to explore potential udnderlying mechanisms. Microinjection of ghrelin in LPBN significantly increased food intake in the first 3 h, while such effect was blocked by [D-Lys3]-GHRP-6 and abolished in GHSR−/− mice. LPBN ghrelin microinjection also significantly increased the firing rate of glucose-excited (GE) neurons and decreased the firing rate of glucose-inhibited (GI) neurons. Additionally, LPBN ghrelin microinjection also significantly increased c-fos expression. Chronic ghrelin administration in the LPBN resulted in significantly increased body weight gain. Meanwhile, no significant changes were observed in both mRNA and protein expression levels of UCP-1 in BAT. These results demonstrated that microinjection of ghrelin in LPBN could increase food intake through the interaction with growth hormone secretagogue receptor (GHSR) in C57BL/6J mice, and its chronic administration could also increase body weight gain. These effects might be associated with altered firing rate in the GE and GI neurons.

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Peripheral and Central Glucocorticoid Signaling Contributes to Positive Energy Balance in Rats

Hormone and Metabolic Research ◽

10.1055/s-0043-100383 ◽

2017 ◽

Vol 49 (06) ◽

pp. 472-479

Author(s):

Tássia Borba ◽

Lígia Galindo ◽

Kelli Ferraz-Pereira ◽

Raquel da Silva Aragão ◽

Ana Toscano ◽

...

Keyword(s):

Energy Balance ◽

Food Intake ◽

Energy Expenditure ◽

Glucocorticoid Receptors ◽

Negative Energy ◽

Positive Energy ◽

Obesity Epidemic ◽

Routes Of Administration ◽

Glucocorticoid Signaling ◽

Positive Energy Balance

AbstractThe obesity epidemic has been the target of several studies to understand its etiology. The pathophysiological processes that take to obesity generally relate to the rupture of energy balance. This imbalance can result from environmental and/or endogenous events. Among the endogenous events, the hypothalamic-pituitary-adrenal axis, which promotes stress response via glucocorticoid activity, is considered a modulator of energy balance. However, it remains controversial whether the increase in plasma levels of glucocorticoids results in a positive or negative energy balance. Furthermore, there are no studies comparing different routes of administration of glucocorticoids in this context. Here, we investigated the effects of intraperitoneal (i.p.) or intracerebroventricular (i.c.v.) administration of a specific agonist for glucocorticoid receptors on food intake and energy expenditure in rats. Sixty-day old rats were treated with i.p. or i.c.v. dexamethasone. Food intake and satiety were evaluated, as well as locomotor activity in order to determine energy expenditure. Both i.p. and i.c.v. dexamethasone increased food intake and decreased energy expenditure. Moreover, i.c.v. dexamethasone delayed the onset of satiety. Together, these results confirm that central glucocorticoid signaling promotes a positive energy balance and supports the role of the glucocorticoid system as the underlying cause of psychological stress-induced obesity.

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Orexin activation precedes increased NPY expression, hyperphagia, and metabolic changes in response to sleep deprivation

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00660.2009 ◽

2010 ◽

Vol 298 (3) ◽

pp. E726-E734 ◽

Cited By ~ 60

Author(s):

Paulo José Forcina Martins ◽

Marina Soares Marques ◽

Sergio Tufik ◽

Vânia D'Almeida

Keyword(s):

