Identification of central projections from amylin-activated neurons to the lateral hypothalamus

Potes, Catarina Soares; Lutz, Thomas; Riediger, Thomas

doi:10.1016/j.brainres.2010.03.114

Cited by 47 publications

(49 citation statements)

References 67 publications

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“…Lesions of the respective brain areas (AP, NTS, and LPB) abolished amylin's effect, and activation (as indicated by c-Fos) was absent in brain areas rostral to the lesion (e.g., in the NTS, LPB, and CeA in AP lesioned rats, or in the CeA in LPB lesioned rats). The direct link between the respective brain areas was confirmed by the use of anterograde and retrograde neuronal tracers; these studies also identified the LPB as the primary relay between the hindbrain and the hypothalamus, including the lateral hypothalamic area, where amylin reduces fasting-induced c-Fos expression Potes et al, 2010a) and the VMH (Mollet et al, 2003b;Roth et al, 2008a;Turek et al, 2010). The latter area received more attention in recent years due to the possible role of the VMH in mediating the interaction between amylin and leptin (see section IX.A).…”

Section: Neuroaxis Activation By Amylinmentioning

confidence: 80%

“…A frequent marker to define stimulus-activated brain areas is based on the expression of the immediate early gene product c-Fos (Rowland et al, 1997;Becskei et al, 2004;Riediger et al, 2004;Mack et al, 2010;Potes et al, 2010a). It is important to note that c-Fos expression does not necessarily have a functional correlate for a behavioral effect of the same stimulus (e.g., see Züger et al, 2013).…”

Section: B Brainstem Mechanisms Mediating Amylin Signalingmentioning

confidence: 99%

“…Evidence for a critical role of specific hindbrain structures, in particular the AP, NTS, and LPB, is compelling; activation of these structures may then affect specific hypothalamic nuclei (Fig. 5), but their individual roles in the effects of amylin on eating are still not clear (Potes et al, 2010a;Trevaskis et al, 2010a;Turek et al, 2010). Furthermore, more studies are required to define the potential contribution of other circumventricular organs such as the SFO (Fry et al, 2007;Hoyda et al, 2009;Mimee et al, 2013).…”

Section: F Summarizing Remarksmentioning

confidence: 99%

See 2 more Smart Citations

Amylin: Pharmacology, Physiology, and Clinical Potential

Hay¹,

Chen²,

Lutz³

et al. 2015

Pharmacol Rev

291

297

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Section: Neuroaxis Activation By Amylinmentioning

confidence: 80%

Section: B Brainstem Mechanisms Mediating Amylin Signalingmentioning

confidence: 99%

Section: F Summarizing Remarksmentioning

confidence: 99%

See 1 more Smart Citation

Amylin: Pharmacology, Physiology, and Clinical Potential

Hay¹,

Chen²,

Lutz³

et al. 2015

Pharmacol Rev

291

297

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“…Fourth, brain structures shown to be synaptically activated by amylin (45,50), namely the NTS, LPB, Ce, and BSTL, also showed increased ERK1/2 phosphorylation after amylin treatment. Fifth, a blockade of the ERK cascade in the AP by injection of the MEK1/2 inhibitor U0126 into the 4V reduced the number of neurons displaying amylin-induced pERK in the AP by about 30%.…”

Section: Discussionmentioning

confidence: 92%

“…It is, however, important to note that the pERK signal in the LPB appeared to follow similar time lines as in the AP, i.e., there was a higher degree of stimulation at the 15-min time point. Our recent tracing studies showed that there is a prominent projection from the AP to the LPB (45). These studies had suggested that the amylin signal may at least in part be transmitted directly from the AP to the LPB, and that the indirect transmission via the NTS may be less important.…”

Section: Discussionmentioning

confidence: 98%

Involvement of the extracellular signal-regulated kinase 1/2 signaling pathway in amylin's eating inhibitory effect

