scholarly journals The Antiobesity Effects of Centrally Administered Neuromedin U and Neuromedin S Are Mediated Predominantly by the Neuromedin U Receptor 2 (NMUR2)

Endocrinology ◽  
2009 ◽  
Vol 150 (7) ◽  
pp. 3101-3109 ◽  
Author(s):  
Andrea Peier ◽  
Jennifer Kosinski ◽  
Kimberly Cox-York ◽  
Ying Qian ◽  
Kunal Desai ◽  
...  
Keyword(s):  
Food Intake ◽  
Energy Homeostasis ◽  
Central Administration ◽  
Diet Induced Obesity ◽  
Inhibit Food Intake ◽  
Selective Agonists ◽  
Treatment Of Obesity ◽  
The Brain ◽  
Deficient Mice

Neuromedin U (NMU) and neuromedin S (NMS) are structurally related neuropeptides that have been reported to modulate energy homeostasis. Pharmacological data have shown that NMU and NMS inhibit food intake when administered centrally and that NMU increases energy expenditure. Additionally, NMU-deficient mice develop obesity, whereas transgenic mice overexpressing NMU are lean and hypophagic. Two high-affinity NMU/NMS receptors, NMUR1 and NMUR2, have been identified. NMUR1 is predominantly expressed in the periphery, whereas NMUR2 is predominantly expressed in the brain, suggesting that the effects of centrally administered NMU and NMS are mediated by NMUR2. To evaluate the role of NMUR2 in the regulation of energy homeostasis, we characterized NMUR2-deficient (Nmur2−/−) mice. Nmur2−/− mice exhibited a modest resistance to diet-induced obesity that was at least in part due to reduced food intake. Acute central administration of NMU and NMS reduced food intake in wild-type but not in Nmur2−/− mice. The effects on activity and core temperature induced by centrally administered NMU were also absent in Nmur2−/− mice. Moreover, chronic central administration of NMU and NMS evoked significant reductions in body weight and sustained reductions in food intake in mice. In contrast, Nmur2−/− mice were largely resistant to these effects. Collectively, these data demonstrate that the anorectic and weight-reducing actions of centrally administered NMU and NMS are mediated predominantly by NMUR2, suggesting that NMUR2-selective agonists may be useful for the treatment of obesity.

The role of amylin in the control of energy homeostasis

2010 ◽  
Vol 298 (6) ◽  
pp. R1475-R1484 ◽  
Author(s):  
Thomas A. Lutz
Keyword(s):  
Energy Homeostasis ◽  
Area Postrema ◽  
Body Weight Gain ◽  
Direct Action ◽  
Central Administration ◽  
Experimental Conditions ◽  
Hypothalamic Area ◽  
Chronic Infusion ◽  
The Brain

Amylin is an important player in the control of nutrient fluxes. Amylin reduces eating via a meal size effect by promoting meal-ending satiation. This effect seems to depend on a direct action in the area postrema (AP), which is an area rich in amylin receptors. Subsequent to the activation of AP neurons, the neural signal is conveyed to the forebrain via relays involving the nucleus of the solitary tract (NTS) and the lateral parabrachial nucleus (lPBN) to the lateral hypothalamic area (LHA) and other hypothalamic nuclei. While the NTS and lPBN seem to be necessary for amylin's eating inhibitory effect, the role of the LHA has not yet been fully investigated. Amylin may also act as an adiposity signal. Plasma levels of amylin are higher in obese individuals, and chronic infusion of amylin into the brain reduces body weight gain and adiposity; chronic infusion of an amylin receptor antagonist into the brain increases body adiposity. Amylin increases energy expenditure in rats; this effect occurs under various experimental conditions after peripheral and central administration. Together, these animal data, but also clinical data in humans, indicate that amylin is a promising candidate for the treatment of obesity; effects are most pronounced when amylin is combined with leptin. Finally, recent findings indicate that amylin acts as a neurotrophic factor in specific brain stem areas. Whether this effect may be relevant under physiological conditions requires further studies.

