Effects of Peripherally Administered Neuromedin U on Energy and Glucose Homeostasis

Neuromedin U (NMU) is a highly conserved peptide reported to modulate energy homeostasis. Pharmacological studies have shown that centrally administered NMU inhibits food intake, reduces body weight, and increases energy expenditure. NMU-deficient mice develop obesity, whereas transgenic mice overexpressing NMU become lean and hypophagic. Two high-affinity NMU receptors, NMUR1 and NMUR2, have been identified. NMUR1 is found primarily in the periphery and NMUR2 primarily in the brain, where it mediates the anorectic effects of centrally administered NMU. Given the broad expression pattern of NMU, we evaluated whether peripheral administration of NMU has effects on energy homeostasis. We observed that acute and chronic peripheral administration of NMU in rodents dose-dependently reduced food intake and body weight and that these effects required NMUR1. The anorectic effects of NMU appeared to be partly mediated by vagal afferents. NMU treatment also increased core body temperature and metabolic rate in mice, suggesting that peripheral NMU modulates energy expenditure. Additionally, peripheral administration of NMU significantly improved glucose excursion. Collectively, these data suggest that NMU functions as a peripheral regulator of energy and glucose homeostasis and the development of NMUR1 agonists may be an effective treatment for diabetes and obesity.

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The contribution of the vagus nerve in interleukin-1β-induced fever is dependent on dose

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.2001.280.4.r929 ◽

2001 ◽

Vol 280 (4) ◽

pp. R929-R934 ◽

Cited By ~ 86

Author(s):

Michael K. Hansen ◽

Kevin A. O'Connor ◽

Lisa E. Goehler ◽

Linda R. Watkins ◽

Steven F. Maier

Keyword(s):

Core Body Temperature ◽

Vagal Afferents ◽

Interleukin 1Β ◽

Blood Levels ◽

Low Doses ◽

Neural Pathway ◽

Subdiaphragmatic Vagotomy ◽

Core Body ◽

Neural Signaling ◽

The Brain

It has been suggested that proinflammatory cytokines communicate to the brain via a neural pathway involving activation of vagal afferents by interleukin-1β (IL-1β), in addition to blood-borne routes. In support, subdiaphragmatic vagotomy blocks IL-1β-induced, brain-mediated responses such as fever. However, vagotomy has also been reported to be ineffective. Neural signaling would be expected to be especially important at low doses of cytokine, when local actions could occur, but only very small quantities of cytokine would become systemic. Here, we examined core body temperature after intraperitoneal injections of three doses of recombinat human IL-1β (rh-IL-1β). Subdiaphragmatic vagotomy completely blocked the fever produced by 0.1 μg/kg, only partially blocked the fever produced by 0.5 μg/kg, and had no effect at all on the fever that followed 1.0 μg/kg rh-IL-1β. Blood levels of rh-IL-1β did not become greater than normal basal levels of endogenous rat IL-β until the 0.5-μg/kg dose nor was IL-1β induced in the pituitary until this dose. These results suggest that low doses of intraperitoneal IL-1β induce fever via a vagal route and that dose may account for some of the discrepancies in the literature.

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Endocrine factors in the hypothalamic regulation of food intake in females: a review of the physiological roles and interactions of ghrelin, leptin, thyroid hormones, oestrogen and insulin

Nutrition Research Reviews ◽

10.1017/s0954422411000035 ◽

2011 ◽

Vol 24 (1) ◽

pp. 132-154 ◽

Cited By ~ 12

Author(s):

V. Somogyi ◽

A. Gyorffy ◽

T. J. Scalise ◽

D. S. Kiss ◽

G. Goszleth ◽

...

