Melanocortinergic Activation by Melanotan II Inhibits Feeding and Increases Uncoupling Protein 1 Messenger Ribonucleic Acid in the Developing Rat

Glavas, Maria M.; Joachim, Sandra E.; Draper, Shin J.; Smith, M. Susan; Grove, Kevin L.

doi:10.1210/en.2007-0184

Cited by 36 publications

(31 citation statements)

References 43 publications

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“…However, the functional significance of the overlap in POMC-and AgRP-positive fibers in target areas is not established. POMC neurons provide excitatory input to postsynaptic cells, as revealed by treatment with melanocortin analogs, which activates Fos gene expression in target neurons (39)(40)(41). Thus, we expected that chronic blockade of melanocortin signaling would reduce the activation of postsynaptic cells when AgRP neurons were ablated and either prevent or retard the rate of starvation.…”

Section: Discussionmentioning

confidence: 99%

Starvation after AgRP neuron ablation is independent of melanocortin signaling

Howell

Cowley

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

107

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Ablation of inhibitory agouti-related protein (AgRP)-expressing neurons in the arcuate nucleus that also synthesize ␥-aminobutyric acid (GABA) and neuropeptide Y in adult mice leads to starvation within 1 week. The removal of inhibition from the AgRP neurons onto neighboring proopiomelanocortin neurons and their common postsynaptic neurons is predicted to stimulate melanocortin signaling, which is known to inhibit appetite. To examine the importance of uncontrolled melanocortin signaling in mediating starvation in this model, we ablated AgRP neurons in A y /a mice that have chronic blockade of the melanocortin signaling. The blockade of melanocortin signaling did not ameliorate the rate of starvation. On both WT and A y /a genetic backgrounds, there was a progressive decrease in meal frequency after AgRP neuron ablation. Surprisingly, intraoral feeding also was dramatically reduced after the ablation of AgRP neurons. These results indicate that both the appetitive and consummatory aspects of feeding become impaired in a melanocortin-independent manner after AgRP neuron ablation.T he melanocortin signaling pathway in the medial hypothalamus has emerged as a critical mediator of hormonal and neuronal signals that regulate energy balance (1-3). Genetic, pharmacological, anatomical, and electrophysiological techniques have established a pivotal role for proopiomelanocortin (POMC) neurons in the arcuate (ARC) and their signaling via melanocortin (␣-MSH) to cells bearing melanocortin-4 receptors (MC4R) in the paraventricular nucleus (PVN) and other brain regions in the control of appetite and metabolism (1,4,5). Neighboring cells that coexpress neuropeptide Y (NPY) and agouti-related protein (AgRP) also have been implicated in appetite and energy balance because these peptides stimulate robust feeding when injected into the brain, and their mRNA levels increase in the ARC under starvation conditions, as well as in obese animals deficient in leptin signaling (2,(6)(7)(8). Various experiments suggest that NPY acts by inhibiting the activity of POMC neurons and postsynaptic MC4R-bearing cells by activating G␣i-coupled NPY Y1 and/or Y5 receptors (7, 9-12). The activation of these receptors is predicted to counteract melanocortin activation of G␣s-coupled MC4R. AgRP acts in concert with NPY by blocking the binding of ␣-MSH to MC4R (8,13,14). The neurons that make NPY and AgRP also produce GABA, which inhibits POMC neurons and probably MC4R-bearing cells (15,16). Thus, these AgRP neurons are poised to inhibit melanocortin signaling by the neighboring POMC cells.The activation of melanocortin signaling by leptin inhibits appetite while stimulating metabolism (1, 2, 6). Consequently, the inactivation of mouse genes encoding leptin, leptin receptor, POMC, or MC4R leads to obesity (17)(18)(19)(20). However, the inactivation of genes encoding NPY, AgRP, or both has little effect on energy balance (21-23). These genetic results suggest that compensatory mechanisms in the KO mice mask the normal role of these peptides. Nevertheles...