Ghrelin microinjection into forebrain sites induces wakefulness and feeding in rats

2007 ◽  
Vol 292 (1) ◽  
pp. R575-R585 ◽  
Author(s):  
Éva Szentirmai ◽  
Levente Kapás ◽  
James M. Krueger
Keyword(s):  
Food Intake ◽  
Suppressive Effect ◽  
Hormone Release ◽  
Central Administration ◽  
Rapid Eye Movement Sleep ◽  
Regulatory Circuit ◽  
Intracerebroventricular Injections ◽  
The Brain ◽  
Brain Peptide

Ghrelin, a gut-brain peptide, is best known for its role in the stimulation of feeding and growth hormone release. In the brain, orexin, neuropeptide Y (NPY), and ghrelin are parts of a food intake regulatory circuit. Orexin and NPY are also implicated in maintaining wakefulness. Previous experiments in our laboratory revealed that intracerebroventricular injections of ghrelin induce wakefulness in rats. To further elucidate the possible role of ghrelin in the regulation of arousal, we studied the effects of microinjections of ghrelin into hypothalamic sites, which are implicated in the regulation of feeding and sleep, such as the lateral hypothalamus (LH), medial preoptic area (MPA), and paraventricular nucleus (PVN) on sleep in rats. Sleep responses, motor activity, and food intake after central administration of 0.04, 0.2, or 1 μg (12, 60, or 300 pmol) ghrelin were recorded. Microinjections of ghrelin into the LH had strong wakefulness-promoting effects lasting for 2 h. Wakefulness was also stimulated by ghrelin injection into the MPA and PVN; the effects were confined to the first hour after the injection. Ghrelin's non-rapid-eye-movement sleep-suppressive effect was accompanied by attenuation in the electroencephalographic (EEG) slow-wave activity and changes in the EEG power spectrum. Food consumption was significantly stimulated after microinjections of ghrelin into each hypothalamic site. Together, these results are consistent with the hypothesis that forebrain ghrelinergic mechanisms play a role in the regulation of vigilance, possibly through activating the components of the food intake- and arousal-promoting network formed by orexin and NPY.

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

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.

scholarly journals Inactivation of Ppp1r15a minimises weight gain and insulin resistance during caloric excess in mice

2018 ◽  
Author(s):  
Vruti Patel ◽  
Guillaume Bidault ◽  
Joseph E. Chambers ◽  
Stefania Carobbio ◽  
Angharad J. T. Everden ◽  
...  
Keyword(s):  
Weight Gain ◽  
Food Intake ◽  
Translation Initiation Factor ◽  
Initiation Factor ◽  
Standard Diet ◽  
Wild Type ◽  
Diet Induced Obesity ◽  
Caloric Excess ◽  
Deficient Mice

AbstractPhosphorylation of the translation initiation factor eIF2α within the mediobasal hypothalamus is known to suppress food intake, but the role of the eIF2α phosphatases in regulating body weight is poorly understood. Mice deficient in active PPP1R15A, a stress-inducible eIF2α phosphatase, are healthy and more resistant to endoplasmic reticulum stress than wild type controls. We report that when Ppp1r15a mutant mice are fed a high fat diet they gain less weight than wild type littermates owing to reduced food intake. This results in healthy leaner Ppp1r15a mutant animals with reduced hepatic steatosis and improved insulin sensitivity, albeit with a modest defect in insulin secretion. By contrast, no weight differences are observed between wild type and Ppp1r15a deficient mice fed a standard diet. We conclude that mice lacking the C-terminal PP1-binding domain of PPP1R15A show reduced dietary intake and preserved glucose tolerance. Our data indicate that this results in reduced weight gain and protection from diet-induced obesity.

scholarly journals Loss of CTRP4 alters adiposity and food intake behaviors in obese mice