Keyword(s):

Food Intake ◽

Energy Expenditure ◽

Thyroid Hormones ◽

Energy Homeostasis ◽

The Body ◽

Feedback Information ◽

Hypothalamic Regulation ◽

The Individual ◽

Desire To Eat ◽

The Brain

Controlling energy homeostasis involves modulating the desire to eat and regulating energy expenditure. The controlling machinery includes a complex interplay of hormones secreted at various peripheral endocrine endpoints, such as the gastrointestinal tract, the adipose tissue, thyroid gland and thyroid hormone-exporting organs, the ovary and the pancreas, and, last but not least, the brain itself. The peripheral hormones that are the focus of the present review (ghrelin, leptin, thyroid hormones, oestrogen and insulin) play integrated regulatory roles in and provide feedback information on the nutritional and energetic status of the body. As peripheral signals, these hormones modulate central pathways in the brain, including the hypothalamus, to influence food intake, energy expenditure and to maintain energy homeostasis. Since the growth of the literature on the role of various hormones in the regulation of energy homeostasis shows a remarkable and dynamic expansion, it is now becoming increasingly difficult to understand the individual and interactive roles of hormonal mechanisms in their true complexity. Therefore, our goal is to review, in the context of general physiology, the roles of the five best-known peripheral trophic hormones (ghrelin, leptin, thyroid hormones, oestrogen and insulin, respectively) and discuss their interactions in the hypothalamic regulation of food intake.

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Pancreatic signals controlling food intake; insulin, glucagon and amylin

Philosophical Transactions of the Royal Society B Biological Sciences ◽

10.1098/rstb.2006.1858 ◽

2006 ◽

Vol 361 (1471) ◽

pp. 1219-1235 ◽

Cited By ~ 138

Author(s):

Stephen C Woods ◽

Thomas A Lutz ◽

Nori Geary ◽

Wolfgang Langhans

Keyword(s):

Body Weight ◽

Food Intake ◽

Energy Homeostasis ◽

Endocrine Pancreas ◽

Situational Factors ◽

Meal Size ◽

Vagus Nerves ◽

Social Emotional ◽

Short Term ◽

The Brain

The control of food intake and body weight by the brain relies upon the detection and integration of signals reflecting energy stores and fluxes, and their interaction with many different inputs related to food palatability and gastrointestinal handling as well as social, emotional, circadian, habitual and other situational factors. This review focuses upon the role of hormones secreted by the endocrine pancreas: hormones, which individually and collectively influence food intake, with an emphasis upon insulin, glucagon and amylin. Insulin and amylin are co-secreted by B-cells and provide a signal that reflects both circulating energy in the form of glucose and stored energy in the form of visceral adipose tissue. Insulin acts directly at the liver to suppress the synthesis and secretion of glucose, and some plasma insulin is transported into the brain and especially the mediobasal hypothalamus where it elicits a net catabolic response, particularly reduced food intake and loss of body weight. Amylin reduces meal size by stimulating neurons in the hindbrain, and there is evidence that amylin additionally functions as an adiposity signal controlling body weight as well as meal size. Glucagon is secreted from A-cells and increases glucose secretion from the liver. Glucagon acts in the liver to reduce meal size, the signal being relayed to the brain via the vagus nerves. To summarize, hormones of the endocrine pancreas are collectively at the crossroads of many aspects of energy homeostasis. Glucagon and amylin act in the short term to reduce meal size, and insulin sensitizes the brain to short-term meal-generated satiety signals; and insulin and perhaps amylin as well act over longer intervals to modulate the amount of fat maintained and defended by the brain. Hormones of the endocrine pancreas interact with receptors at many points along the gut–brain axis, from the liver to the sensory vagus nerve to the hindbrain to the hypothalamus; and their signals are conveyed both neurally and humorally. Finally, their actions include gastrointestinal and metabolic as well as behavioural effects.

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STAT3 but Not ERK2 Is a Crucial Mediator Against Diet-Induced Obesity via VMH Neurons

10.2337/figshare.14448147 ◽

2021 ◽

Author(s):

Gabriel Henrique Marques Gonçalves ◽

Sabrina Mara Tristão ◽

Rafaella Eduarda Volpi ◽

Gislaine Almeida-Pereira ◽

Beatriz de Carvalho Borges ◽

...

