Aminoprocalcitonin-mediated suppression of feeding involves the hypothalamic melanocortin system

2013 ◽  
Vol 304 (12) ◽  
pp. E1251-E1262 ◽  
Author(s):  
Eva Tavares ◽  
Rosario Maldonado ◽  
Francisco J. Miñano
Keyword(s):  
Food Intake ◽  
Energy Homeostasis ◽  
Arcuate Nucleus ◽  
Suppressive Effect ◽  
Neural Pathways ◽  
Peptidergic Neurons ◽  
Melanocortin System ◽  
Pomc Mrna ◽  
Calcitonin Receptors ◽  
Fasted Rats

Aminoprocalcitonin (N-PCT), a neuroendocrine peptide encoded by the calcitonin-I (CALC-I) gene, suppresses food intake when administered centrally in rats. However, the neural pathways underlying this effect remain unclear. N-PCT and calcitonin receptors (CT-R) have been identified in hypothalamic regions involved in energy homeostasis, including the arcuate nucleus (ARC). Here, we hypothesized an involvement of the hypothalamic ARC in mediating the anorexic effects of central N-PCT based on its content of peptidergic neurons involved in feeding and its expression of N-PCT and CT-R. Fasting strongly reduced expression of the N-PCT precursor gene CALC-I in the ARC, and central immunoneutralization of endogenous N-PCT increased food intake. Intracerebroventricular administration of N-PCT reduced food intake in fed and fasted rats, and its effect was attenuated by a neutralizing anti-N-PCT antibody. Immunohistochemistry for N-PCT showed that it is expressed in astrocytes and neurons in the ARC and is colocalized with anorexigenic proopiomelanocortin (POMC) neurons. Fasting reduced coexpression of N-PCT and POMC, and N-PCT administration activated hypothalamic neurons, including rostral POMC neurons. We also found that N-PCT stimulates POMC mRNA expression in fed and fasted rats, whereas it reduced the expression of orexigenic peptides neuropeptide Y (NPY) and agouti-related peptide (AgRP) only in fasted rats in which those mRNAs are normally elevated. Finally, we showed that the melanocortin-3/4 receptor antagonist SHU 9119 attenuates the intake-suppressive effect of N-PCT. These data demonstrate that hypothalamic N-PCT is involved in control of energy balance and that its anorexigenic effects are mediated through the melanocortin system.

scholarly journals Arcuate Nucleus Proopiomelanocortin Neurons Mediate the Acute Anorectic Actions of Leukemia Inhibitory Factor via gp130

Endocrinology ◽  
2010 ◽  
Vol 151 (2) ◽  
pp. 606-616 ◽  
Author(s):  
Aaron J. Grossberg ◽  
Jarrad M. Scarlett ◽  
XinXia Zhu ◽  
Darren D. Bowe ◽  
Ayesha K. Batra ◽  
...  
Keyword(s):  
Food Intake ◽  
Proinflammatory Cytokine ◽  
Leukemia Inhibitory Factor ◽  
Arcuate Nucleus ◽  
Ex Vivo ◽  
Inhibitory Factor ◽  
Neural Pathways ◽  
Disease States ◽  
Inhibit Food Intake ◽  
Anorexigenic Peptide

The proinflammatory cytokine leukemia inhibitory factor (LIF) is induced in disease states and is known to inhibit food intake when administered centrally. However, the neural pathways underlying this effect are not well understood. We demonstrate that LIF acutely inhibits food intake by directly activating pro-opiomelanocortin (POMC) neurons in the arcuate nucleus of the hypothalamus. We show that arcuate POMC neurons express the LIF-R, and that LIF stimulates the release of the anorexigenic peptide, α-MSH from ex vivo hypothalami. Transgenic mice lacking gp130, the signal transducing subunit of the LIF-R complex, specifically in POMC neurons fail to respond to LIF. Furthermore, LIF does not stimulate the release of α-MSH from the transgenic hypothalamic explants. These findings indicate that POMC neurons mediate the acute anorectic actions of central LIF administration and provide a mechanistic link between inflammation and food intake.

scholarly journals Serotonin 5-HT2C Receptor Agonist Promotes Hypophagia via Downstream Activation of Melanocortin 4 Receptors