2020 ◽  
Vol 319 (6) ◽  
pp. E1084-E1100
Author(s):  
Dylan C. Sarver ◽  
Ashley N. Stewart ◽  
Susana Rodriguez ◽  
Hannah C. Little ◽  
Susan Aja ◽  
...  
Keyword(s):  
Weight Gain ◽  
Food Intake ◽  
Energy Homeostasis ◽  
Physiological Role ◽  
Central Administration ◽  
Loss Of Function ◽  
Low Fat Diet ◽  
Obesogenic Diet ◽  
Food Intake Patterns

Central and peripheral mechanisms are both required for proper control of energy homeostasis. Among circulating plasma proteins, C1q/TNF-related proteins (CTRPs) have recently emerged as important regulators of sugar and fat metabolism. CTRP4, expressed in brain and adipose tissue, is unique among the family members in having two tandem globular C1q domains. We previously showed that central administration of recombinant CTRP4 suppresses food intake, suggesting a central nervous system role in regulating ingestive physiology. Whether this effect is pharmacological or physiological remains unclear. We used a loss-of-function knockout (KO) mouse model to clarify the physiological role of CTRP4. Under basal conditions, CTRP4 deficiency increased serum cholesterol levels and impaired glucose tolerance in male but not female mice fed a control low-fat diet. When challenged with a high-fat diet, male and female KO mice responded differently to weight gain and had different food intake patterns. On an obesogenic diet, male KO mice had similar weight gain as wild-type littermates. When fed ad libitum, KO male mice had greater meal number, shorter intermeal interval, and reduced satiety ratio. Female KO mice, in contrast, had lower body weight and adiposity. In the refeeding period following food deprivation, female KO mice had significantly higher food intake due to longer meal duration and reduced satiety ratio. Collectively, our data provide genetic evidence for a sex-dependent physiological role of CTRP4 in modulating food intake patterns and systemic energy metabolism.

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

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.

scholarly journals Functional Role of c-Jun-N-Terminal Kinase in Feeding Regulation

Endocrinology ◽  
2010 ◽  
Vol 151 (2) ◽  
pp. 671-682 ◽  
Author(s):  
Elizabeth K. Unger ◽  
Merisa L. Piper ◽  
Louise E. Olofsson ◽  
Allison W. Xu
Keyword(s):  
Functional Role ◽  
Central Administration ◽  
Peripheral Tissues ◽  
Immunological Responses ◽  
Feeding Regulation ◽  
Central Inhibition ◽  
The Brain ◽  
Nuclear Immunoreactivity ◽  
Deficient Mice

c-Jun-N-terminal kinase (JNK) is a signaling molecule that is activated by proinflammatory signals, endoplasmic reticulum (ER) stress, and other environmental stressors. Although JNK has diverse effects on immunological responses and insulin resistance in peripheral tissues, a functional role for JNK in feeding regulation has not been established. In this study, we show that central inhibition of JNK activity potentiates the stimulatory effects of glucocorticoids on food intake and that this effect is abolished in mice whose agouti-related peptide (AgRP) neurons are degenerated. JNK1-deficient mice feed more upon central administration of glucocorticoids, and glucocorticoid receptor nuclear immunoreactivity is enhanced in the AgRP neurons. JNK inhibition in hypothalamic explants stimulates Agrp expression, and JNK1-deficient mice exhibit increased Agrp expression, heightened hyperphagia, and weight gain during refeeding. Our study shows that JNK1 is a novel regulator of feeding by antagonizing glucocorticoid function in AgRP neurons. Paradoxically, JNK1 mutant mice feed less and lose more weight upon central administration of insulin, suggesting that JNK1 antagonizes insulin function in the brain. Thus, JNK may integrate diverse metabolic signals and differentially regulate feeding under distinct physiological conditions.

scholarly journals Improvement of obesity-associated disorders by a small-molecule drug targeting mitochondria of adipose tissue macrophages