Body Weight ◽

Energy Balance ◽

Food Intake ◽

Sleep Deprivation ◽

Weight Control ◽

Time Course ◽

Energy Homeostasis ◽

Negative Energy ◽

Negative Energy Balance ◽

Mrna Levels

Several pieces of evidence support that sleep duration plays a role in body weight control. Nevertheless, it has been assumed that, after the identification of orexins (hypocretins), the molecular basis of the interaction between sleep and energy homeostasis has been provided. However, no study has verified the relationship between neuropeptide Y (NPY) and orexin changes during hyperphagia induced by sleep deprivation. In the current study we aimed to establish the time course of changes in metabolite, endocrine, and hypothalamic neuropeptide expression of Wistar rats sleep deprived by the platform method for a distinct period (from 24 to 96 h) or sleep restricted for 21 days (SR-21d). Despite changes in the stress hormones, we found no changes in food intake and body weight in the SR-21d group. However, sleep-deprived rats had a 25–35% increase in their food intake from 72 h accompanied by slight weight loss. Such changes were associated with increased hypothalamus mRNA levels of prepro-orexin (PPO) at 24 h followed by NPY at 48 h of sleep deprivation. Conversely, sleep recovery reduced the expression of both PPO and NPY, which rapidly brought the animals to a hypophagic condition. Our data also support that sleep deprivation rapidly increases energy expenditure and therefore leads to a negative energy balance and a reduction in liver glycogen and serum triacylglycerol levels despite the hyperphagia. Interestingly, such changes were associated with increased serum levels of glucagon, corticosterone, and norepinephrine, but no effects on leptin, insulin, or ghrelin were observed. In conclusion, orexin activation accounts for the myriad changes induced by sleep deprivation, especially the hyperphagia induced under stress and a negative energy balance.

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A Negative Energy Balance Is Associated with Metabolic Dysfunctions in the Hypothalamus of a Humanized Preclinical Model of Alzheimer’s Disease, the 5XFAD Mouse

International Journal of Molecular Sciences ◽

10.3390/ijms22105365 ◽

2021 ◽

Vol 22 (10) ◽

pp. 5365

Author(s):

Antonio J. López-Gambero ◽

Cristina Rosell-Valle ◽

Dina Medina-Vera ◽

Juan Antonio Navarro ◽

Antonio Vargas ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Energy Balance ◽

Food Intake ◽

Energy Expenditure ◽

Mouse Model ◽

Negative Energy ◽

Negative Energy Balance ◽

5Xfad Mouse ◽

5Xfad Mice ◽

Metabolic Dysfunctions

Increasing evidence links metabolic disorders with neurodegenerative processes including Alzheimer’s disease (AD). Late AD is associated with amyloid (Aβ) plaque accumulation, neuroinflammation, and central insulin resistance. Here, a humanized AD model, the 5xFAD mouse model, was used to further explore food intake, energy expenditure, neuroinflammation, and neuroendocrine signaling in the hypothalamus. Experiments were performed on 6-month-old male and female full transgenic (Tg5xFAD/5xFAD), heterozygous (Tg5xFAD/-), and non-transgenic (Non-Tg) littermates. Although histological analysis showed absence of Aβ plaques in the hypothalamus of 5xFAD mice, this brain region displayed increased protein levels of GFAP and IBA1 in both Tg5xFAD/- and Tg5xFAD/5xFAD mice and increased expression of IL-1β in Tg5xFAD/5xFAD mice, suggesting neuroinflammation. This condition was accompanied by decreased body weight, food intake, and energy expenditure in both Tg5xFAD/- and Tg5xFAD/5xFAD mice. Negative energy balance was associated with altered circulating levels of insulin, GLP-1, GIP, ghrelin, and resistin; decreased insulin and leptin hypothalamic signaling; dysregulation in main metabolic sensors (phosphorylated IRS1, STAT5, AMPK, mTOR, ERK2); and neuropeptides controlling energy balance (NPY, AgRP, orexin, MCH). These results suggest that glial activation and metabolic dysfunctions in the hypothalamus of a mouse model of AD likely result in negative energy balance, which may contribute to AD pathogenesis development.

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Adolescent Inhalant Abuse Results in Adrenal Dysfunction and a Hypermetabolic Phenotype with Persistent Growth Impairments

Neuroendocrinology ◽

10.1159/000493686 ◽

2018 ◽

Vol 107 (4) ◽

pp. 340-354 ◽

Cited By ~ 3

Author(s):

Rose Crossin ◽

Zane B. Andrews ◽

Natalie A. Sims ◽

Terence Pang ◽

Michael Mathai ◽

...

