Neurobiology of Feeding Behaviour (A*) Flashcards
1
Q
Half A*:
Describe the central mechanism underlying long-term regulation of nutritional intake
Describe the central mechanisms underlying short-term regulation of nutritional intake.
A
- In the 1950s, two prominent theories, the glucostatic theory (Mayer, 1953) and lipostatic theory (Kennedy, 1950) were conceived to explain the means by which the CNS is informed of the availability of energy stores.
- The glucostatic theory posits that central control of feeding behaviour is governed by acute changes in plasma glucose, whereas the lipostatic theory suggests that it is influenced by the chronic exposure of the CNS to adipocyte-derived hormones, notably leptin, and to other ‘adiposity signals’ such as insulin (which reflects total body fat although not synthesised by adipocytes).
- The glucostatic and lipostatic theories are not mutually exclusive, and together explain both short-and long-term changes in feeding behaviour.
- The hypothalamus has long been considered an important structure in both long- and short-term control of energy intake / expenditure. Pioneering research in the central control of feeding behaviour found that lesions made to the hypothalamus in rats resulted in aberrant feeding behaviour and drastic changes to body weight.
- Subsequent studies found that both leptin receptors and insulin receptors, although expressed in numerous regions throughout the brain, have a particularly high expression in these regions targeted for lesioning, especially the arcuate nucleus of the hypothalamus.
- The central effects of insulin and leptin on feeding behaviour were observed in early studies which found that intracerebroventricular administration of insulin and leptin in rodents induced anorectic behaviour, and that inhibition of insulin and leptin receptor function induced orexigenic behaviour. *in essay, define anorectic and orexigenic
- Since changes to circulating insulin and leptin occur over relatively long periods of time, they are thought to govern long-term changes in energy intake and expenditure. It is now known that these factors influence feeding behaviour through a network of interconnected hypothalamic nuclei:
- The arcuate nucleus forms synapses with numerous other hypothalamic nuclei, notably the paraventricular nucleus (PVN), ventromedial hypothalamic nucleus (VMH) and lateral hypothalamic nucleus (LH), through two distinct GABAergic pathways (see card below for details on how these nuclei influence feeding).
- One GABAergic pathway, the excitatory anorectic pathway, is stimulated by adiposity signals and glucose, and promotes anorectic behaviour.
- The other GABAergic pathway, the inhibitory orexigenic pathway, is inhibited by adiposity signals and glucose, and promotes orexigenic behaviour.
- These pathways differ physiologically in that they corelease different neuropeptides.
- The anorectic pathway releases:
1 - Pro-opiomelanocortin (POMC), which is metabolised to form a number of peptides, notably alpha-melanocyte-stimulating hormone (alpha-MSH) and adrenocorticotropic hormone (ACTH).
- Alpha-MSH induces an anorectic and catabolic effect through action at at melanocortin 4 receptors (MC4Rs) in hypothalamic nuclei. In humans, inherited mutations in MC4Rs are associated with severe obesity, and MC4R knockout mice also show weight gain.
- Various synthetic derivatives of alpha-MSH (e.g. MTII and other MTII-derived drugs) have been developed as anti-obesity drugs that act by stimulating MC4Rs.
2 - Cocaine and amphetamine regulated transcript (CART).
- The orexigenic pathway releases:
1 - Neuropeptide Y.
2 - Agouti-related peptide, an antagonist of MC4Rs.
- The nucleus tractus solitarius (NTS) is involved in the short-term regulation of nutritional intake:
- It has been theorised that neurones producing the gut hormone and neuropeptide, CCK, in the NTS are the means by which glucose is sensed by the CNS to induce changes in feeding behaviour, as Meyer’s glucostatic theory describes.
- However, the evidence supporting Mayer’s glucostatic theory is arguably less convincing compared to that supporting Kennedy’s lipostatic theory. One important observation on which the glucostatic theory was founded was that reductions in circulating glucose were associated with increased feeding in rats (MacKay et al., 1940). In the following decades, the theory was seemingly upheld by findings that inhibitors of glycolysis induce a similar increase in feeding. Furthermore, distinct electrophysiological activity was identified following local application of glucose in the hypothalamus. However, it is known that buffering systems act to stabilise blood glucose, such that even minor changes to the glucose concentration would be met with a rapid homeostatic response to reestablish a physiological concentration. Moreover, any minor change to blood glucose that might occur before being corrected by homeostatic systems would not be sufficient so as to induce a change in glucose delivery to the brain, since glucose delivery to the brain is normally oversaturated to ensure that maximal delivery is met even following a fall in plasma glucose concentration (Seeley and Woods, 2003). Hence, experimentally-induced hypoglycaemia that is sufficient to cause changes in feeding behaviour is unlikely to represent physiological conditions, and may instead reflect a life-threatening situation of severe hypoglycaemia. Overall, the evidence suggests that the glucostatic theory holds water, but only occurs in a specific set of conditions and does not make a substantial contribution to feeding behaviour in physiological conditions.
- Nonetheless, more concrete evidence suggests that the NTS also responds to other factors relating to energy availability, such as neural input from the GIT relaying satiety signals.