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Yawei Wang ◽  
Binlin Tang ◽  
Lei Long ◽  
Peng Luo ◽  
Wei Xiang ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Oxidative Phosphorylation ◽  
Near Infrared ◽  
Mitochondrial Metabolism ◽  
Diet Induced Obesity ◽  
Adipose Tissue Macrophages ◽  
Inflammatory Activation ◽  
Treatment Of Obesity ◽  
Pharmaceutical Agents

AbstractPro-inflammatory activation of adipose tissue macrophages (ATMs) is causally linked to obesity and obesity-associated disorders. A number of studies have demonstrated the crucial role of mitochondrial metabolism in macrophage activation. However, there is a lack of pharmaceutical agents to target the mitochondrial metabolism of ATMs for the treatment of obesity-related diseases. Here, we characterize a near-infrared fluorophore (IR-61) that preferentially accumulates in the mitochondria of ATMs and has a therapeutic effect on diet-induced obesity as well as obesity-associated insulin resistance and fatty liver. IR-61 inhibits the classical activation of ATMs by increasing mitochondrial complex levels and oxidative phosphorylation via the ROS/Akt/Acly pathway. Taken together, our findings indicate that specific enhancement of ATMs oxidative phosphorylation improves chronic inflammation and obesity-related disorders. IR-61 might be an anti-inflammatory agent useful for the treatment of obesity-related diseases by targeting the mitochondria of ATMs.

The Role of Tanycytes in the Hypothalamus-Pituitary-Thyroid Axis and the Possibilities for Their Genetic Manipulation

2019 ◽  
Vol 128 (06/07) ◽  
pp. 388-394
Author(s):  
Helge Müller-Fielitz ◽  
Markus Schwaninger
Keyword(s):  
Energy Homeostasis ◽  
Genetic Manipulation ◽  
Heart Function ◽  
Feedback Regulation ◽  
Target Organs ◽  
Pituitary Thyroid Axis ◽  
Thyroid Axis ◽  
Hpt Axis ◽  
The Brain

AbstractThyroid hormone (TH) regulation is important for development, energy homeostasis, heart function, and bone formation. To control the effects of TH in target organs, the hypothalamus-pituitary-thyroid (HPT) axis and the tissue-specific availability of TH are highly regulated by negative feedback. To exert a central feedback, TH must enter the brain via specific transport mechanisms and cross the blood-brain barrier. Here, tanycytes, which are located in the ventral walls of the 3rd ventricle in the mediobasal hypothalamus (MBH), function as gatekeepers. Tanycytes are able to transport, sense, and modify the release of hormones of the HPT axis and are involved in feedback regulation. In this review, we focus on the relevance of tanycytes in thyrotropin-releasing hormone (TRH) release and review available genetic tools to investigate the physiological functions of these cells.

The melanocortin system

2003 ◽  
Vol 284 (3) ◽  
pp. E468-E474 ◽  
Author(s):  
Ira Gantz ◽  
Tung M. Fong
Keyword(s):  
Sexual Function ◽  
Energy Homeostasis ◽  
Melanocortin Receptors ◽  
Experimental Basis ◽  
Melanocortin System ◽  
Genetic Studies ◽  
Melanocortin Peptides ◽  
Selective Agonists ◽  
Made In

The melanocortin system consists of melanocortin peptides derived from the proopiomelanocortin gene, five melanocortin receptors, two endogenous antagonists, and two ancillary proteins. This review provides an abbreviated account of the basic biochemistry, pharmacology, and physiology of the melanocortin system and highlights progress made in four areas. In particular, recent pharmacological and genetic studies have affirmed the role of melanocortins in pigmentation, inflammation, energy homeostasis, and sexual function. Development of selective agonists and antagonists is expected to further facilitate the investigation of these complex physiological functions and provide an experimental basis for new pharmacotherapies.

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