Inhibition of Central Amylin Signaling Increases Food Intake and Body Adiposity in Rats

Rushing, Paul A.; Hagan, Mary M.; Seeley, Randy J.; Lutz, Thomas; D’Alessio, David A.; Air, Ellen L.; Woods, Stephen C.

doi:10.1210/endo.142.11.8593

Cited by 137 publications

(66 citation statements)

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“…Thus, upcoming studies should explore and define the brain areas involved in the ability of sCT to regulate alcohol-mediated behaviours. Moreover, in light of the findings that amylin receptor inhibition increases food intake as well as body adiposity in rats (Rushing et al 2001;Reidelberger et al 2004), future experiments exploring the possibility that an amylinergic receptor antagonist increases alcohol intake are warranted.…”

Section: Discussionmentioning

confidence: 99%

Activation of amylin receptors attenuates alcohol‐mediated behaviours in rodents

2018

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Alcohol expresses its reinforcing properties by activating areas of the mesolimbic dopamine system, which consists of dopaminergic neurons projecting from the ventral tegmental area to the nucleus accumbens. The findings that reward induced by food and addictive drugs involve common mechanisms raise the possibility that gut-brain hormones, which control appetite, such as amylin, could be involved in reward regulation. Amylin decreases food intake, and despite its implication in the regulation of natural rewards, tenuous evidence support amylinergic mediation of artificial rewards, such as alcohol. Therefore, the present experiments were designed to investigate the effect of salmon calcitonin (sCT), an amylin receptor agonist and analogue of endogenous amylin, on various alcohol-related behaviours in rodents. We showed that acute sCT administration attenuated the established effects of alcohol on the mesolimbic dopamine system, particularly alcohol-induced locomotor stimulation and accumbal dopamine release. Using the conditioned place preference model, we demonstrated that repeated sCT administration prevented the expression of alcohol's rewarding properties and that acute sCT administration blocked the reward-dependent memory consolidation. In addition, sCT pre-treatment attenuated alcohol intake in low alcohol-consuming rats, with a more evident decrease in high alcohol consumers in the intermittent alcohol access model. Lastly, sCT did not alter peanut butter intake, blood alcohol concentration and plasma corticosterone levels in mice. Taken together, the present data support that amylin signalling is involved in the expression of alcohol reinforcement and that amylin receptor agonists could be considered for the treatment of alcohol use disorder in humans.

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Section: Discussionmentioning

confidence: 99%

Activation of amylin receptors attenuates alcohol‐mediated behaviours in rodents

2018

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“…The amylin receptor antagonist AC187 (R&D Systems, Minneapolis, MN, USA) was dissolved in aCSF. Dose responses for drugs were selected from the literature (Hayes et al, 2011;Lutz et al, 2000;Mollet et al, 2004;Rushing et al, 2001Rushing et al, , 2000Wielinga et al, 2007).…”

Section: Drugsmentioning

confidence: 99%

“…To address this issue, rats received counterbalanced intra-VTA injections of the amylin receptor antagonist AC187 (Mollet et al, 2004;Rushing et al, 2001;0.3 .05)). Subsequent chow intake (b), total 24 h energy intake (c), and 24 h body weight change (d) were also reduced by sCT, but only by the higher (0.04 mg) dose of drug (*significantly different from vehicle (Po0.05)).…”

Section: Amylin Receptor Signaling In the Vta Is Physiologically And mentioning

confidence: 99%

Amylin Receptor Signaling in the Ventral Tegmental Area is Physiologically Relevant for the Control of Food Intake

Mietlicki‐Baase

Rupprecht

Olivos

et al. 2013

Neuropsychopharmacol

116

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The ability of amylin, a pancreatic b-cell-derived neuropeptide, to promote negative energy balance has been ascribed to neural activation at the area postrema. However, despite amylin binding throughout the brain, the possible role of amylin signaling at other nuclei in the control of food intake has been largely neglected. We show that mRNA for all components of the amylin receptor complex is expressed in the ventral tegmental area (VTA), a mesolimbic structure mediating food intake and reward. Direct activation of VTA amylin receptors reduces the intake of chow and palatable sucrose solution in rats. This effect is mediated by reductions in meal size and is not due to nausea/malaise or prolonged suppression of locomotor activity. VTA amylin receptor activation also reduces sucrose selfadministration on a progressive ratio schedule. Finally, antagonist studies provide novel evidence that VTA amylin receptor blockade increases food intake and attenuates the intake-suppressive effects of a peripherally administered amylin analog, suggesting that amylin receptor signaling in the VTA is physiologically relevant for food intake control and potentially clinically relevant for the treatment of obesity.