Endocrinology ◽  
2007 ◽  
Vol 149 (3) ◽  
pp. 1323-1328 ◽  
Author(s):  
Daniel D. Lam ◽  
Magdalena J. Przydzial ◽  
Simon H. Ridley ◽  
Giles S. H. Yeo ◽  
Justin J. Rochford ◽  
...  
Keyword(s):  
Energy Balance ◽  
Food Intake ◽  
Arcuate Nucleus ◽  
Weight Percent ◽  
Ingestive Behavior ◽  
The Novel ◽  
Functional Importance ◽  
Serotonin 2C Receptor ◽  
Pomc Mrna ◽  
Melanocortin 4 Receptor

The neurotransmitter serotonin (5-hydroxytryptamine) is a well-established modulator of energy balance. Both pharmacological and genetic evidence implicate the serotonin 2C receptor (5-HT2CR) as a critical receptor mediator of serotonin’s effects on ingestive behavior. Here we characterized the effect of the novel and selective 5-HT2CR agonist BVT.X on energy balance in obese and lean mice and report that BVT.X significantly reduces acute food intake without altering locomotor activity or oxygen consumption. In an effort to elucidate the mechanism of this effect, we examined the chemical phenotype of 5-HT2CR-expressing neurons in a critical brain region affecting feeding behavior, the arcuate nucleus of the hypothalamus. We show that 5-HT2CRs are coexpressed with neurons containing proopiomelanocortin, known to potently affect appetite, in the arcuate nucleus of the hypothalamus of the mouse. We then demonstrate that prolonged infusion with BVT.X in obese mice significantly increases Pomc mRNA and reduces body weight, percent body fat, and initial food intake. To evaluate the functional importance of melanocortin circuitry in the effect of BVT.X on ingestive behavior, we assessed mice with disrupted melanocortin pathways. We report that mice lacking the melanocortin 4 receptor are not responsive to BVT.X-induced hypophagia, demonstrating that melanocortins acting on melanocortin 4 receptor are a requisite downstream pathway for 5-HT2CR agonists to exert effects on food intake. The data presented here not only indicate that the novel 5-HT2CR agonist BVT.X warrants further investigation as a treatment for obesity but also elucidate specific neuronal pathways potently affecting energy balance through which 5-HT2CR agonists regulate ingestive behavior.

scholarly journals Involvement of the Acyl-CoA binding domain containing 7 in the control of food intake and energy expenditure in mice

eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
Damien Lanfray ◽  
Alexandre Caron ◽  
Marie-Claude Roy ◽  
Mathieu Laplante ◽  
Fabrice Morin ◽  
...  
Keyword(s):  
Food Intake ◽  
Energy Expenditure ◽  
Arcuate Nucleus ◽  
Binding Domain ◽  
Nucleotide Polymorphism ◽  
Melanocortin System ◽  
Single Nucleotide ◽  
Hypothalamic Arcuate Nucleus ◽  
Paralog Gene ◽  
G Protein Coupled

Acyl-CoA binding domain-containing 7 (Acbd7) is a paralog gene of the diazepam-binding inhibitor/Acyl-CoA binding protein in which single nucleotide polymorphism has recently been associated with obesity in humans. In this report, we provide converging evidence indicating that a splice variant isoform of the Acbd7 mRNA is expressed and translated by some POMC and GABAergic-neurons in the hypothalamic arcuate nucleus (ARC). We have demonstrated that the ARC ACBD7 isoform was produced and processed into a bioactive peptide referred to as nonadecaneuropeptide (NDN) in response to catabolic signals. We have characterized NDN as a potent anorexigenic signal acting through an uncharacterized endozepine G protein-coupled receptor and subsequently via the melanocortin system. Our results suggest that ACBD7-producing neurons participate in the hypothalamic leptin signalling pathway. Taken together, these data suggest that ACBD7-producing neurons are involved in the hypothalamic control exerted on food intake and energy expenditure by the leptin-melanocortin pathway.

scholarly journals A novel satiety sensor detects circulating glucose and suppresses food consumption via insulin-producing cells in Drosophila

Cell Research ◽  
2020 ◽  
Author(s):  
Wei Qi ◽  
Gaohang Wang ◽  
Liming Wang
Keyword(s):  
Food Intake ◽  
Food Consumption ◽  
Energy Homeostasis ◽  
Animal Species ◽  
Suppressive Effect ◽  
Food Ingestion ◽  
Neural Regulation ◽  
Insulin Producing Cells ◽  
Survival Skill ◽  
Regulate Food Intake