- The CCK-producing neurones stimulate melanocortin cells in the paraventricular nucleus (D’Agostino et al., 2016).
- These cells partake in the anorectic pathway (see card below) and so decrease appetite.
2
Q
Describe the roles of the paraventricular nucleus, ventromedial hypothalamus and lateral hypothalamus in feeding behaviour.
A
- The paraventricular nucleus (PVN) promotes anorectic physiological changes:
1 - Sending efferents to the brainstem, where it can influence autonomic activity to increase energy expenditure by altering metabolism.
2 - Sending efferents to the pituitary where it can influence endocrine activity of the HPA axis to increase energy expenditure by releasing hormones that alter metabolism.
- The ventromedial hypothalamus (VMH) promotes anorectic behavioural changes:
1 - Decreases nutritional intake.
2 - Expresses leptin receptors of its own.
3 - Releases BDNF. BDNF indicates that the VMH is a plastic region that can change its leptin receptor expression to alter its influence on nutritional intake.
- The lateral hypothalamus (LH) promotes orexigenic behavioural changes through two types of neurones:
1 - Orexin neurones promote arousal and feeding.
2 - Melanin-concentrating hormone (MCH) neurones promote feeding.
- These types of neurones make reciprocal projections with each other and with the arcuate nucleus.
3
Q
What proportion of cases of obesity have a genetic component?
A
- 50% of all cases of obesity are in some way driven by genetics.
- This is likely a multigenetic and epigenetic effect (except in rare cases like leptin receptor mutations).
4
Q
What is the difference between satiety and palatability?
What are the mechanisms by which palatability influences nutritional intake?
A
- Satiety is needing food whereas palatability is wanting food.
- Palatability influences nutritional intake by triggering dopaminergic reward pathways that are linked to hypothalamic function.
- Dopaminergic connections between the ventral tegmental area and nucleus accumbens synapse with the lateral hypothalamus (which remember makes connections to the arcuate nucleus to influence feeding behaviour).
- The ventral tegmental area receives information from various other brain regions, including the brainstem (see A* card 12).
- The adaptability of palatability (acquiring a liking for a particular food) likely involves neuroplastic changes in these dopaminergic-hypothalamic circuits.
5
Q
List the neurotransmitters used by neurones of the ventral tegmental area that participate in palatability pathways.
A
Neurones of the ventral tegmental area use:
1 - GABA (act through GABAA receptors).
2 - Opioids.
3 - Cannabinoids.
This is why heroin abusers are often very thin and marijuana abusers get the ‘m0nchies’ (see A card 11-13).
6
Q
List 2 drug treatments for obesity that have targets in the CNS.
Describe their mechanisms of action.
A
1 - Rimonabant.
- Rimonabant targets the cannabinoid neurones of the ventral tegmental area to decrease palatability.
- It is unclear whether Rimonabant is a CB1 partial agonist or a CB1 antagonist.
- Rimonabant was withdrawn in 2008 due to having a range of side effects, including increasing risk of psychiatric disorders.
- Numerous studies have since been carried out, and are ongoing, to develop similar CB1 antagonists that do pose a lesser risk for adverse events. A* examples:
- Taranabant showed similar efficacy compared to rimonabant for promoting weight loss, but was not pursued as an anti-obesity drug as it also displayed a similar risk of adverse events.
- AM251 is another CB1 antagonist similar in structure to rimonabant. Thus far, it has been shown in preclinical trials to decrease energy intake and increase energy expenditure in obese rats. It has also been shown to protect against obesity-induced kidney disease and reduce inflammation in adipocytes. Hence, AM251 is a promising anti-obesity drug for which clinical trials have yet to be carried out.
2 - Sibutramine.
- This targets monoaminergic neurones of the arcuate nucleus to increase satiety and increase thermogenesis in brown fat.
- Sibutramine is a serotonin-noradrenaline reuptake inhibitor (SNRI).
- Sibutramine was withdrawn due to its cardiovascular side effects.
7
Q
A*:
Describe the role of 5-HT2C receptors in feeding behaviour.
A
- Lorcaserin is a 5-HT2C agonist that has FDA approval for use as an anti-obesity drug.
- Lorcaserin was shown to promote satiety in rats (Higgs et al., 2016).
- Also, when sibutramine, an SNRI appetite suppressant, was coadministered with a selective 5-HT 2C antagonist, the anorectic effect of sibutramine was reversed (Higgs et al., 2010).
- Together, the evidence implies that activation of 5-HT2C receptors has an anorectic effect.
- 5-HT2C is thought to activate POMC neurones of the anorectic pathway in the hypothalamus, increasing satiety.
8
Q
A*:
Describe the role of 5-HT6 receptors in feeding behaviour.
A
- Administration of a 5-HT6 receptor antagonist was found to reduce glucose intake in rats (Higgs et al., 2016).
- This implies that activation of 5-HT6 has an orexigenic effect.
- 5-HT6 is thought to activate neurones in the paraventricular nucleus, promoting anorectic physiological (rather than behavioural) changes (see card 2).
- The 5-HT6 antagonist opposes this action, resulting in an anorectic response.