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“…When administered exogenously (peripherally or centrally), acute amylin dose-dependently decreases food intake, causing a decrease in meal size though having no effect on the intermeal interval [14,15]. Furthermore, the decrease in meal size is not a result of an aversive or toxic effect of amylin [14,16].…”

Section: Introductionmentioning

confidence: 99%

Influence of high-fat feeding, diet-induced obesity, and hyperamylinemia on the sensitivity to acute amylin

Boyle¹,

Rossier²,

Lutz³

2011

Physiology & Behavior

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Obesity results in the increased secretion of various hormones controlling food intake and body weight, such as leptin, and insulin; increased circulating levels of pancreatic amylin have also been described in obese humans and rodents. Because leptin-resistance is present in diet-induced obese (DIO) rats, and because hyperleptinemia seems necessary for the full development of leptin resistance, we tested whether amylin sensitivity is inversely correlated with adiposity, such that DIO reduces the anorectic action of acute amylin. We also determined if hyperamylinemia leads to a change in amylin sensitivity. In the first experiment, rats were chronically exposed to a high fat (HF; 60% fat) diet or fed standard chow for control. The anorectic response to amylin was tested on several occasions over a 14 week observation period. HF feeding led to the expected increase in body adiposity; the response to an acute amylin injection (5-50 g/kg s.c.) was unaltered for 10 weeks of HF feeding. Even after 12 weeks on a HF diet, which clearly caused obesity, acute administration of amylin (5 g/kg, s.c.) was still able to suppress food intake, although the suppression was not statistically significant. Further experiments using additional doses of amylin will be necessary to demonstrate possible amylin resistance after HF feeding or in DIO rats. In the second experiment, we tested more specifically whether hyperamylinemia that may result from HF feeding and subsequent obesity, reduces the sensitivity of the amylin signaling system. To avoid confounding factors, we chronically infused lean chow fed rats with amylin (5 or 10 g/kg/day s.c.) to elevate their plasma amylin concentration to levels observed in obese rats (30-40 pM). In the absence of obesity, hyperamylinemia did not lead to a reduced sensitivity to acute amylin (5-20 g/kg s.c.) injections; acute amylin reduced eating similarly in all groups of rats. Overall, we concluded that direct diet effects by short term exposure to HF appear to be of little importance for amylin sensitivity; further, long-term maintenance on a HF diet and the resulting obesity only slightly attenuated the anorectic response to acute amylin. Because we observed no marked changes in amylin sensitivity in lean, chow fed rats with induced hyperamylinemia, amylin receptor downregulation in chronic hyperamylinemia does not seem to occur. 1 Long-term maintenance on a HF diet only slightly attenuates acute amylin action.2 Attenuation of amylin action seems more related to obesity than HF exposure.3 Acute amylin sensitivity is not reduced by chronic hyperamylinemia.3 ABSTRACTObesity results in the increased secretion of various hormones controlling food intake and body weight, such as leptin, and insulin; increased circulating levels of pancreatic amylin have also been described in obese humans and rodents. Because leptinresistance is e.g. present in diet-induced obese (DIO) rats, and because hyperleptinemia seems necessary for the full development of leptin resistance, we tested whether amyl...

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Inhibition of Central Amylin Signaling Increases Food Intake and Body Adiposity in Rats

Cited by 137 publications

References 0 publications

Activation of amylin receptors attenuates alcohol‐mediated behaviours in rodents

Activation of amylin receptors attenuates alcohol‐mediated behaviours in rodents

Amylin Receptor Signaling in the Ventral Tegmental Area is Physiologically Relevant for the Control of Food Intake

Influence of high-fat feeding, diet-induced obesity, and hyperamylinemia on the sensitivity to acute amylin

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