Amylin activates distributed CNS nuclei to control energy balance

Highlights

• Amylin receptors are expressed in many energy balance-relevant nuclei.

• Amylin activates hindbrain, hypothalamic, and mesolimbic sites to control feeding.

• Amylin may be produced by structures other than the pancreas, including in the CNS.

• Amylin-based combination pharmacotherapies may be useful for treating obesity.

Abstract

Amylin is a pancreas-derived neuropeptide that acts in the central nervous system (CNS) to reduce food intake. Much of the literature describing the anorectic effects of amylin are focused on amylin's actions in the area postrema, a hindbrain circumventricular structure. Although the area postrema is certainly an important site that mediates the intake-suppressive effects of amylin, several pieces of evidence indicate that amylin may also promote negative energy balance through action in additional CNS nuclei, including hypothalamic and mesolimbic structures. Therefore, this review highlights the distributed neural network mediating the feeding effects of amylin signaling with special attention being devoted to the recent discovery that the ventral tegmental area is physiologically relevant for amylin-mediated control of feeding. The production of amylin by alternative, extra-pancreatic sources and its potential relevance to food intake regulation is also considered. Finally, the utility of amylin and amylin-like compounds as a component of combination pharmacotherapies for the treatment of obesity is discussed.

Introduction

Amylin, also known as islet amyloid polypeptide (IAPP), is a 37-amino acid peptide hormone that is produced by pancreatic β-cells and co-secreted with insulin in response to the presence of nutrients in the gastrointestinal tract [1], [2]. Amylin has several physiological functions, but perhaps the most well-studied amylin-mediated effects are those of reduced food intake and improved glycemic control [3], [4]. In fact, the amylin analog pramlintide (Symlin) is FDA-approved for the treatment of diabetes mellitus [5], but has the additional effect of producing body weight loss in humans [6]. The actions of amylin to suppress food intake and body weight will be the focus of this review.

Amylin acts centrally to control energy balance, and this effect has been attributed primarily to activation of amylin receptors on neurons of the area postrema (AP), a hindbrain circumventricular structure. The evidence supporting the AP as an important amylin-responsive site has been extensively reviewed [2], [7], [8] and is discussed briefly below. However, the neural control of energy balance is not restricted to a select nucleus or subset of nuclei, but rather is distributed across the entire CNS [9], [10]. Given that amylin binds to sites throughout the CNS [11], [12], [13], [14], [15], the idea that amylin may act at nuclei other than the AP to control feeding has received surprisingly little attention. Recent data from our laboratory [16] and others [17], [18], [19], [20] have begun to highlight the importance of additional CNS structures in contributing to the intake- and body weight-suppressive effects of amylin. Specifically, we have recently shown that the ventral tegmental area (VTA), a mesolimbic nucleus important in food intake, food reward, and motivated behavior [21], [22], [23], is a physiologically relevant site for the actions of amylin to reduce food intake [16]. Thus, the ability of amylin to promote negative energy balance through activation of extra-AP sites is the main focus of this review.