Keyword(s):

Energy Balance ◽

Food Intake ◽

Energy Expenditure ◽

Adrenal Insufficiency ◽

Fasting Blood Glucose ◽

Negative Energy ◽

Negative Energy Balance ◽

Metabolic Phenotype ◽

Adolescent Male ◽

Inhalant Abuse

Background/Aims: Abuse of toluene products (e.g., glue-sniffing) primarily occurs during adolescence and has been associated with appetite suppression and weight impairments. However, the metabolic phenotype arising from adolescent inhalant abuse has never been fully characterised, and its persistence during abstinence and underlying mechanisms remain unknown. Methods: Adolescent male Wistar rats (post-natal day 27) were exposed to inhaled toluene (10,000 ppm) (n = 32) or air (n = 48) for 1 h/day, 3 days/week for 4 weeks, followed by 4 weeks of abstinence. Twenty air rats were pair-fed to the toluene group, to differentiate the direct effects of toluene from under-nutrition. Food intake, weight, and growth were monitored. Metabolic hormones were measured after exposure and abstinence periods. Energy expenditure was measured using indirect calorimetry. Adrenal function was assessed using adrenal histology and hormone testing. Results: Inhalant abuse suppressed appetite and increased energy expenditure. Reduced weight gain and growth were observed in both the toluene and pair-fed groups. Compared to the pair-fed group, and despite normalisation of food intake, the suppression of weight and growth for toluene-exposed rats persisted during abstinence. After exposure, toluene-exposed rats had low fasting blood glucose and insulin compared to the air and pair-fed groups. Consistent with adrenal insufficiency, adrenal hypertrophy and increased basal adrenocorticotropic hormone were observed in the toluene-exposed rats, despite normal basal corticosterone levels. Conclusions: Inhalant abuse results in negative energy balance, persistent growth impairment, and endocrine changes suggestive of adrenal insufficiency. We conclude that adrenal insufficiency contributes to the negative energy balance phenotype, potentially presenting a significant additional health risk for inhalant users.

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LEAP-2: An Emerging Endogenous Ghrelin Receptor Antagonist in the Pathophysiology of Obesity

Frontiers in Endocrinology ◽

10.3389/fendo.2021.717544 ◽

2021 ◽

Vol 12 ◽

Author(s):

Xuehan Lu ◽

Lili Huang ◽

Zhengxiang Huang ◽

Dandan Feng ◽

Richard J. Clark ◽

...

Keyword(s):

Growth Hormone ◽

Energy Balance ◽

Food Intake ◽

Antimicrobial Peptide ◽

Molar Ratio ◽

Positive Energy ◽

Energy Status ◽

Growth Hormone Secretagogue Receptor ◽

Growth Hormone Secretagogue ◽

Ghrelin Receptor

Liver-expressed antimicrobial peptide 2 (LEAP-2), originally described as an antimicrobial peptide, has recently been recognized as an endogenous blocker of growth hormone secretagogue receptor 1a (GHS-R1a). GHS-R1a, also known as ghrelin receptor, is a G protein-coupled receptor (GPCR) widely distributed on the hypothalamus and pituitary gland where it exerts its major functions of regulating appetite and growth hormone (GH) secretion. The activity of GHS-R1a is controlled by two counter-regulatory endogenous ligands: Ghrelin (activation) and LEAP-2 (inhibition). Ghrelin activates GHS-R1a on the neuropeptide Y/Agouti-related protein (NPY/AgRP) neurons at the arcuate nucleus (ARC) to promote appetite, and on the pituitary somatotrophs to stimulate GH release. On the flip side, LEAP-2, acts both as an endogenous competitive antagonist of ghrelin and an inverse agonist of constitutive GHS-R1a activity. Such a biological property of LEAP-2 vigorously blocks ghrelin’s effects on food intake and hormonal secretion. In circulation, LEAP-2 displays an inverse pattern as to ghrelin; it increases with food intake and obesity (positive energy balance), whereas decreases upon fasting and weight loss (negative energy balance). Thus, the LEAP-2/ghrelin molar ratio fluctuates in response to energy status and modulation of this ratio conversely influences energy intake. Inhibiting ghrelin’s activity has shown beneficial effects on obesity in preclinical experiments, which sheds light on LEAP-2’s anti-obesity potential. In this review, we will analyze LEAP-2’s effects from a metabolic point of view with a focus on metabolic hormones (e.g., ghrelin, GH, and insulin), and discuss LEAP-2’s potential as a promising therapeutic target for obesity.

