Control of energy homeostasis by amylin

Abstract

Amylin is an important control of nutrient fluxes because it reduces energy intake, modulates nutrient utilization by inhibiting postprandial glucagon secretion, and increases energy disposal by preventing compensatory decreases of energy expenditure in weight-reduced individuals. The best investigated function of amylin which is cosecreted with insulin is to reduce eating by promoting meal-ending satiation. This effect is thought to be mediated by a stimulation of specific amylin receptors in the area postrema. Secondary brain sites to mediate amylin action include the nucleus of the solitary tract and the lateral parabrachial nucleus, which convey the neural signal to the lateral hypothalamic area and other hypothalamic nuclei. Amylin may also signal adiposity because plasma levels of amylin are increased in adiposity and because higher amylin concentrations in the brain result in reduced body weight gain and adiposity, while amylin receptor antagonists increase body adiposity. The central mechanisms involved in amylin's effect on energy expenditure are much less known. A series of recent experiments in animals and humans indicate that amylin is a promising option for anti-obesity therapy especially in combination with other hormones. The most extensive dataset is available for the combination therapy of amylin and leptin. Ongoing research focuses on the mechanisms of these interactions.

Fig. 1

Satiation diagram. The working model assumes that noradrenergic (NA) neurons in the area postrema (AP) mediate amylin’s satiating effect. Intracellular signaling systems involved in amylin action include cGMP and pERK but their necessity for amylin-induced NA neurotransmission needs to be investigated. AP projections reach the lateral parabrachial nucleus (LPB) directly or indirectly via the nucleus of the solitary tract (NTS). The NTS is the most likely site for the interaction between cholecystokinin (CCK) and amylin. Projections from the LPB reach several hypothalamic nuclei such as the lateral hypothalamic area (LHA), the ventromedial hypothalamus (VMH) where histamine receptors of the H1 subtype (H1R) may be involved and where amylin interacts with leptin (see also Fig. 2), and perhaps the hypothalamic arcuate nucleus (ARC). 3 V third cerebral ventricle

Fig. 2

Adiposity signal diagram. The working model assumes that the potential role of amylin as adiposity signal requires a primary amylin action via the area postrema (AP). AP projections via the lateral parabrachial nucleus (LPB) reach the ventromedial hypothalamus (VMH) where amylin interacts with leptin. Because amylin deficient mice have a lower expression of leptin receptors in the mediobasal hypothalamus, the leptin/amylin interaction in the VMH may depend on a direct action of leptin on VMH neurons; however, the potential role of an indirect input via the hypothalamic arcuate nucleus (ARC) requires further studies. Histamine receptors of the H1 subtype (H1R) may be involved in the leptin/amylin interaction but the signal that triggers histamine release from neurons in the tuberomamillary nucleus (TMN) is unknown. 3 V third cerebral ventricle