Feeding dynamics: Why rats eat in meals and what this means for foraging and feeding regulation.

Progranulin (PGRN) is a secreted glycoprotein with multiple biological functions, including modulation of wound healing and inflammation. Hypothalamic PGRN has been implicated in the development of sexual dimorphism. In the present study, a potential role for PGRN in the hypothalamic regulation of appetite and body weight was investigated. In adult rodents, PGRN was highly expressed in periventricular tanycytes and in hypothalamic neurons, which are known to contain glucose-sensing machinery. Hypothalamic PGRN expression levels were decreased under low-energy conditions (starvation and 2-deoxy-D-glucose administration) but increased under high-energy condition (postprandially). Intracerebrovetricular administration of PGRN significantly suppressed nocturnal feeding as well as hyperphagia induced by 2-deoxyglucose, neuropeptide Y, and Agouti-related peptide. Moreover, the inhibition of hypothalamic PGRN expression or action increased food intake and promoted weight gain, suggesting that endogenous PGRN functions as an appetite suppressor in the hypothalamus. Investigation of the mechanism of action revealed that PGRN diminished orexigenic neuropeptide Y and Agouti-related peptide production but stimulated anorexigenic proopiomelanocortin production, at least in part through the regulation of hypothalamic AMP-activated protein kinase. Notably, PGRN was also expressed in hypothalamic microglia. In diet-induced obese mice, microglial PGRN expression was increased, and the anorectic response to PGRN was blunted. These findings highlight a physiological role for PGRN in hypothalamic glucose-sensing and appetite regulation. Alterations in hypothalamic PGRN production or action may be linked to appetite dysregulation in obesity.

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Peripheral tissue–brain interactions in the regulation of food intake

Proceedings of The Nutrition Society ◽

10.1017/s0029665107005368 ◽

2007 ◽

Vol 66 (1) ◽

pp. 131-155 ◽

Cited By ~ 50

Author(s):

Miguel López ◽

Sulay Tovar ◽

María J. Vázquez ◽

Lynda M. Williams ◽

Carlos Diéguez

Keyword(s):

Fatty Acid Synthase ◽

Molecular Mechanisms ◽

Developed Countries ◽

Peripheral Tissue ◽

Feeding Regulation ◽

Pharmacological Targets ◽

The Central Nervous System ◽

Treatment Of Obesity ◽

Brain Interactions

More than 70 years ago the glucostatic, lipostatic and aminostatic hypotheses proposed that the central nervous system sensed circulating levels of different metabolites, changing feeding behaviour in response to the levels of those molecules. In the last 20 years the rapid increase in obesity and associated pathologies in developed countries has involved a substantial increase in the knowledge of the physiological and molecular mechanism regulating body mass. This effort has resulted in the recent discovery of new peripheral signals, such as leptin and ghrelin, as well as new neuropeptides, such as orexins, involved in body-weight homeostasis. The present review summarises research into energy balance, starting from the original classical hypotheses proposing metabolite sensing, through peripheral tissue–brain interactions and coming full circle to the recently-discovered role of hypothalamic fatty acid synthase in feeding regulation. Understanding these molecular mechanisms will provide new pharmacological targets for the treatment of obesity and appetite disorders.

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Ghrelin: a novel peptide for growth hormone release and feeding regulation

Current Opinion in Clinical Nutrition & Metabolic Care ◽

10.1097/00075197-200207000-00007 ◽

2002 ◽

Vol 5 (4) ◽

pp. 391-395 ◽

Cited By ~ 67

Author(s):

Fumiki Yoshihara ◽

Masayasu Kojima ◽

Hiroshi Hosoda ◽

Masamitsu Nakazato ◽

Kenji Kangawa

Keyword(s):

Growth Hormone ◽

Hormone Release ◽

Growth Hormone Release ◽

Feeding Regulation

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The Anorexigenic Neural Pathways of Oxytocin and Their Clinical Implication

Neuroendocrinology ◽

10.1159/000489263 ◽

2018 ◽

Vol 107 (1) ◽

pp. 91-104 ◽

Cited By ~ 12

Author(s):

Yuko Maejima ◽

Shoko Yokota ◽

Katsuhiko Nishimori ◽

Kenju Shimomura

Keyword(s):

Adipose Tissue ◽

Food Intake ◽

Fat Mass ◽

Physiological Role ◽

Leptin Resistance ◽

Neural Pathways ◽

Feeding Regulation ◽

Food Intake Regulation ◽

Intake Regulation ◽

The Brain

Oxytocin was discovered in 1906 as a peptide that promotes delivery and milk ejection; however, its additional physiological functions were determined 100 years later. Many recent articles have reported newly discovered effects of oxytocin on social communication, bonding, reward-related behavior, adipose tissue, and muscle and food intake regulation. Because oxytocin neurons project to various regions in the brain that contribute to both feeding reward (hedonic feeding) and the regulation of energy balance (homeostatic feeding), the mechanisms of oxytocin on food intake regulation are complicated and largely unknown. Oxytocin neurons in the paraventricular nucleus (PVN) receive neural projections from the arcuate nucleus (ARC), which is an important center for feeding regulation. On the other hand, these neurons in the PVN and supraoptic nucleus project to the ARC. PVN oxytocin neurons also project to the brain stem and the reward-related limbic system. In addition to this, oxytocin induces lipolysis and decreases fat mass. However, these effects in feeding and adipose tissue are known to be dependent on body weight (BW). Oxytocin treatment is more effective in food intake regulation and fat mass decline for individuals with leptin resistance and higher BW, but is known to be less effective in individuals with normal BW. In this review, we present in detail the recent findings on the physiological role of oxytocin in feeding regulation and the anorexigenic neural pathway of oxytocin neurons, as well as the advantage of oxytocin usage for anti-obesity treatment.

