Energy Homoeostasis Central Control
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 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.
Introduction
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).