Keyword(s):

Body Weight ◽

Food Intake ◽

Energy Expenditure ◽

Energy Homeostasis ◽

Specific Pattern ◽

Conditional Knockout ◽

Steroidogenic Factor 1 ◽

Diet Induced Obesity ◽

Affect Body Weight

Leptin plays an important role in the protection against diet-induced obesity (DIO) by its actions in ventromedial hypothalamic (VMH) neurons. However, little is known about the intracellular mechanisms involved in these effects. To assess the role of the STAT3 and ERK2 signaling in neurons that express the steroidogenic factor 1 (SF1) in the VMH on energy homeostasis, we used cre-lox technology to generate male and female mice with specific disruption of STAT3 or ERK2 in SF1 neurons of the VMH. We demonstrated that the conditional knockout of STAT3 in SF1 neurons of the VMH did not affect body weight, food intake, energy expenditure and glucose homeostasis in animals on regular chow. However, when challenged with high-fat diet (HFD), loss of STAT3 in SF1 neurons caused a significant increase in body weight, food intake and energy efficiency that was more remarkable in females which also showed a decrease in energy expenditure. In contrast, deletion of ERK2 in SF1 neurons of VMH did not have any impact on energy homeostasis in both regular diet and HFD conditions. In conclusion, STAT3 but not ERK2 signaling in SF1 neurons of VMH plays a crucial role to protect against DIO in a sex-specific pattern.

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Selective Inactivation of Socs3 in SF1 Neurons Improves Glucose Homeostasis without Affecting Body Weight

Endocrinology ◽

10.1210/en.2008-0805 ◽

2008 ◽

Vol 149 (11) ◽

pp. 5654-5661 ◽

Cited By ~ 59

Author(s):

Ren Zhang ◽

Harveen Dhillon ◽

Huali Yin ◽

Akihiko Yoshimura ◽

Bradford B. Lowell ◽

...

Keyword(s):

Body Weight ◽

Food Intake ◽

Energy Expenditure ◽

Glucose Homeostasis ◽

Leptin Resistance ◽

High Fat ◽

Leptin Signaling ◽

Leptin Sensitivity ◽

High Fat Diets ◽

Fat Diets

Suppressor of cytokine signaling 3 (Socs3) has been identified as a mediator of central leptin resistance, but the identity of specific neurons in which Socs3 acts to suppress leptin signaling remains elusive. The ventromedial hypothalamus (VMH) was recently shown to be an important site for leptin action because deleting leptin receptor within VMH neurons causes obesity. To examine the role of VMH Socs3 in leptin resistance and energy homeostasis, we generated mice lacking Socs3 specifically in neurons positive for steroidogenic factor 1 (SF1), which is expressed abundantly in the VMH. These mice had increased phosphorylation of signal transducer and activator of transcription-3 in VMH neurons, suggesting improved leptin signaling, and consistently, food intake and weight-reducing effects of exogenous leptin were enhanced. Furthermore, on either chow or high-fat diets, these mice had reduced food intake. Unexpectedly, energy expenditure was reduced as well. Mice lacking Socs3 in SF1 neurons, despite no change in body weight, had improved glucose homeostasis and were partially protected from hyperglycemia and hyperinsulinemia induced by high-fat diets. These results suggest that Socs3 in SF1 neurons negatively regulates leptin signaling and plays important roles in mediating leptin sensitivity, glucose homeostasis, and energy expenditure.

