Energy Homoeostasis Central Control - pediagenosis
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Saturday, May 8, 2021

Energy Homoeostasis Central Control

Energy Homoeostasis Central Control
Clinical scenario
PG, a 15-year-old boy, presented to the paediatric endocrine clinic with delayed puberty and complaining of thirst and polyuria. Investigations revealed hypopituitarism and diabetes insipidus caused by a craniopharyngioma, a cystic tumour of the hypothalamus. He was treated with surgery and radiotherapy. Postoperatively he had deficiencies of all the anterior pituitary hormones requiring hormone replacement and persistent diabetes insipidus treated with DDAVP (see Chapter 35). In the year following treatment he gained 22 kg in weight. He found it extremely difficult to control his food intake and his mother noticed he would continue to eat any food that was in front of him. Attempts to follow a calorierestricted diet failed.

Energy Homoeostasis: II Central Control

Energy homeostasis is controlled by the integration of autonomic input and peripheral signals by the brain. Hypothalamic regions involved in this process have been identified in experimental systems, predominantly involving two neuronal populations, the orexigenic neuropeptide Y/Agouti-related peptide neurones and the anorexic pro-opiomelanocortin/ cocaine and amphetamine-related transcript (CART) system. These are interconnected and affected by a number of hormones including insulin, glucocorticoids and leptin. It is likely that the hypothalamic obesity syndrome seen in patients with diseases of the hypothalamus and suprasellar regions relates to disruption of these homeostatic mechanisms.

Several lines of evidence point to an important neural role in the control of energy homeostasis, whose status depends mainly on the synchronization of food intake, energy utilization and energy storage. This synchronization appears to be effected largely by the autonomic and neuroendocrine systems. Lesions in the lateral hypothalamus block feeding behaviour in rats to the point of starvation, while lesions in the ventromedial area cause voracious feeding and massively obese rats (Fig. 45a). Humoral signals from the GIT, for example, CCK, or insulin from the pancreas, or glucocorticoids from the adrenal gland, are orexigenic, that is they promote feeding behaviour, while certain hypothalamic hormones, for example TRH and CRH are anorexigenic. The satiety hormone leptin, which is secreted by adipose cells, is an important mediator of the balance between food intake and energy expenditure and conservation. The hypothalamus monitors its blood levels and adjusts feeding behaviour accordingly.

Central regulation of feeding behaviour
The arcuate nucleus is an anatomically small group of cells located in the medial hypothalamus in the most ventral part of the third ventricle near the entrance of the infundibular recess (Fig. 45a). Arcuate nucleus neurones are responsive to several circulating endocrine hormones, including the gonadal and adrenal steroids, insulin, ghrelin, leptin, the GIT peptide PYY(3–36) and glucose, and the arcuate nucleus may also be an autonomous generator of diurnal rhythms. The arcuate nucleus is part of the central appetite control system through: (i) neuropeptide Y (NPY) and Agouti gene-related peptide (AgRP) neurones, whose stimulation promotes feeding behaviour; and (ii) through pro-opiomelanocortin (POMC) and cocaine and amphetamine-regulated transcript (CART) neurones, whose stimulation inhibits feeding. There is a reciprocal interaction in that activation of NPY/AgRP-expressing neurones inhibits the POMC/ CART neurones. Thus, inhibition or destruction of the arcuate nucleus removes an important regulatory control from the lateral hypothalamic centres.
Arcuate NPY/AgRP-expressing neurones and POMC/CART neurones project to the paraventricular nucleus (PVN) and to the lateral hypothalamic area (LHA) (Fig. 45b), whose destruction, as mentioned above, resulted in loss of feeding behaviour in rats. It is thought that activation of the PVN and
LHA by the NPY/AgRP-expressing neurones promotes feeding behaviour through activation of the PVN/LHA centres. Conversely, the POMC/CART-expressing neurones inhibit the PVN/LHA centres. This hypothesis is derived largely from the observation that leptin, the satiety hormone, inhibits the arcuate NPY/AgRP-expressing neurones while activating the arcuate POMC/CART neurones (Fig. 45b).
POMC neurones produce the peptide pro-opiomelanocortin, which is spliced into several other active peptides, including α-MSH (see Chapter 18). α-MSH is believed to be the product responsible, through the agency of the MCR-4 receptor, for the inhibitory action of the POMC system on feeding behaviour. This is far from established, however, since other products of POMC splicing, such as ACTH, γ-LPH and β-MSH may bind the MCR-4 receptor.
Signals from the hypothalamic feeding centres are relayed to the periphery via the brainstem nucleus of the tractus solitarius (NTS), which also receives afferent signals from the GIT via the autonomic nervous system. The GIT sends humoral messages to the central nervous system through several other hormones, including the gastric hormone ghrelin, which activates the NPY/AgRP-expressing neurones while a colon peptide called PYY(3–36), inhibits them.
The LHA produces yet another set of orexigenic peptides called the orexins or hypocretins. (Fig. 45b). Two orexins have been discovered, designated A and B, and appear to mediate food-seeking behaviour, arousal and sleep–wakefulness in several brain areas, through their activation of pathways from the LHA to other brain centres, including the amygdaloid nuclei and the brainstem. The orexin neurones in turn appear to be regulated by humoral cues, including those provided by leptin, glucose, ghrelin, the endocannabinoids and the neurotransmitters norepinephrine and acetylcholine.
In summary, there appears to be a regulatory feedback loop that operates to sustain a balance between energy intake and expenditure (see Fig. 43a). The loop allows the brain to assess the extent of adipose tissue through leptin and govern feeding behaviour accordingly. The situation, particularly in humans, is not as simple as the above would suggest. Leptin production is indeed related to adipose tissue mass; in humans, however, circulating leptin concentrations are not easily related to adiposity. Furthermore, there do not appear to be the short-term changes in circulating leptin that might be expected with intermittent food intake. Also, women generally have higher circulating leptin levels than do men. It is more likely that in humans, leptin forms part of a regulatory system designed to sustain levels of stored energy for the purpose of longer-term survival. Ghrelin may be an endogenous regulator of feeding while peptide PYY may be a medium-term satiety factor.
In humans and possibly other primates, behaviour related to the intake of food has been liberated from the more primitive imperatives of the neuroendocrine loop, analogous to the freedom from imperatives that through hormonal changes allow or forbid female reproductive behaviour. Thus humans can choose to override satiety signals, which may be a factor in the phenomenon of human obesity, although there is some evidence for a genetic predisposition to obesity (see Chapter 46).

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