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Effects of Naltrexone on Energy Balance and Hypothalamic Melanocortin Peptides in Male Mice Fed a High-Fat Diet

Journal of the Endocrine Society ◽

10.1210/js.2018-00379 ◽

2019 ◽

Vol 3 (3) ◽

pp. 590-601 ◽

Cited By ~ 4

Author(s):

Sunil K Panigrahi ◽

Kana Meece ◽

Sharon L Wardlaw

Keyword(s):

Body Weight ◽

Energy Balance ◽

Food Intake ◽

Energy Homeostasis ◽

Body Weight Gain ◽

High Fat ◽

Melanocortin System ◽

Endogenous Opioid ◽

Processing Enzymes ◽

Agouti Related Protein

Abstract The hypothalamic melanocortin system composed of proopiomelanocortin (POMC) and agouti-related protein (AgRP) neurons plays a key role in maintaining energy homeostasis. The POMC-derived peptides, α-MSH and β-EP, have distinct roles in this process. α-MSH inhibits food intake, whereas β-EP, an endogenous opioid, can inhibit POMC neurons and stimulate food intake. A mouse model was used to examine the effects of opioid antagonism with naltrexone (NTX) on Pomc and Agrp gene expression and POMC peptide processing in the hypothalamus in conjunction with changes in energy balance. There were clear stimulatory effects of NTX on hypothalamic Pomc in mice receiving low- and high-fat diets, yet only transient decreases in food intake and body weight gain were noted. The effects on Pomc expression were accompanied by an increase in POMC prohormone levels and a decrease in levels of the processed peptides α-MSH and β-EP. Arcuate expression of the POMC processing enzymes Pcsk1, Pcsk2, and Cpe was not altered by NTX, but expression of Prcp, an enzyme that inactivates α-MSH, increased after NTX exposure. NTX exposure also stimulated hypothalamic Agrp expression, but the effects of NTX on energy balance were not enhanced in Agrp-null mice. Despite clear stimulatory effects of NTX on Pomc expression in the hypothalamus, only modest transient decreases in food intake and body weight were seen. Effects of NTX on POMC processing, and possibly α-MSH inactivation, as well as stimulatory effects on AgRP neurons could mitigate the effects of NTX on energy balance.

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OR04-03 Calcitonin Receptor Expressing Neurons in the PVH Regulate Feeding Behavior

Journal of the Endocrine Society ◽

10.1210/jendso/bvaa046.410 ◽

2020 ◽

Vol 4 (Supplement_1) ◽

Author(s):

Ian Enrique Gonzalez ◽

Wenwen Cheng ◽

Warren Pan ◽

Chunxia Lu ◽

Julliana Ramirez-Matias ◽

...

Keyword(s):

