I. General points on the central control of energy balance and food intake

1. Integrative centers

Control of energy balance and food intake involves many brain areas and neurotransmitters, in which the cortical and limbic areas, hypothalamus, and brainstem play a central role. The hypothalamus receives information on internal and behavioral states as well as on the cognitive and nutritional aspects of food. The brain stem is considered as a central processor of peripheral information further relayed to other brain areas, particularly the hypothalamus. Both areas harbor a specific access to blood flow (the median eminence in the hypothalamus and the area postrema in the brainstem) via fenestrated capillaries, allowing detection of hormonal and nutrient signals at higher concentration than in other areas of the brain.

The hypothalamus
The hypothalamus can be divided into four principle zones (Figure 1). The periventricular zone, including the arcuate (ARC) nucleus, is mainly involved in the detection of signals from the circulation and in the organization and control of endocrine responses. The medial zone is primarily composed of large nuclei, such as the dorsomedial (DMN) and ventromedial (VMN) nuclei, which receive various sensory inputs, interconnected heavily with the rest of the hypothalamus, and which are involved in the organization of adaptive behaviors. The lateral zone (LHA) has an extensive intra- and extra-hypothalamic
communication system and could be viewed as the interface between more medial hypothalamic areas with cortical/limbic areas on the one hand and the somatic
and autonomic motor systems on the other. The paraventricular nucleus (PVN) can be considered as a microcosm within the hypothalamus, because of its connection with all three effector systems (endocrine, autonomic, and behavioral).1
Within hypothalamic nuclei, the ARC nucleus has an integrator role including connections to the lateral zone, brain stem, and cortical and limbic systems.2,3 The ARC nucleus is in a position to receive an impressive array of information on energy balance. Information arrives concerning the status of long-term energy stores (via leptin from adipose tissue), intermediate available fuels (via hormones such as insulin and ghrelin and vagal afferents from the gastrointestinal tract and liver), and immediate available fuels (via local nutrient sensing). Additional interoceptive information about energy
balance and other homeostatic needs can reach the ARC neurons via the abundant intrahypothalamic connections. Neural inputs from the various cortical areas and limbic structures are likely to carry information relating to emotional aspects of particular foods and to other impeding needs and behaviors. In turn, ARC neurons have easy access to endocrine effectors in the medial hypothalamus and pituitary, to cognitive reward and emotion-related areas of the forebrain, and to motor and autonomic areas of the brain stem and the spinal cord, either directly or via connections in the LHA.
In the ARC nucleus, two main populations of neurons are involved in feeding behavior (Figure 1). These populations constitute the first-order neurons of the melanocortinergic system. Neurons co-expressing proopiomelanocortin (POMC) and cocaine-amphetamine-related transcript (CART) rapidly respond to nutritional information by inducing anorexigenic signals. POMC is cleaved into melanocyte-stimulating hormones (MSH), which exert anorectic stimuli by binding to melanocortin receptors (MC3 and MC4R on second-order neurons). Conversely, neurons co-expressing neuropeptide Y (NPY) and agouti-related protein (AgRP) induce orexigenic signals. NPY/AgRP neurons have an opposite effect to POMC/CART neurons through the antagonism of AgRP on MC3 and MC4R. NPY can also directly control the activity of POMC/CART neurons via its binding to its Y1 receptor. POMC/CART and NPY/AgRP neurons express several
nutrient and hormonal receptors, including insulin, leptin, and glucocorticoids.4

The brain stem and the parabrachial nucleus
The brain stem, harboring major visceral sensory and motor output pathways, is an integration center with the nucleus of the solitary tract (NTS) and the parabrachial nucleus (PBN) receiving most attention. The dorsal vagal complex is composed of the NTS, the area postrema and the dorsal motor nucleus of the vagus (dmnX). Nutrients and gastrointestinal hormones have direct access to the NTS through receptors expressed in the area postrema and via numerous projections from the area postrema to the NTS. Apart from the ARC nucleus, the NTS is the only brain area expressing POMC neurons, and the NTS and dmnX nuclei exhibit the highest level of MC4R within the brain.5 The dorsal vagal complex contains leptin receptors along with receptors and enzymatic machinery
required for the detection of nutrients. Moreover, the NTS is connected to the brain areas involved in the regulation of food intake and energy balance (cortical/limbic areas and hypothalamic nuclei). Although there are no direct projections from the NTS to the cortex, there are rich polysynaptic projections via the PBN, thalamus and amygdala. Moreover, the cortex receives information from the NTS via brain stem arousal systems such as the locus coeruleus and raphe nuclei (Figure 2).1
The PBN is localized in the dorsal pons and is considered to integrate sensory information via reciprocal projections to various brainstem, dicencephalic
and forebrain areas. Concerning the regulation of energy balance and food intake, the PBN receives sensory inputs from the NTS in the medial and lateral
part, which in turn project to various hypothalamic nuclei such as PVN, ARC, VMN, and LHA.3 The descending projections from the PBN are directed toward the lateral NTS and the spinal cord. Based on the strategic location and anatomical connection of the NTS and PBN, both structures are considered as part of the central processor circuit regulating energy balance and food intake.1

2. The autonomic nervous system and pancreatic function

The autonomic and enteric nervous systems and the pituitary-endocrine axis significantly modulate metabolic processing of food as well as the partition and oxidation of metabolites. They are thus considered as part of the output system controlling energy balance and food intake. The efferent autonomic nervous system is composed of parasympathetic and sympathetic outflows. The parasympathetic system is composed of vagal nerves and the sympathetic system is mainly composed of the splanchnic nerve.1
The autonomic nervous system plays a crucial role in pancreatic function. The parasympathetic pathway potentiates insulin secretion induced by yperglycemia. This potentiation is mediated by acetylcholine, which binds to the muscarinic receptor m3AchR on β-cells, but might also involve PACAP, VIP, and GRP (gastrin). Parasympathetic activity can also be modulated by mild hypoglycemia to trigger the release of glucagon.7
The sympathetic system affects both α- and β-cell function. Whereas norepinephrine stimulates glucagon secretion through binding to β2 adrenergic receptors in α-cells, it inhibits insulin secretion through activation of the α2 receptors in β-cells. Sympathetic activity is an important response to hypoglycemia, which is activated at deeper hypoglycemic levels than the parasympathetic pathway.8
Moreover, the parasympathetic system is involved in the induction of β-cell proliferation in adults and in the postnatal period, whereas the sympathetic pathway has a role in the architecture and maturation of the islet during development.9

“Neural Orchestration of Metabolism and Islet function”
I. General points on the central control of energy balance and food intake
II. Mechanisms of direct detection of nutrients and hormones by the brain
III. Gastrointestinal and vagal detection of nutrients
IV. Control of β-cell function by the brain
V. Conclusion
References
Lectures during IGIS meeting