AbstractSensing satiety is a crucial survival skill for all animal species including human. Despite the discovery of numerous neuromodulators that regulate food intake in Drosophila, the mechanism of satiety sensing remains largely elusive. Here, we investigated how neuropeptidergic circuitry conveyed satiety state to influence flies’ food consumption. Drosophila tackykinin (DTK) and its receptor TAKR99D were identified in an RNAi screening as feeding suppressors. Two pairs of DTK+ neurons in the fly brain could be activated by elevated D-glucose in the hemolymph and imposed a suppressive effect on feeding. These DTK+ neurons formed a two-synapse circuitry targeting insulin-producing cells, a well-known feeding suppressor, via TAKR99D+ neurons, and this circuitry could be rapidly activated during food ingestion and cease feeding. Taken together, we identified a novel satiety sensor in the fly brain that could detect specific circulating nutrients and in turn modulate feeding, shedding light on the neural regulation of energy homeostasis.

Chronic food restriction and acute food deprivation decrease mRNA levels of opioid peptides in arcuate nucleus

1996 ◽  
Vol 270 (5) ◽  
pp. R1019-R1024 ◽  
Author(s):  
E. M. Kim ◽  
C. C. Welch ◽  
M. K. Grace ◽  
C. J. Billington ◽  
A. S. Levine
Keyword(s):  
Body Weight ◽  
Food Intake ◽  
Food Deprivation ◽  
Food Restriction ◽  
Arcuate Nucleus ◽  
Mrna Levels ◽  
Endogenous Opioid ◽  
Pomc Mrna ◽  
Opioid Administration ◽  
Ad Libitum Intake

Although opioid administration induces food intake, the relationship between endogenous opioid synthesis and food consumption is unclear. Two studies examined the effects of food restriction and deprivation on opioid mRNA levels in the arcuate nucleus (ARC) of the rat. Body weight significantly decreased following food restriction and deprivation (P < 0.0001). In experiment 1, food restriction of 10,20,30, and 40% (g) of ad libitum intake for 14 days decreased proDynorphin (proDyn), proEnkephalin (proEnk), and proOpiomelanocortin (POMC) mRNA levels in a linear fashion relative to changes in body weight (r = 0.398, P = 0.0011; r = 0.455, P = 0.0028; r = 0.292, P = 0.0642, respectively). In experiment 2, 48 h deprivation significantly decreased mRNA levels of proDyn and POMC by 23.7% (P < 0.05) and 45.6% (P < 0.01), respectively, whereas 24 h food deprivation decreased POMC mRNA by 43.% (P < 0.01). proEnk mRNA was not affected by 24- or 48-h food deprivation. Restricting food intake suppressed mRNA levels of proDyn, proEnk, and POMC by 29.7, 22.3, and 44.4%, respectively, in 20% restricted rats and by 35.5, 26.8, and 45.6%, respectively, in 40%restricted rats (P < 0.01). It appears that ARC mRNA levels of proDyn, proEnk, and POMC are directly related to the amount of food consumed and/or changes in body weight in food-restricted and food-deprived rats.

scholarly journals Arcuate nucleus and lateral hypothalamic CART neurons in the mouse brain exert opposing effects on energy expenditure

eLife ◽  
2018 ◽  
Vol 7 ◽  
Author(s):  
Aitak Farzi ◽  
Jackie Lau ◽  
Chi Kin Ip ◽  
Yue Qi ◽  
Yan-Chuan Shi ◽  
...  
Keyword(s):  
Physical Activity ◽  
Food Intake ◽  
Energy Expenditure ◽  
Lateral Hypothalamus ◽  
Energy Homeostasis ◽  
Arcuate Nucleus ◽  
Neuronal Populations ◽  
Neuron Activation ◽  
Important Regulator ◽  
Opposing Effects

Cocaine- and amphetamine-regulated transcript (CART) is widely expressed in the hypothalamus and an important regulator of energy homeostasis; however, the specific contributions of different CART neuronal populations to this process are not known. Here, we show that depolarization of mouse arcuate nucleus (Arc) CART neurons via DREADD technology decreases energy expenditure and physical activity, while it exerts the opposite effects in CART neurons in the lateral hypothalamus (LHA). Importantly, when stimulating these neuronal populations in the absence of CART, the effects were attenuated. In contrast, while activation of CART neurons in the LHA stimulated feeding in the presence of CART, endogenous CART inhibited food intake in response to Arc CART neuron activation. Taken together, these results demonstrate anorexigenic but anabolic effects of CART upon Arc neuron activation, and orexigenic but catabolic effects upon LHA-neuron activation, highlighting the complex and nuclei-specific functions of CART in controlling feeding and energy homeostasis.