9
Q
A*:
Describe the role of the subthalamic nucleus in feeding behaviour.
A
- Feeding was found to activate neurones of the subthalamic nucleus in mice (Wu et al., 2020).
- The same group found that stimulation of the subthalamic nucleus in mice reduced feeding behaviour, whereas inhibition of the subthalamic nucleus increased feeding behaviour.
- This implies that the subthalamus is activated by feeding to promote satiety.
- This might explain why subthalamic deep brain stimulation in Parkinson’s disease leads to weight gain (because DBS inhibits the subthalamic nucleus). It would also explain why stroke patients report decreased satiety where there is lesioning of the subthalamic nucleus. (Wu et al., 2020).
- Pharmacological activation of the subthalamic nucleus is therefore a potential drug target for obesity.
10
Q
A*:
Describe the role of endocannabinoids in feeding behaviour.
A
- Activation of CB1 receptors in humans is thought to increase appetite and increase palatability.
- Feeding was found to increase release of the endogenous CB-1 receptor agonist, 2-AG, in the hypothalamus in rats (Kirkham et al., 2002).
- Potential sites of action of cannabinoids for increasing appetite include hypothalamic nuclei, the ventral tegmental area, brainstem and nucleus accumbens.
- CB1 receptors in the hypothalamic nuclei mediate the increase in appetite and other sites such as the ventral tegmental area, brainstem and nucleus accumbens mediate the increase in palatability.
11
Q
A*:
Describe the effect of benzodiazepines on feeding behaviour.
How does benzodiazepine exert this effect?
A
- Benzodiazepines are thought to increase palatability of foods.
- The site of action of benzodiazepines for increasing palatability is thought to be in the brainstem, specifically the parabrachial nucleus located near the fourth ventricle (Higgs and Cooper, 1996).
- The parabrachial nucleus sends projections into pathways that are involved in feeding behaviour, such as the ventral tegmental area, amygdala and hypothalamus.
- In the ventral tegmental area, it is able to influence dopaminergic reward pathways involved in feeding behaviour (see card 5).
12
Q
A*:
Describe the role of opioids in feeding behaviour.
A
- All opioid receptor subtypes play a role in reward, but mu receptors are thought to have the most significant contribution.
- Administration of a mu opioid agonist in the nucleus accumbens was shown to increase appetite for palatable foods in rats (Cooper 1983).
- This implies that opioid receptor activation drives feeding behaviour in response to palatable foods (rather than in response to low energy) through stimulating VTA-Acb mesolimbic neurones.
- When the hypothalamus was exposed to orexin, the expression of enkephalin (an endogenous opioid receptor agonist) increased in the amygdala, paraventricular nucleus and ventral tegmental area (Karatayev et al., 2009).
- This is one possible mechanism by which the neurones of the lateral hypothalamic nucleus in the orexigenic pathway are able to indirectly stimulate appetite, as the increase in enkephalin expression leads to an increase in reward-inducing opioid receptor activation, driving feeding behaviour.
13
Q
A*:
Describe the role of the amygdala in feeding behaviour.
A
- The basolateral and central nuclei of the amygdala make connections with various pathways involved in feeding behaviour:
1 - Both nuclei make projections to the hypothalamic nuclei involved in feeding behaviour.
2 - Both nuclei receive input from the NTS (see card 1).
3 - The central nucleus synapses with the nucleus accumbens.
4 - The central nucleus receives input from the parabrachial nucleus (see A* card 12).
- Generally, it is thought that the central nucleus stimulates feeding behaviour in response to low energy stores, whereas the basolateral nucleus stimulates feeding in response to palatable foods.
14
Q
A*:
Describe the epidemiology of obesity in the UK.
A
- The NHS estimates that over 60% of the adult population in the UK are overweight, and that 1/4 of these individuals are obese.
- In 2018, over 11,000 hospital admissions were attributable to obesity, reflecting the obesity epidemic in the UK.
- These figures have seen a continuous rise in the past decades, and there is therefore a great need for novel interventions.
15
Q
A*:
What are insulin mimetics?
How do they work?
Give an example.
A
- Insulin mimetics are small compounds that trigger signalling cascades, such as tyrosine kinase signalling, downstream of the insulin receptor without directly activating the insulin receptor. Hence, these drugs are useful for treating insulin-resistant patients, as they circumvent the dysfunctional signalling mechanisms.
- In contrast to insulin, insulin mimetics do not induce weight gain. This is likely due to their greater central bioavailability compared to insulin, as they are able to cross the BBB by diffusion rather than through a transporter-mediated mechanism. This means that they are able to exert a stronger anorectic effect on feeding behaviour, and also induce secretion of hormones that upregulate metabolism. Hence, insulin mimetics have a net catabolic effect through their action at central structures, and potentially also via less well-characterised peripheral mechanisms.
- Oral administration of insulin mimetics in rodents has been shown to reduce body weight, reduce energy intake, reduce hyperglycaemia and decrease insulin resistance in rats.
- Of particular interest was asterriquinone, which showed promise in preclinical trials but did not reach clinical trials due to poor specificity for the insulin receptor (causing numerous side effects).