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The central melanocortin system and human obesity

Journal of Molecular Cell Biology ◽

10.1093/jmcb/mjaa048 ◽

2020 ◽

Author(s):

Yongjie Yang ◽

Yong Xu

Keyword(s):

Body Weight ◽

Food Intake ◽

Energy Expenditure ◽

Genetic Variants ◽

Energy Homeostasis ◽

Critical Role ◽

Human Obesity ◽

Melanocortin System ◽

Prevalence Of Obesity

Abstract The prevalence of obesity and the associated comorbidities highlight the importance of understanding the regulation of energy homeostasis. The central melanocortin system plays a critical role in controlling body weight balance. Melanocortin neurons sense and integrate the neuronal and hormonal signals, and then send regulatory projections, releasing anorexigenic or orexigenic melanocortin neuropeptides, to downstream neurons to regulate the food intake and energy expenditure. This review summarizes the latest progress in our understanding of the role of the melanocortin pathway in energy homeostasis. We also review the advances in the identification of human genetic variants that cause obesity via mechanisms that affect the central melanocortin system, which have provided rational targets for treatment of genetically susceptible patients.

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Effects of nicotine on homeostatic and hedonic components of food intake

Journal of Endocrinology ◽

10.1530/joe-17-0166 ◽

2017 ◽

Vol 235 (1) ◽

pp. R13-R31 ◽

Cited By ~ 14

Author(s):

Andrea Stojakovic ◽

Enma P Espinosa ◽

Osman T Farhad ◽

Kabirullah Lutfy

Keyword(s):

Weight Loss ◽

Body Weight ◽

Food Intake ◽

General Population ◽

Nicotinic Acetylcholine Receptors ◽

Acetylcholine Receptors ◽

Energy Homeostasis ◽

Brain Areas ◽

Nicotinic Acetylcholine ◽

The Brain

Chronic tobacco use leads to nicotine addiction that is characterized by exaggerated urges to use the drug despite the accompanying negative health and socioeconomic burdens. Interestingly, nicotine users are found to be leaner than the general population. Review of the existing literature revealed that nicotine affects energy homeostasis and food consumption via altering the activity of neurons containing orexigenic and anorexigenic peptides in the brain. Hypothalamus is one of the critical brain areas that regulates energy balance via the action of these neuropeptides. The equilibrium between these two groups of peptides can be shifted by nicotine leading to decreased food intake and weight loss. The aim of this article is to review the existing literature on the effect of nicotine on food intake and energy homeostasis and report on the changes that nicotine brings about in the level of these peptides and their receptors that may explain changes in food intake and body weight induced by nicotine. Furthermore, we review the effect of nicotine on the hedonic aspect of food intake. Finally, we discuss the involvement of different subtypes of nicotinic acetylcholine receptors in the regulatory action of nicotine on food intake and energy homeostasis.

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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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Breast Milk Hormones and Regulation of Glucose Homeostasis

International Journal of Pediatrics ◽

10.1155/2011/803985 ◽

2011 ◽

Vol 2011 ◽

pp. 1-11 ◽

Cited By ~ 14

Author(s):

Francesco Savino ◽

Stefania Alfonsina Liguori ◽

Miriam Sorrenti ◽

Maria Francesca Fissore ◽

Roberto Oggero

Keyword(s):

Food Intake ◽

Breast Milk ◽

Energy Expenditure ◽

Glucose Homeostasis ◽

Energy Homeostasis ◽

Storage Organs ◽

The Central Nervous System ◽

Complex Regulation ◽

Regulation Of Growth ◽

Milk Hormones

Growing evidence suggests that a complex relationship exists between the central nervous system and peripheral organs involved in energy homeostasis. It consists in the balance between food intake and energy expenditure and includes the regulation of nutrient levels in storage organs, as well as in blood, in particular blood glucose. Therefore, food intake, energy expenditure, and glucose homeostasis are strictly connected to each other. Several hormones, such as leptin, adiponectin, resistin, and ghrelin, are involved in this complex regulation. These hormones play a role in the regulation of glucose metabolism and are involved in the development of obesity, diabetes, and metabolic syndrome. Recently, their presence in breast milk has been detected, suggesting that they may be involved in the regulation of growth in early infancy and could influence the programming of energy balance later in life. This paper focuses on hormones present in breast milk and their role in glucose homeostasis.

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