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

2019 ◽  
Vol 3 (3) ◽  
pp. 590-601 ◽  
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.

scholarly journals The central melanocortin system and human obesity

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.

scholarly journals Arcuate Nucleus-Specific Leptin Receptor Gene Therapy Attenuates the Obesity Phenotype of Koletsky (fak/fak) Rats

Endocrinology ◽  
2003 ◽  
Vol 144 (5) ◽  
pp. 2016-2024 ◽  
Author(s):  
Gregory J. Morton ◽  
Kevin D. Niswender ◽  
Christopher J. Rhodes ◽  
Martin G. Myers ◽  
James E. Blevins ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Body Weight ◽  
Food Intake ◽  
Energy Homeostasis ◽  
Arcuate Nucleus ◽  
Leptin Receptor ◽  
Receptor Expression ◽  
Wild Type ◽  
Leptin Signaling ◽  
Adenoviral Gene Therapy

Leptin signaling in the hypothalamic arcuate nucleus (ARC) is hypothesized to play an important role in energy homeostasis. To investigate whether leptin signaling limited to this brain area is sufficient to reduce food intake and body weight, we used adenoviral gene therapy to express the signaling isoform of the leptin receptor, leprb, in the ARC of leptin receptor-deficient Koletsky (fak/fak) rats. Successful expression of adenovirus containing leprb (Ad-leprb) selectively in the ARC was documented by in situ hybridization. Using real-time PCR, we further demonstrated that bilateral microinjection of Ad-leprb into the ARC restored low hypothalamic levels of leprb mRNA to values approximating those of wild-type (Fak/Fak) controls. Restored leptin receptor expression in the ARC reduced both mean daily food intake (by 13%) and body weight gain (by 33%) and increased hypothalamic proopiomelanocortin mRNA by 65% while decreasing neuropeptide Y mRNA levels by 30%, relative to fak/fak rats injected with a control adenovirus (Ad-lacZ) (P &lt; 0.05 for each comparison). In contrast, Ad-leprb delivery to either the lateral hypothalamic area of fak/fak rats or to the ARC of wild-type Fak/Fak rats had no effect on any of these parameters. These findings collectively support the hypothesis that leptin receptor signaling in the ARC is sufficient to mediate major effects of leptin on long-term energy homeostasis. Adenoviral gene therapy is thus a viable strategy with which to study the physiological importance of specific molecules acting in discrete brain areas.

scholarly journals Central administration of resistin promotes short-term satiety in rats

2005 ◽  
Vol 153 (3) ◽  
pp. R1-R5 ◽  
Author(s):  
Sulay Tovar ◽  
Rubén Nogueiras ◽  
Loraine Y C Tung ◽  
Tamara R Castañeda ◽  
María Jesús Vázquez ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Food Intake ◽  
Energy Homeostasis ◽  
Therapeutic Potential ◽  
Central Administration ◽  
Fos Protein ◽  
Physiological Relevance ◽  
Affect Body Weight ◽  
Hypothalamic Structure ◽  
Fasted Rats

Objective: Several hormones expressed in white adipose tissue influence food intake at the central level. We sought to determine whether resistin, a circulating adipose-derived hormone in rodents, has actions on the hypothalamus by determining the effects of central resistin injection on food intake and on hypothalamic Fos protein expression. Design: As resistin expression in adipose tissue is influenced by altered nutritional status, we studied the effect of central resistin in both fed and pre-fasted rats. Results: In fasted rats, central injection of resistin decreased food intake acutely and increased the number of cells that express Fos protein in the arcuate nucleus but not in any other hypothalamic structure. The effect on food intake was dose-dependent and did not result in the formation of a conditioned taste aversion. Conclusions: Taken together, these results provide the first evidence documenting a central action of resistin, which could be involved in a feedback loop targeting the hypothalamus. On the other hand, since we observed resistin mRNA in the arcuate and ventromedial nuclei of the hypothalamus, it is also possible that brain-derived resistin serves as a neuropeptide involved in the regulation of energy homeostasis. However, since resistin-induced satiety was modest and transient, as central administration for several days did not affect body weight, the physiological relevance and therapeutic potential of the observed principal phenomenon may be limited.

Sign in / Sign up

Export Citation Format

Share Document