Potes

Boyle

Wookey

et al. 2012

American Journal of Physiology-Regulatory, Integrative and Comp

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Potes CS, Boyle CN, Wookey PJ, Riediger T, Lutz TA. Involvement of the extracellular signal-regulated kinase 1/2 signaling pathway in amylin's eating inhibitory effect. Am J Physiol Regul Integr Comp Physiol 302: R340 -R351, 2012. First published November 30, 2011 doi:10.1152/ajpregu.00380.2011.-Peripheral amylin inhibits eating via the area postrema (AP). Because amylin activates the extracellular-signal regulated kinase 1/2 (ERK) pathway in some tissues, and because ERK1/2 phosphorylation (pERK) leads to acute neuronal responses, we postulated that it may be involved in amylin's eating inhibitory effect. Amylin-induced ERK phosphorylation (pERK) was investigated by immunohistochemistry in brain sections containing the AP. pERK-positive AP neurons were double-stained for the calcitonin 1a/b receptor, which is part of the functional amylin-receptor. AP sections were also phenotyped using dopamine-␤-hydroxylase (DBH) as a marker of noradrenergic neurons. The effect of fourth ventricular administration of the ERK cascade blocker U0126 on amylin's eating inhibitory action was tested in feeding trials. The number of pERK-positive neurons in the AP was highest ϳ10 -15 min after amylin treatment; the effect appeared to be dosedependent (5-20 g/kg amylin). A portion of pERK-positive neurons in the AP carried the amylin-receptor and 22% of the pERK-positive neurons were noradrenergic. Pretreatment of rats with U0126 decreased the number of pERK-positive neurons in the AP after amylin injection. U0126 also attenuated the ability of amylin to reduce eating, at least when the animals had been fasted 24 h prior to the feeding trial. Overall, our results suggest that amylin directly stimulates pERK in AP neurons in a time-and dose-dependent manner. Part of the AP neurons displaying pERK were noradrenergic. At least under fasting conditions, pERK was shown to be a necessary part in the signaling cascade mediating amylin's anorectic effect.ERK; MAPK; area postrema; amylin receptor; U0126 THE HOMEOSTATIC SYSTEM CONTROLLING food intake and body weight relies to a large extent on peripheral satiation signals.One of these signals is amylin, a peptide cosecreted with insulin by pancreatic ␤-cells in response to nutrient ingestion (12, 41). At near-physiological plasma concentrations, amylin effectively decreases food intake in rats, and is considered a physiological satiation signal (4, 27). The amylin analog pramlintide causes weight loss in obese humans that is accompanied by sustained reductions in 24-h food intake, portion sizes, fast food intake, and binge eating tendencies (5, 57).Pharmacological and lesioning studies implicate the area postrema (AP) as the primary site of amylin's anorectic action (29,30,35), and an excitatory action of amylin on AP neurons has been confirmed by electrophysiological studies (49). Immunohistochemical studies using the immediate early gene product c-Fos as a marker of neuronal activation showed that peripheral amylin activates the AP, and subsequently the nucleus of the solitary tract (NTS),...

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Brain microvascular injury and white matter disease provoked by diabetes‐associated hyperamylinemia

Verma

et al. 2017

Annals of Neurology

137

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Objectives The brain blood vessels of patients with type-2 diabetes and dementia have deposition of amylin, an amyloidogenic hormone co-secreted with insulin. It is not known whether vascular amylin deposition is a consequence or a trigger of vascular injury. We tested the hypothesis that the vascular amylin deposits cause endothelial dysfunction and microvascular injury and are modulated by the amylin transport in the brain via plasma apolipoproteins. Methods Rats overexpressing amyloidogenic (human) amylin in the pancreas (HIP rats) and amylin knockout (AKO) rats intravenously infused with aggregated amylin were used for in vivo phenotyping. We also carried out biochemical analyses of human brain tissues and studied the effects of the aggregated amylin on endothelial cells, ex vivo. Results Amylin deposition in brain blood vessels is associated with vessel wall disruption and abnormal surrounding neuropil in patients with type-2 diabetes and dementia, in HIP rats, and in AKO rats infused with aggregated amylin. HIP rats have brain microhemorrhages, white matter injury and neurologic deficits. Vascular amylin deposition provokes loss of endothelial cell coverage and tight junctions. Intravenous infusion in AKO rats of human amylin, or combined human amylin and apolipoprotein E4, showed that amylin binds to plasma apolipoproteins. The intravenous infusion of apolipoprotein E4 exacerbated the brain accumulation of aggregated amylin and vascular pathology in HIP rats. Interpretation These data identify vascular amylin deposition as a trigger of brain endothelial dysfunction that is modulated by plasma apolipoproteins and represents a potential therapeutic target in diabetes-associated dementia and stroke.

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Identification of central projections from amylin-activated neurons to the lateral hypothalamus

Cited by 47 publications

References 67 publications

Amylin: Pharmacology, Physiology, and Clinical Potential

Amylin: Pharmacology, Physiology, and Clinical Potential

Involvement of the extracellular signal-regulated kinase 1/2 signaling pathway in amylin's eating inhibitory effect

Brain microvascular injury and white matter disease provoked by diabetes‐associated hyperamylinemia

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