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Neuropeptide Y in normal eating and in genetic and dietary-induced obesity

Philosophical Transactions of the Royal Society B Biological Sciences ◽

10.1098/rstb.2006.1855 ◽

2006 ◽

Vol 361 (1471) ◽

pp. 1159-1185 ◽

Cited By ~ 127

Author(s):

B Beck

Keyword(s):

Neuropeptide Y ◽

Diet Composition ◽

High Energy ◽

Glucose Sensing ◽

Feeding Regulation ◽

Treatment Of Obesity ◽

The Brain ◽

Diet Type

Neuropeptide Y (NPY) is one the most potent orexigenic peptides found in the brain. It stimulates food intake with a preferential effect on carbohydrate intake. It decreases latency to eat, increases motivation to eat and delays satiety by augmenting meal size. The effects on feeding are mediated through at least two receptors, the Y1 and Y5 receptors. The NPY system for feeding regulation is mostly located in the hypothalamus. It is formed of the arcuate nucleus (ARC), where the peptide is synthesized, and the paraventricular (PVN), dorsomedial (DMN) and ventromedial (VMN) nuclei and perifornical area where it is active. This activity is modulated by the hindbrain and limbic structures. It is dependent on energy availability, e.g. upregulation with food deprivation or restriction, and return to baseline with refeeding. It is also sensitive to diet composition with variable effects of carbohydrates and fats. Leptin signalling and glucose sensing which are directly linked to diet type are the most important factors involved in its regulation. Absence of leptin signalling in obesity models due to gene mutation either at the receptor level, as in the Zucker rat, the Koletsky rat or the db / db mouse, or at the peptide level, as in ob / ob mouse, is associated with increased mRNA abundance, peptide content and/or release in the ARC or PVN. Other genetic obesity models, such as the Otsuka–Long–Evans–Tokushima Fatty rat, the agouti mouse or the tubby mouse, are characterized by a diminution in NPY expression in the ARC nucleus and by a significant increase in the DMN. Further studies are necessary to determine the exact role of NPY in these latter models. Long-term exposure to high-fat or high-energy palatable diets leads to the development of adiposity and is associated with a decrease in hypothalamic NPY content or expression, consistent with the existence of a counter-regulatory mechanism to diminish energy intake and limit obesity development. On the other hand, an overactive NPY system (increased mRNA expression in the ARC associated with an upregulation of the receptors) is characteristic of rats or rodent strains sensitive to dietary-induced obesity. Finally, NPY appears to play an important role in body weight and feeding regulation, and while it does not constitute the only target for drug treatment of obesity, it may nevertheless provide a useful target in conjunction with others.

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Hypothalamic Neuropeptides and Feeding Regulation

Appetite and Body Weight ◽

10.1016/b978-012370633-1/50004-9 ◽

2007 ◽

pp. 67-98 ◽

Cited By ~ 1

Author(s):

Bernard Beck

Keyword(s):

Feeding Regulation ◽

Hypothalamic Neuropeptides

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Orexin-A Exerts Equivocal Role in Atherosclerosis Process Depending on the Duration of Exposure: In Vitro Study

Nutrients ◽

10.3390/nu12010053 ◽

2019 ◽

Vol 12 (1) ◽

pp. 53

Author(s):

Narjes Nasiri Ansari ◽

Flora Spentza ◽

Georgios Dimitriadis ◽

Aphrodite Daskalopoulou ◽

Angeliki Karapanagioti ◽

...

Keyword(s):

Gelatin Zymography ◽

In Vitro Study ◽

Tissue Inhibitor Of Metalloproteinase ◽

Intermittent Fasting ◽

Mrna Levels ◽

High Concentration ◽

Orexin A ◽

Monocyte Chemoattractant Protein 1 ◽

Feeding Regulation

Orexin-A is a peptide hormone that plays a crucial role in feeding regulation and energy homeostasis. Diurnal intermittent fasting (DIF) has been found to increase orexin-A plasma levels during fasting hours, while Ramadan fasting which resembles DIF, has led to beneficial effects on endothelial function. Herein, we aimed to investigate the effects of orexin-A on the expression of molecules involved in the atherogenesis process: Monocyte chemoattractant protein-1 (MCP-1), matrix metalloproteinases 2 and 9 (MMP-2 and MMP-9) and tissue inhibitor of metalloproteinase-1 and 2 (TIMP-1 and TIMP-2), in human aortic endothelial cells (HAECs). HAECs were incubated with orexin-A at concentrations of 40 ng/mL, 200 ng/mL and 400 ng/mL for 6, 12 and 24 h. The mRNA levels of MCP-1, MMP-2, MMP-9, TIMP-1, and TIMP-2 and orexin-1 receptor were measured by real-time qPCR. We also evaluated the MMP-2, p38, phospho-p38, NF-κΒ/p65 as well as TIMP-1 protein levels by Western blot and ELISA, respectively. MMP-2 activity was measured by gelatin zymography. Short-term 6-h incubation of HAECs with orexin-A at a high concentration (400 ng/mL) decreased MCP-1, MMP-2 expression, MMP-2/TIMP-1 ratio (p < 0.05), and MMP-2 activity, while incubation for 24 h increased MCP-1, MMP-2 expression (p < 0.05), MMP-2/TIMP-1 and MMP-2/TIMP-2 ratio (p < 0.01 and p < 0.05, respectively) as well as MMP-2 activity. The dual effects of orexin-A are mediated, at least in part, via regulation of p38 and NF-κΒ pathway. Orexin-A may have an equivocal role in atherosclerosis process with its effects depending on the duration of exposure.

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