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Section: Discussionmentioning

confidence: 99%

Starvation after AgRP neuron ablation is independent of melanocortin signaling

Howell

Cowley

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

107

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“…ii) BAT thermogenesis is mainly mediated by the melanocortin system. More than 80% of the neurons projecting to BATexpress melanocortin receptors (Song et al 2008), and administration of melanocortin receptor agonists induces UCP1 activation in BAT (Brito et al 2007, Glavas et al 2007) and enhances SNS activity to both WAT and BAT (Brito et al 2007). Therefore, the stimulatory effect of estrogen on the melanocortin system also probably affects BAT thermogenesis.…”

Section: Estrogen and Melanocortin/leptin-mediated Thermogenesismentioning

confidence: 99%

Role of sex hormones in modulation of brown adipose tissue activity

Quarta

Mazza²,

Pasquali³

et al. 2012

Journal of Molecular Endocrinology

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The recent demonstration that metabolically active brown adipose tissue (BAT) is present with a high prevalence in humans undoubtedly represents one of the major advancements in the field of metabolic research in the last few years. The increasing interest in BAT is justified by preclinical observations highlighting an important role of this tissue in energy dissipation and metabolic clearance of substrates from the blood. These findings imply that stimulation of BAT activity may represent a new therapeutic approach for obesity and associated comorbidities. However, before proposing BAT as a target organ for therapeutics in a clinical setting, many further notions about BAT function and modulation need to be explored. Keeping in mind the importance of sex dimorphism in energy metabolism control under physiological and pathological conditions, sex hormones may play a relevant role in the regulation of BAT activity in both males and females. Much of the evidence acquired in the past supports the concept of an important role for different sex hormones in BAT thermogenesis and indicates that this tissue mediates the ability of sex hormones to modulate energy balance. These findings make it plausible that a modified interaction between BAT and sex hormones may contribute to the development and the maintenance of obesity and associated metabolic complications.Journal of Molecular Endocrinology (2012) 49, R1-R7

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“…agonists, such as Melanotan II (MTIIFa synthetic analog of amelanocyte-stimulating hormone), induce UCP1 in BAT 68,69 while enhancing SNS discharge to both adipose tissues. 69 Song et al 19,70 and Voss-Andreae et al 71 have clearly established a connection between the MC4R-containing neurons and BAT or WAT.…”

Section: 60-62mentioning

confidence: 99%

Determinants of brown adipocyte development and thermogenesis

et al. 2010

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The brown adipocyte is a thermogenic cell. Its thermogenic potential is conferred by uncoupling protein-1, which 'uncouples' adenosine triphosphate synthesis from energy substrate oxidation. Brown fat cells in so-called classical brown adipose tissue (BAT) share their origin with myogenic factor-5-expressing myoblasts. The development of myocyte/brown adipocyte progenitor cells into a brown adipocyte lineage is apparently triggered by bone morphogenetic protein-7, which stimulates inducers of brown fat cell differentiation, such as PRD1-BF1-RIZ1 homologous domain-containing-16 and peroxisome proliferator-activated receptor-g co-activator-1-a. The control of brown fat cell development and activity is physiologically ensured by the sympathetic nervous system (SNS), which densely innervates BAT. SNS-mediated thermogenesis is largely governed by hypothalamic and brainstem neurons. With regard to energy balance, the leptin-melanocortin pathway appears to be a major factor in controlling brown adipocyte thermogenesis. The involvement of this homeostatic pathway further supports the role of the brown adipocyte in energy balance regulation. The interest for the brown fat cell and its potential role in energy balance has been further rejuvenated recently by the demonstration that BAT can be present in substantial amounts in humans, in contrast to what has always been thought. Positron emission tomography/computed tomography scanning investigations have indeed revealed the presence in humans of important neck and shoulder cold-activable BAT depots, in particular, in young, lean and female subjects. This short review summarizes recent progress made in the biology of the brown fat cell and focuses on the determinants of the brown adipocyte development and activity.

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Melanocortinergic Activation by Melanotan II Inhibits Feeding and Increases Uncoupling Protein 1 Messenger Ribonucleic Acid in the Developing Rat

Cited by 36 publications

References 43 publications

Starvation after AgRP neuron ablation is independent of melanocortin signaling

Starvation after AgRP neuron ablation is independent of melanocortin signaling

Role of sex hormones in modulation of brown adipose tissue activity

Determinants of brown adipocyte development and thermogenesis

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