Energy Balance ◽

Food Intake ◽

Energy Expenditure ◽

Feeding Behavior ◽

Tetanus Toxin ◽

Energy Homeostasis ◽

Balance Control ◽

Brain Regions ◽

Calcitonin Receptor ◽

Cumulative Food Intake

Abstract The paraventricular nucleus of the hypothalamus (PVH) is a brain region crucial for energy homeostasis. Abnormal PVH development or damage leads to hyperphagic obesity and energy expenditure deficits underscoring the importance of PVH neuronal activity in energy balance control. Application of salmon calcitonin (sCT) to the PVH suppresses feeding and calcitonin receptor (CalcR) is highly expressed in the PVH of rodents suggesting that CalcR-expressing PVH neurons contribute to energy homeostasis. In situ hybridization reveals that many CalcRPVH neurons express melanocortin-4 receptor (MC4R), a receptor required for normal feeding behavior. To investigate the physiologic roles of CalcRPVH neurons, we generated CalcR-2a-Cre knock-in mice to manipulate CalcR-expressing cells. Deletion of MC4R from CalcR expressing cells using Cre-loxP technology resulted in profound obesity in both male and female mice by 16 weeks of age. This weight gain was attributable to hyperphagia, as cumulative food intake of the MC4R deleted mice was significantly greater than the controls and energy expenditure measurements acquired through CLAMS analysis were not significantly different. To determine the brain regions engaged by CalcRPVH neurons, we used anterograde Cre-dependent viral tracing reagents injected into the PVH of CalcR-Cre mice, and found that CalcRPVH neurons project to brain regions implicated in energy balance control, including the nucleus of the solitary tract and the parabrachial nucleus. To assess the acute effects of activating CalcRPVH neurons, we used DREADD technology to chemogenetically activate CalcRPVH neurons. CalcRPVH neuron activation suppressed feeding but had no significant effect on energy expenditure. To determine if the activity of CalcRPVH neurons is required for energy homeostasis, we silenced them using Cre-dependent tetanus toxin virus. Male mice with tetanus toxin silenced CalcRPVH neurons were obese 7 weeks following injection in part due to greater cumulative food intake; CLAMS analysis revealed no differences in energy expenditure. Mice with silenced CalcRPVH neurons as well as mice with CalcR deleted from the PVH had normal anorectic responses to sCT, suggesting sCT-induced anorexia does not require CalcRPVH neurons or CalcR expression in the PVH. Taken together, these findings suggest CalcRPVH neurons are an essential component of feeding and energy homeostatic circuitry.

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A Functional Leptin System Is Essential for Sodium Tungstate Antiobesity Action

Endocrinology ◽

10.1210/en.2008-0881 ◽

2009 ◽

Vol 150 (2) ◽

pp. 642-650 ◽

Cited By ~ 10

Author(s):

Ignasi Canals ◽

María C. Carmona ◽

Marta Amigó ◽

Albert Barbera ◽

Analía Bortolozzi ◽

...

Keyword(s):

Body Weight ◽

Adipose Tissue ◽

Weight Gain ◽

Food Intake ◽

Energy Expenditure ◽

Energy Homeostasis ◽

Sodium Tungstate ◽

Body Weight Gain ◽

Dependent Manner ◽

Leptin System

Sodium tungstate is a novel agent in the treatment of obesity. In diet-induced obese rats, it is able to reduce body weight gain by increasing energy expenditure. This study evaluated the role of leptin, a key regulator of energy homeostasis, in the tungstate antiobesity effect. Leptin receptor-deficient Zucker fa/fa rats and leptin-deficient ob/ob mice were treated with tungstate. In lean animals, tungstate administration reduced body weight gain and food intake and increased energy expenditure. However, in animals with deficiencies in the leptin system, treatment did not modify these parameters. In ob/ob mice in which leptin deficiency was restored through adipose tissue transplantation, treatment restored the tungstate-induced body weight gain and food intake reduction as well as energy expenditure increase. Furthermore, in animals in which tungstate administration increased energy expenditure, changes in the expression of key genes involved in brown adipose tissue thermogenesis were detected. Finally, the gene expression of the hypothalamic neuropeptides, Npy, Agrp, and Cart, involved in the leptin regulation of energy homeostasis, was also modified by tungstate in a leptin-dependent manner. In summary, the results indicate that the effectiveness of tungstate in reducing body weight gain is completely dependent on a functional leptin system. Anti-obesity activity of tungstate is due to an increase in thermogenesis and a reduction in food intake and depends entirely on a functional leptin system.

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