Amylin Acts in the Lateral Dorsal Tegmental Nucleus to Regulate Energy Balance Through Gamma-Aminobutyric Acid Signaling

Abstract

Background The pancreatic- and brain-derived hormone amylin promotes negative energy balance and is receiving increasing attention as a promising obesity therapeutic. However, the neurobiological substrates mediating amylin’s effects are not fully characterized. We postulated that amylin acts in the lateral dorsal tegmental nucleus (LDTg), an understudied neural-processing hub for reward and homeostatic feeding signals. Methods We used immunohistochemical (IHC) and quantitative PCR analyses to examine expression of the amylin receptor complex in rat LDTg tissue. Behavioral experiments were performed to examine the mechanisms underlying the hypophagic effects of amylin receptor activation in the LDTg. Results IHC and quantitative PCR analyses show expression of the amylin receptor complex in the LDTg. Activation of LDTg amylin receptors by the agonist salmon calcitonin dose-dependently reduces body weight, food intake, and motivated feeding behaviors. Acute pharmacological studies and longer-term adeno-associated viral (AAV)-knockdown experiments indicate that LDTg amylin receptor signaling is physiologically and potentially pre-clinically relevant for energy balance control. Finally, IHC data indicate that LDTg amylin receptors are expressed on gamma-aminobutyric acid (GABA)-ergic neurons and behavioral results suggest that local GABA receptor signaling mediates the hypophagia following LDTg amylin receptor activation. Conclusions These findings identify the LDTg as a novel nucleus with therapeutic potential in mediating amylin’s effects on energy balance through GABA receptor signaling.

Activation of amylin receptors attenuates alcohol‐mediated behaviours in rodents

“…On a similar note, a recent clinical study investigating the effects of acamprosate on alcohol-dependent individuals attributed the drug's effects to calcium levels and not to a specific CNS target (Spanagel et al 2014). Nevertheless, a number of studies investigating the effects of locally administered sCT on food intake accompanied by immunohistochemistry data have identified central sites of action, especially in areas of the mesolimbic dopamine system (Mietlicki-Baase et al 2013;Mietlicki-Baase & Hayes 2014;Reiner et al 2017). Thus, we argue that the present findings do not fall under the scope of calcium levels regulation, but they are a result of sCT's central action.…”

“…Studies have presented that amylin receptor signalling in VTA, NAc and LDTg (Baisley & Baldo 2014;MietlickiBaase et al 2015b;Reiner et al 2017) is involved in the control of food intake. Albeit these areas are part of the cholinergic-dopaminergic pathway, which is well established as an important pathway involved in reward-related behaviours (Soderpalm & Ericson 2013), very little is known about the role of amylin receptor signalling within these areas in regard to artificial reinforcers, such as alcohol.…”

“…Other hormones, for example, amylin, have been recently studied for their role to control energy balance through gut-brain axis regulation (Reda, Geliebter, & Pi-Sunyer 2002;Lutz 2009). Amylin seems to regulate food intake through central mechanisms, by acting in areas of the mesolimbic dopamine system such as the VTA and LDTg (MietlickiBaase et al 2015b;Reiner et al 2017), identifying it an interesting candidate for exploring its potential rewardregulating properties.…”

“…In fact, amylin and sCT express their anorexigenic effects through central mechanisms involving the area postrema and the nucleus of the solitary tract (Lutz et al 2001a;Potes & Lutz 2010;Braegger et al 2014). Recent studies show that amylin receptors in the NAc, VTA and LDTg (Baisley & Baldo 2014;Mietlicki-Baase et al 2015a;Reiner et al 2017) and more specifically amylin receptors on ventral tegmental dopaminergic neurons mediate the effect of sCT on the control of energy balance (Mietlicki-Baase et al 2013;Mietlicki-Baase et al 2015b). Thus, amylin's action on the mesolimbic dopamine system suggests a potential role that extends beyond regulation of natural rewards, and tenuous evidence supports a possible amylinergic mediation of artificial rewards, such as alcohol.…”

Metabolism and Memory: Obesity, Diabetes, and Dementia

“…In this issue of Biological Psychiatry , Reiner et al . (8) explore how this effect is mediated. A separate study from 2014 showed that among elderly people, plasma amylin positively correlated with cognitive health, even after controlling for other metabolic risk factors such as diabetes and hyperlipidemia (9).…”